Thank you, Nishant, and good afternoon and good evening, everyone, depending on the time zone you're in. So I'm going to talk a lot about both a little bit about the pathophysiology and then as well as some of the therapies for autonomic modulation of ventricular arrhythmia. The focus is mostly going to be on the sympathetic nervous system because that's where most of the data currently is, but there's actually a lot of exciting therapies coming along for parasympathetic modulation for ventricular arrhythmias, and at hopefully a different session, I'll have a chance to talk to you about that as well. So continuing, let me see if this will allow me to advance my slides. It actually doesn't. Okay. I'll be here. Okay. So these are my acknowledgements. This is where I get most of the funding from my lab to do the work that we do. Starting with anatomy and physiology, then we're going to go on to neuromodeling and cardiovascular disease, and then we'll talk about some of the neuromodulatory therapies that are out there. So I think one of the first points that I want to get across is that although we don't see them, we don't pay attention to them in our cardiac imaging studies, there are both parasympathetic, sympathetic, and afro nerve fibers that simply encase the heart. This is a cleared mouse heart where there was special staining done for the nerves on the heart, and you can see that there really isn't any spars on the myocardium that is not innervated. And on the left-hand here, you have PGP 9.5 staining. On the right-hand side, you have tyrosine hydroxylate staining. This was done by one of our MSTP students in the lab, Pradeep Rajendran, but there are both sympathetic and parasympathetic fibers as well as sensory afferent fibers innervating atria and ventricles as well as the conduction system, which is something that is classically taught when you're in medical school. Now when it comes to the cardiac sympathetic nervous system, the postganglionic sympathetic neurons for the heart specifically generally sit in the stellate ganglia, T2, T3, and T4 ganglia, and these guys send postganglionic sympathetic fibers through the mediastinum down to the heart. There's also a little ganglion here called the middle cervical ganglion, which is often ignored but actually sits on the superior aspect of the stellate ganglion that also contains a significant amount of sympathetic cardiac neurons that when activated can also cause sympathetic excitation in many of the physiology we attribute to the sympathetic nervous system, such as increased heart rate and decreased action potential duration. Now these nerves come on to the mediastinum sort of right around the trachea and the esophagus, and at this point, what most of the nerves that you're looking at are not just sympathetic nerve fibers, but they also have now branches coming off the vagus. So these cardiopulmonary nerves are actually mixed nerves, and not only do they contain sympathetic fibers, but they also contain preganglionic vagal fibers as well as afferent fibers that use the same highways to get information back from the heart up onto the brain. Now the other concept that I hope to get across today when it comes to understanding neuromodulatory therapies as well as how the autonomic nervous system works is that there are multiple levels of processing for information for the heart. So there are afferent fibers that actually feed onto the intrinsic cardiac ganglia, the ones that, for example, people like to target at times for atrial fibrillation, and they can modulate how these neurons then subsequently affect cardiomyocyte function. There are afferent fibers that go to the stellate ganglia and process information from the heart in the stellate ganglia and can actually modulate subsequent sympathetic outflow. There are afferent fibers that go through the dorsal root ganglia onto the spinal cord, and there are afferent fibers that go through the vagus up via the notos ganglia onto the brainstem. And at each of these levels, autonomic nerves are modulated so that heart function is controlled and processing is performed. Now cardiac sympathetic innervation is generally, when we think about it, we generally think about norepinephrine being released onto the myocardium, and that is actually the case. In fact, there's a study we did in the lab a long time ago where we put a microdialysis catheter on the left ventricle of a pig, and here's a duodecopolar catheter you might use in the lab. And we looked to see what happened to action potential duration and norepinephrine concentration in the actual myocardium with microdialysis when we stimulated the left and the right stellate ganglia. And a lot of the reasons we did this study was also to see if this thought process that the LSG was the predominant innervator of the left ventricle was really true or not. And actually what we found is that norepinephrine concentrations increased from baseline, whether you stimulate the left stellate ganglion or the right stellate ganglion, so that really both ganglia innervated the left ventricle, and they both provided norepinephrine, caused norepinephrine release in the left ventricle. And obviously it's been well known now in human hearts, what I showed you is a pig heart, that there is a significant amount of TH positive nerves, these are the nerves that we think about when it comes to sympathetic innervation. More at the base of the heart than the apex. And there's a significant amount of acetylcholinesterase positive nerves as well as TH positive nerves in human hearts, innervating both the left ventricle and the right ventricle. And although today I'm not really, you know, focusing a lot on vagal innervation and how that works, I want to keep this in mind because this study was done in 2003. And really at least when I went to medical school, parasympathetic innervation of the ventricles was something you didn't hear about. It was known that they innervated the atria, it was thought that, you know, there was vagal innervation of the SA and the AV node, but certainly not of the ventricles. And more recent data, I would say in the past few decades, is beginning to show that there's at least some parasympathetic innervation of the ventricles. Nevertheless, for most of our neuromodulatory therapies, we're still targeting, like I said, the sympathetic nervous system and the norepinephrine that's being released at the level of the heart. So our understanding of sympathovagal balance, this is now three decades ago, was we were already knew that when we stimulated the sympathetic nervous system, we had norepinephrine release and that acted on beta-adrenergic receptors. And at the same time, there was, you know, a good amount of baseline vagal tone that caused acetylcholine release, and that bind to the musculoprenic receptors. Now it was also pretty well established at that time that acetylcholine through receptors that were on the sympathetic fibers could actually inhibit norepinephrine release. And it was also pretty established that norepinephrine through alpha receptors on parasympathetic fibers could inhibit acetylcholine release. So there was this yin and yang between norepinephrine and acetylcholine, and whichever one was the predominant could actually inhibit the release of the other. Our more recent understanding involves these neuropeptides that we know are also released often with norepinephrine in states of very high sympathetic excitation. And this leads to release of norepinephrine, but also dysnorepeptide has its own Y1 receptors on the myocytes. But there are also Y2 receptors on parasympathetic fibers that when NPY binds them can subsequently inhibit acetylcholine release. When you have myocardial infarction and you get that initial sympathetic excitation, it's important to realize that now norepinephrine and NPY are being released in massive amounts. And not only are you now increasing sympathetic tone by increasing the binding to beta adrenergic receptors and these Y1 receptors on the myocardium, but you're also significantly inhibiting acetylcholine release. So at the same time that you have sympathetic excitation, you actually have decreased release of acetylcholine, even just at the nerve myocyte interface. And that in itself causes parasympathetic dysfunction and withdrawal. Now, do these neuropeptides themselves have any type of electrophysiological activity or do they just function sort of synergistically with norepinephrine? Well, I can tell you that for the longest time it was thought that neuropeptide Y, for example, which actually has been shown to have, you know, high levels have been shown to have poor prognosis in the setting of heart failure, was working synergistically with norepinephrine. To really tease out if neuropeptide Y had any independent effects electrophysiologically on its own, we actually had to, in this pig study, give high doses of a beta-blocker to be able to block the effects of norepinephrine. And these aren't average amounts of beta-blockers, this is like one mg per kg IV, maybe five to 10 times the dose that you'd give in an ACLS protocol. And so at the same time that we gave the propranolol and we blocked our beta-1 receptors, we now looked to see if giving a Y1 receptor blocker called BIBO actually had any effects on action potential duration. To make a long story short, we did see that blocking the Y1 receptor can prevent action potential duration shortening during sympathetic activation. So that there does seem to be some modest effect of neuropeptide Y in being able to independently modulate action potential duration. This slide is to really remind me to move on to what happens when you otherwise stimulate the stellate and the middle cervical ganglia. Well, as electrophysiologists, we love maps, and here is an ARI map or an action potential duration map. The shorter action potentials are shown down here, 242 milliseconds, and the longer ones up here. And what I want you to notice, as I mentioned before, that whether you stimulate the stellates, the SGS is bilateral stellate ganglion stimulation, or that you stimulate the middle cervical ganglia, that little ganglion that's sitting sort of on top of the stellate above the subclavian artery, you get significant action potential duration with both of them. So that's sort of proof that there's actually cardiac neurons, sympathetic cardiac neurons in the middle cervical ganglia. These neurons are not the ones we remove when we talk about cardiac sympathetic denervation, because there's significant innervation to the head and neck otherwise that's provided by the middle cervical ganglia, so we really can't touch that ganglion. So when we talk about the procedure of cardiac sympathetic denervation, which is something that I'll get to later on in this talk, and we talk about doing a sympathectomy, we're not really doing a total sympathectomy. We're simply removing a portion of cardiac sympathetic neurons and trying to tilt that balance of sympathetic excitation, right, towards a more beneficial effect, reduce that sympathetic excitation slightly. So in some ways, sympathetic denervation or sympathectomy with the procedure that has been described is a little bit of a misnomer, because we leave the middle cervical ganglion intact, and we in fact leave the upper half of the stellate ganglion intact, because of the other side effects that could occur if we remove them. All right, so we talked about this for a little bit. The other thing that I want to point out is that whether you stimulate the left stellate or the right stellate, or both of them, you get this significant whole heart dispersion of repolarization, even in normal animals. Now going back to sort of basic electrophysiology, you know, when you have, you need a difference between conduction and action potential duration to be able to set up the substrate for arrhythmias. And whenever you can increase that difference or dispersion, then you end up with more likelihood that ventricular arrhythmias can occur. And in fact, in normal pigs, when you do left stellate stimulation, you can sort of cause enough dispersion repolarization that you can set off a VF, even just in the setting of a structurally normal heart. But you know, most of the patients that we deal with don't have normal hearts. And so this is where the dynamic interplay really becomes even more complicated. You already have a substrate, a scar, an infarct that is made up of areas of viable islands of myocardium, collagen, necrosis. So it's already a heterogeneous substrate. And as electrophysiologists, some of the things we like to do is to actually ablate these areas of normal myocardium or circuits that seem to be sitting within scars and causing these reentrant arrhythmias. But it's important to realize that this heterogeneous substrate that we're talking about is actually being dynamically modulated by the autonomic nervous system, which can make those basic electrophysiological heterogeneities that are there because of the scar even worse and predisposed to VTBF. That's actually one of the main reasons why many of the therapies that we have that have not only been shown to improve heart failure, but reduce the risk of sudden death, actually target the sympathetic nervous system, the beta blockers, the ACE inhibitors, the aldosterone antagonists. Now, when you have myocardial infarction, I should actually say myocardial injury, that infarction and injury doesn't just damage the heart. It actually damages all those axons that I showed you that encase the heart, right? All the inflammation that occurs kills off those axons. And so the heart in many regions and the areas that have been injured becomes denervated. This was a study that was performed by fellow Valita and colleagues in Italy. What they showed is that in patients actually with ICDs, those who had a greater amount of denervation, as shown on carbon hydroxyphedron imaging, actually were at increased risk of more ICD therapies and ventricular arrhythmias. So more denervation, increased risk. And in addition to that, I'm going to skip this slide. What I want you to know is that the level of denervation that you see is not the same in scar, border zone, or viable myocardium. In fact, you have very little norepinephrine in areas that we would consider a sort of dense scar, heterogeneous amounts of norepinephrine in areas that we consider border zones. And then you have sort of relatively normal, but not completely normal myocardium, norepinephrine, normal areas of myocardium. And then what was shown later on by Kim and colleagues, this was in collaboration with Mike Fischbein, our lab, and Peng Chen, is that certain regions of these border zones, areas that seem to contain norepinephrine, have actually these areas of hyper-enervation. So the initial denervation that is caused by the injury and the inflammation is actually followed by re-enervation, a process of re-enervation. These are peripheral nerves. Your cell bodies for the sympathetic nerves are sitting in the stellar ganglion. They want to regenerate. What's been shown though is that they can't regenerate and re-enervate the scar normally. So you end up with zones that have this hyper-enervation where you find norepinephrine and areas potentially right next to that, where you have no norepinephrine and no nerves. So now imagine what happens in the setting of sympathetic activation. You get areas that might be able to really shorten their action potential duration. And right next to them are areas that are not able to shorten action potential duration at all. Again, setting up that heterogeneity that you need to set up reentrant circuits and ventricular and predisposed to ventricular arrhythmias. And to make a long story short, we actually showed this in human studies where we took patients that were undergoing VT ablation and obtained action potential duration recordings using standard electrode, multi-electrode catheters in the EP lab, and then gave these patients isoprotenol to directly activate the beta receptors that may be there. And then nitroprusside to try to indirectly activate their sympathetic nervous system. And just focusing on the nitroprusside, you can see there is a very heterogeneous response in scar border zone and even normal sites in terms of what you see. Suggesting that the re-enervation process that is trying to occur after myocardial infarction is really heterogeneous. The other thing I just want to bring home is that the neural remodeling that we see isn't just a neural modeling. I mean, is the changes sort of in the innervation that we see isn't sort of localized to the level of the heart, but it's actually also seen in the stellaganglia. And what I'm going to show you is actually in the brains of patients who've had cardiac injury. So that this was a study that was done by, you know, Olu who gave a talk yesterday where he took the stellaganglia of patients with normal hearts, ischemic cardiomyopathy, non-schemic cardiomyopathy patients that were undergoing cardiac sympathetic denervation for VT and showed that there were not only just changes in the size of these neurons, but there were significant changes in synaptophysin immunoreactivity, which is sort of a measure of their synaptic efficacy, as well as GAP43 immunoreactivity. Actually, this was non-significant. But the synaptophysin and the size suggests that there are significant changes that are occurring in the stellaganglia of these patients, especially the ischemic and the non-schemic cardiomyopathy patients that may be predisposing them to sympathetic activation and ventricular arrhythmias. He actually followed up this study by another study that looked like oxidative stress in these ganglia and showed that there was greater oxidative stress and changes consistent with oxidative stress in the stellaganglia of cardiomyopathy patients as compared to stellaganglia of patients with normal hearts. But in a word, that these changes, like I said, aren't confined to the stellaganglia, that there are changes in the brainstem, as well as the brain, of the cortex of patients with heart failure that you can see when you do different maneuvers to try to activate their insular cortex, for example, so that whatever neuromodeling is occurring isn't confined to the level of the heart, but it really goes up the neuroaxis all the way up to the cortex. So to kind of come up with a unifying hypothesis, it seems that myocardial infraction and injury causes a whole host of release of cytokines and neural growth factor. There's denervation followed by an attempt at reinnervation that occurs at the level of the myocardium, and there's significant neuromodeling that occurs in the stellaganglia, and like I said, at the level of the spinal cord in the brain, so that in the setting of sympathetic activation, when you're running at the airport to catch that plane, which luckily nobody's doing these days, you get this sympathetic activation can cause EADs, DADs, and dispersional repolarization that can lead to VTBF. And in our dynamic interplay, what I wanted to show is when you looked at the same PGP 9.5 staining that was done in clear mousehot, this is sort of what that area of the infarct looks like. It's sort of much more heterogeneous in its reinnervation and innervation as it is as compared to a normal heart. Two words about cardiac and renal neurotransmission, because one of the neuromodulatory therapies I'm going to talk about later in this talk is renal denervation. And I just wanted to say that there's a couple of things that we know just to kind of establish the science. One is that when you stimulate cardiac sympathetic afferents, right, let's just say you have ischemia, for example, on the heart, that's one way to stimulate cardiac sympathetic afferents, right? You actually get renal sympathetic nerve firing. So the heart and the renal nerves, the heart nerve, nerves from the heart and the nerves from the kidneys are actually linked. The other finding is that when you stimulate the renal afferents, those nerves that are sitting around the arteries and the veins of the kidneys, then you actually see that the firing is in regions that are very close to where the cardiac neurons are located. So that in reality, you can have sympathetic afferent firing can lead to release of, you know, catecholamines from the kidneys. And the same thing, that you can have renal afferent stimulation that can subsequently affect your heart rate, for example. So in that sense, as a unifying hypothesis, we know that there is sympathetic activation, parasympathetic withdrawal in the setting of heart disease. This causes increased dispersion of reprovisation or factoriness, causes altered conduction velocity and functional block. It causes increased triggered activity, decreased acetylcholine release, decreased bioreceptor sensitivity and decreased heart rate variability. And if this wasn't enough to cause VTBF, you also have other neurohormonal changes occurring at the level of the kidneys, because like I said, the decrease in cardiac output will be sensed by the kidneys as we send their afferent signals up to the brain. And then you will have subsequent release of catecholamines and angiotensin and renin from the adrenal gland and the kidneys, but you will also have sympathetic activation to the heart. In general, the things that are released from the kidneys, like the angiotensin, are known to increase fibrosis, cause GAMP junction remodeling. And that increased release of catecholamines from the adrenal gland obviously can also activate the beta receptors and cause dispersion of repolarization. And so all of this together works to create the substrate that you need for ventricular arrhythmias through the autonomic nervous system. So is it really real? Are these just our hypotheses? So we stimulate some ganglia and pigs and we stimulate some nerves and the kidneys, and we assume that therefore this is going to be beneficial in patients if we interrupt that neurotransmission. And the truth of matter is actually the first data, at least at our center that we had, there's really something real to interrupting autonomic nerves and looking at ventricular arrhythmias came from heart transplant patients, because as many of you know, they have essentially both their vagal and sympathetic neurotransmission interrupted. Now when we looked at this series of orthotopic heart transplantation, the idea for looking at them came from one patient, a patient that as part of his post-transplant workup was getting a treadmill stress test every year. And he came to the treadmill, this was his baseline EKG, and we started exercising on the treadmill. He fell and went into PEA. When we transferred him to the hospital in the cardiac catheterization laboratory, what he was found to have wasn't massive rejection, but this occlusion of the left main coronary artery, something that you would have thought in any other scenario may have actually caused VF. And so we went ahead and we looked at these series of 628 orthotopic heart transplantation and looked at the data on the patients that had died in the hospital so we could evaluate their heart rhythm at the time of death. Regardless of whether they had ischemia or not, VF was seen least commonly in this patient population. So if you take care of a transplant patient, you know that many of them, when they arrest, they arrest because of asystole or PEA. So VF was the least common presentation in a denervated heart in this patient population. And so that gave us some clues that maybe for treatment of VF, we could interrupt those sympathetic nerves. Now, in general, I can tell you that many of the therapies that you'll read about now and in the future have really focused on those interruptions. And they have done it through thoracic epidural anesthesia, stellar ganglion blockade, cardiac sympathetic denervation, and renal denervation. And many of these therapies that remain to still be evaluated for ventricular arrhythmias that are aimed at increasing parasympathetic tone are sort of going to be up and coming. In other words, there isn't a whole lot of ventricular arrhythmia data, for example, for vagal nerve stimulation, but once we actually figure out what parameters to use and what duration and dosing to use, I think that you'll find is there'll be a lot more coming for treatment of ventricular arrhythmias by activating the parasympathetic nervous system. But for now, we'll start with the sympathetics. And we'll start with thoracic epidural anesthesia, sort of working our way down to renal denervation. So what happens to electrophysiological parameters when you place a thoracic epidural catheter and infuse something like lidocaine and papivacaine in a patient who has an infarct? So we actually carried out this experiment in pigs because it's easier to evaluate all their parameters. But basically, in this chronic porcine infarct model, when you place an epidural catheter and you infuse lidocaine, you notice that the AH interval increases. The HV interval actually stays more or less unchanged, and that both atrial effector refractory period and ventricular effector refractory period increase. So there's a suggestion that by increasing atrial effector refractory and ventricular effector period, thoracic epidural anesthesia could be antiarrhythmic. The other really interesting finding we saw that we didn't really expect was that actually the thoracic epidural anesthesia improved baroreceptor sensitivity. So not only did it stabilize ventricular electrophysiological parameters, but it improved parasympathetic function, that interrupting those sympathetic efferent, but also much more likely afferent fibers that are going up to the brain through the spinal cord had a beneficial effect on parasympathetic function. In humans, in the case series where patients have undergone thoracic epidural anesthesia, the good news is that there hasn't been a significant change in mean arterial blood pressure before or after TEA. These patients are predominantly at rest. So we haven't seen any major drops, for example, in their blood pressure, but there is a significant drop in the number of VT episodes post-TA as compared to pre-TA. Now, these are small numbers. For example, this case series only had 11 patients in it. There was a study that came out in circulation about a decade ago that also had only about eight or nine patients in it. So we're looking at small numbers, but at least with these small numbers, we're not seeing significant harm. We're not seeing massive drops in blood pressures. And there does seem to be efficacy in terms of the VT burden. It's important to keep in mind who is and is not a candidate for TEA. And some of the absolute contraindications for thoracic epidural anesthesia include active infection, dual antiplatelet therapy, and then requirement for uninterrupted therapeutic anticoagulation. So if you have a patient that, for whatever reason, needs ongoing heparin, you won't be able to place an epidural catheter. The relative contraindications obviously are an acute MI at the time that things are occurring, that you're trying to place your catheter. And then if there's potential need for a medical or surgical procedure that is major and non-cardiac. The general patient population where TEA is considered is if you're dealing with an incessant VT and you already have two endorhythmias on board, whether it be AMI or lidocaine. When you're having continued VT storm despite an ablation attempt. The other place where it can really help you is if you notice a decrease in VT burden due to deep sedation. Because generally that means you've also been able to reduce the sympathetic tone. And so you might see some benefit. The benefit of TEA over general anesthesia, over just bringing the patients, intubating and sedating them, is that when you have a TEA in a patient, you can actually take them up and they can talk to you and they can participate in their decision-making process, whether that be another ablation or an LVAD or a transplant. Whereas when you have them intubated and sedated, you don't have that luxury anymore. They've actually been removed from that whole discussion and decision-making process. So if you don't have thoracic epidural anesthesia available to your center, there are many anesthesiologists that are able to do stellate ganglion blockade. And stellate ganglion blockade is done percutaneously. It can be done under ultrasound or fluoroscopy. And this was basically a review of all the cases in the literature, looking at arrhythmic episodes, defibrillation shocks, as well as ejection fraction in patients with cardiomyopathy and VT who had received stellate ganglion block. And you can see that overall, there is a reduction in the number of arrhythmic episodes per day, and there's a reduction in defibrillator shocks. Now, one of the limitations of the study is that some patients may have unilateral blocks, some patients may have bilateral stellate block. If, as I mentioned, and I showed you earlier, you can get norepinephrine release in your heart, whether you have left or right stellate ganglion stimulation. So if you only do unilateral block, you may not be able to achieve as much efficacy as with bilateral stellate ganglion block. But it really depends on what your anesthesiologist is also comfortable with. Thoracic epidural anesthesia is nice because it works at the level of the epidural, right? And it blocks both. It's gonna be able to block preganglionic sympathetic fibers going to both stellates. Nevertheless, though, with stellate ganglion block, there's definitely a signal here, reduction in number of arrhythmic episodes per day. When you do bilateral stellectomy now, so forget blocking it, we now remove the stellate ganglion. We first wanted to start this in animal models to see what kind of results we saw. What you can see is in a chronic infractional animal, there is an increase in APD duration in general in the areas where you have the scar. So again, these are shorter duration, APDs are shown in blue, longer APDs are shown in red. And you can see pre-stellectomy as opposed to post-stellectomy, there is a modest increase in the APD duration. What that means is that the tissue has become a little bit more refractory. And so that in itself may be antiarrhythmic. The other thing that you notice when you map these hearts and you actually start to pace from within where the scar is located, is that often pre-CSD, you see these areas that can potentially serve as lines of functional block that are resolved after post-CSD. And this can be true both at baseline as well as during sympathetic stimulation. This is now with middle cervical ganglion stimulation because the stellate has been removed. And you can see there are generally areas that can develop during sympathetic stimulation, these areas of functional block that you can now imagine circuits kind of going around that then have more homogeneous conduction after sympathectomy or after stellectomy. And in these animals, there was a significant reduction even acutely in VT inducibility. This was done with program stimulation pre as compared to post-stellectomy. Now, what about humans? And I'm gonna, there are a lot of smaller studies but I'm just gonna describe this study which was of 121 patients across five sites. Patients with refractory VT or VT storm who in fact, 75% of these patients had presented with VT storm who underwent cardiac sympathetic denervation. And so the idea was what is their VT fruit survival? What happens to their burden of VT afterwards? It's important to note that a lot of these patients had actually had a prior ablation and many of them up to 40% had polymorphic VT in addition to monomorphic VT. So this was sort of a more challenging population. The other thing to note is depending on the center about 20% only had a left-sided cardiac sympathetic denervation procedure because at the time sort of some people still felt that, you know, bilateral may be too much. But despite all of that, what we found in this patient population of one year is that there was about a 58% ICD shock free transplant free survival at one year. Now, most of these patients also had non-schemic cardiomyopathy. The schemic cardiomyopathy population was 27%. That means that, you know, 73% of these patients had non-schemic cardiomyopathy and this number actually isn't necessarily worse than what you would be able to do with VT ablation. But the other really meaningful finding in these patients because a lot of these patients had come in with a significant number of shocks in the year prior to the procedure, right? The median number of shocks here was somewhere between 10 to 12. There was a significant reduction in post-CSD in the number of shocks that they experienced up to a year after the procedure. The other thing that, you know, we noticed is, remember I said about 20% of them had left CSD. Well, it turned out that the bilateral CSD patients had the much better ICD-BT shock free survival as compared to the left side. And, you know, given the physiology data out there and the pathophysiology data out there, I think this makes sense. It's not a completely benign procedure. There's still a small risk of hemothorax and pneumothorax when you do this procedure. And in our center, it is the thoracic surgeons that do it, but in other centers, either cardiothoracic surgeons or vascular surgeons can do this procedure. There was about also 13% of the patients would require vasopressor support for 24 hours after the procedure. And then there was sort of some rare complications, either related to an seizure, related to infection that occurred. What we wanted to do really though, is figure out whether there were certain things before the procedure that would predict who would recur after cardiac sympathetic denervation. And if you look at this curve, something that becomes very obvious very quickly is that if you presented with NYHA class four, there was nothing we could do for you, basically. That within two months, right? Almost all those NYHA class four patients had already recurred with VT, suggesting that just like any of the other sort of therapies that we have, including beta blockers, starting them earlier is more beneficial than later. In sort of a systematic analysis, this was in our proxy-professional hazard models, we looked to see what predicted VT, ICD shock, death and OHT. The two or three things that stood out, obviously was hazard ratios for functional class three and four are very high, but also VT cycle length was a predictor of recurrence. So slower VTs, especially those that were less than 150 beats per minute, were more likely to recur after CSD than the faster VTs. The other thing we wanted to know was, one of the problems with the previous study was it was a very heterogeneous population. And as I mentioned, a lot of these patients, up to 40% had polymorphic VT. So we wanted to know what percent, what would happen if you removed those patient? What is the benefit of cardiac sympathetic denervation if you have only patients that present with monomorphic ventricular tachycardia and don't have any evidence of polymorphic VT, either on their ICD interrogations or in their clinical presentation? And so the first thing we did to be able to evaluate that, this was a single center study at our center, was we developed a model to see what predicted VT recurrence and sustained VT and ICD shock in all patients that came in for VT ablation. And in those patients, what we found is that as expected and reported in other studies, having non-schemic cardiomyopathy, having VT storm, having an emergent indication, or NYJ class three or four were predictors of VT recurrence after VT ablation. Those are well-reported variables. But if you now take the patient population that underwent cardiac sympathetic denervation and only had monomorphic VT, and you looked at based on these models, because they're often a much sicker population, what would be their VT recurrence rate? And then compared that VT recurrence rate to what actually happened to them. What was the true VT recurrence rate? What you'll see is that after CST, the VT recurrence rate is actually much lower than what is predicted based on how sick they are by our models. So that even in the setting of monomorphic ventricular tachycardia, whether you look at VT recurrence, this includes all ATPs, or sustained VT and ICD shocks, you saw a reduction in the hazard ratios for the observed rate of VT recurrence as compared to what would be expected based on their comorbidities, based on the models that we have for VT ablation patients. So that was good news. I'm just gonna put in a plug here and say that we've also looked at the effect of vagal nerve stimulation after cardiac sympathetic denervation, and have shown that the two can potentially work synergistically and reduce VT inducibility in animals that are still inducible after CST with high doses of isopropyl. All right, so moving on to neurohormonal activation. So as I mentioned, there are sort of renal nerves around these arteries and veins that can sense things like cardiac outlet, and that therefore these afferents get activated and can go actually all the way to the ciliary ganglion through the spinal cord, and then they can efferent, they can activate the efferent nervous system, and that can increase the release of renin, angiotensin, angiotensin 2, and then also at the same time, you can have release of catecholamines from the adrenal gland. So how do we interrupt that cycle? And really the only way we've had so far when it comes to treatment of ventricular arrhythmias is by doing renal denervation. And so far, all renal denervation is really being performed through the renal arteries. And here you can see sort of there is contrast injection in that renal artery. There's an ablation catheter that's placed there. And this was just a very preliminary study of four patients that came out in 2014 that suggested that renal denervation may actually have a benefit. RDN was performed here at follow-up in the number of VT episodes in these patients. There was another study of 10 patients that was published in Jack Cardiovascular Interventions, predominantly non-schemic cardiomyopathy and actually Chagassic disease. This was a South American study. And actually what was interesting in this patient population is that most of them had not even had a cardiac ablation procedure. And despite all of that, after renal denervation, what they noted is a significant reduction in the number of VTBF episodes at one month and six month, both in actual VTBF, as well as the number of ATP episodes that they saw on their devices. Again, suggesting that there is benefit in interrupting that neurohormonal access with renal denervation. And finally, this was a study of neuromodulation with renal denervation in patients who had failed cardiac sympathetic denervation. So a study of 10 patients that despite having multiple ablations, all the end-treatments you see here and CSD went on to have recurrent VT. And more or less what this study shows is that at six month post-RDN, there are a good number of patients, some don't, and I'm not, by any means, this is not necessarily going to add, like everything else that we have, it doesn't work in everyone. But there is a reduction in the majority of the patients, six months post-renal denervation as compared to pre-renal denervation. And remember that the cardiac sympathetic denervation and renal denervation are really targeting different aspects of the autonomic nervous system. So again, it's not necessarily a surprise that you're seeing an effect. There are definite problems, I think, with renal denervation that need to be worked out. One is that we don't really understand the distribution of these nerves around the renal arteries. And you can see that here is distance from the lumen to the nerve, that it's a variable on the ventral versus the dorsal aspects of the arteries. And when we do renal denervation, if any of you have seen it, we just kind of go up and down and stay as proximal in the renal arteries as possible because we don't want to cause damage and dissection more distally in the renal arteries. But nevertheless, we don't really have a good understanding of where the renal nerves around our artery are located. The other interesting study that's come out recently is that potentially there is a way to look at what's called a hotspot or a pressor response spot, and potentially only ablate in those regions. So you could potentially stimulate these renal arteries and then only ablate in regions where you see a blood pressure response as opposed to at other times, you may actually see an inhibitory spot or a neutral spot, and maybe those are not good areas to start denervating. The other important aspect I think that we need to keep in mind is that the anatomy around the renal arteries are variable. And depending on what structures are sitting there, they can affect your ablation success. So for example, lymph nodes tend to draw heat so that if your catheter is here and you're ablating, the lymph nodes that are sitting there tend to draw that energy towards them. Whereas blood vessels, for example, can sort of serve as these cooling zones and can actually dispel that heat away so that you don't actually tend to ablate the nerves that are around the smaller blood vessels as well. So something else to kind of keep in mind as we're trying to figure out how to best do renal denervations. And this was actually a study that showed that basically when you have lymph nodes in certain regions, the lymph nodes tend to draw your radio frequency energy towards them, whereas when you have these smaller veins and arteries, they actually tend to repel. And so if you have sympathetic nerves, even if they were equally distributed, just given the structures that are surrounding these nerves, you wouldn't get sort of a homogenous renal denervation that you wanted to. So with that, I'm going to actually end and I have 10 to 14, 15 minutes for questions. If there are any questions, I'm happy to take them. It was a lot of material we covered. Let me know. Okay, that was great. Thank you. Fantastic talk. So if anyone has questions, feel free to send them through the chat. Maybe I'll ask a couple things. It seems like you talked about a lot of different targets, sympathetics, parasympathetics, renal denervation for atrial arrhythmia as we worry about the GPs. And in the heart failure literature, it seems like they're being focused on each individually and then tested. Do you have a sense of a hierarchy of what's more important, less important? Should we just be targeting all of this stuff because the patients are really sick and we want to do whatever we can to suppress? So obviously the higher in the hierarchy that you target, the more likely you are able to see an effect, but the more likely you're also able to see an off-target effect. Does that make sense? So whether you, if you, that's sort of when you intubate and sedate a patient, a lot of the times you'll see that the burden of VT or VF goes down. That's, you've taken the brain and probably a lot of the sympathetic nervous system out of the question there. And so that does help, but you obviously can't keep a patient that way. Ideally, what we want is targets that are at the organ. We're looking for organ level targets, but to be honest, we don't have those. So vagal nerve stimulation, for example, one of the reasons I believe that a lot of the trials were negative is because they weren't able to necessarily push the parameters to where they needed to push them to capture enough of those cardiomotor, efferent, parasympathetic fibers to be able to see, you know, the effects that they had shown in animal models were more likely than not, they were able to push their parameters much higher without off-target effects. So I think that in the hierarchy, you want to stay as close to the organ as possible, when possible. Obviously, we don't have a lot of drugs that can target all the sympathetic nerves, including all the things that they release, including neuropeptide Y, for example, at the level of heart. But, you know, beta-adenergic receptors and blockers or blockers for adenergic receptors currently work. So, ideally, you want to stay at the level of the heart, but it's true that the higher that you target, right, the more likely you're able to see a result, but also more likely to see off-target effects. And then maybe I can ask a couple of questions about sympathectomy, because we're early in our experience with thoracic surgery. Sounds good. I guess, in general, if, you know, someone's watching whose center doesn't really do that, what advice would you give them in terms of dealing with surgery in order to get their program up and running? Okay, so that's a really good question. So, you know, this is one of those programs that is a collaboration, I feel like, between electrophys... At the moment, at least, till we develop a percutaneous way to do this or an interventional way to do this where it becomes kind of completely our procedure. It's basically a collaboration between, like I said, your electrophysiologist and your surgeon. So the first thing to do, really, is to figure out if there's a surgeon that has any type of expertise in this procedure. And if they don't have it for VT, they may have it for hyperhidrosis, for example, right? Because that's a routine procedure that's done by a lot of thoracic surgeons or that they're trained in. And the only difference between the cardiac somatic innervation that we do for VT and the hyperhidrosis procedure is that, you know, a lot of the times for hyperhidrosis, they leave the stellate alone. And so for this procedure, you're going to ask them to take a little bit more, the lower half or a third of the stellate ganglion. The patients that are VT patients that are going under cardiac sympathetic innervation generally have a lot of adhesions. So in the thorax, we don't really know why they do. It's not necessarily the ones that have had, let's say, bypass surgery or cardiac surgery otherwise. But maybe it's because of all of that inflammation that we talked about that occurs as a result of myocardial injury. So that means that doing sympathetic immune patients with VTVF for surgeons in certain patients can be a little bit more challenging in terms of the dissection than it is in patients with long QT syndrome or in patients that have hyperhidrosis and normal hearts otherwise. So the advice is, you know, figure out if you have a surgeon that can do the procedure. And generally what I say is like, our surgeons are more than happy generally to talk to anyone who's interested in performing this procedure and give them the know-how. We're also putting together a video that we'd love to give different sites that are trying to start their own program for their surgeons. We actually have an information packet for the patients, kind of what to expect before and after. For example, one of the things that we, for our center we weren't initially doing is putting patients on Neurontin. One of the things that we realized a lot of the times after the surgery is about 10% of our patients complain of neuropathic pain afterwards. Now it resolves, you know, by six months to a year, nobody still has their neuropathic pain, but we started starting our patients on Neurontin prior to their surgery and kind of getting them on the 300 BID or TID dosing to make sure they tolerate it. And then they seem to have less neuropathy afterwards. So I would say, you know, talk to your surgeons, talk to your anesthesiologist. We have a team of surgeons and anesthesiologists that do this procedure with us. And then, you know, follow these patients carefully and we're happy to provide, you know, any information and are happy to have our surgeons talk to your surgeons in being able to set up this program. So that's generally where it starts. Okay, great. There's a question here about VT storm patients that have primarily polymorphic VT as opposed to monomorphic VT. Right. Do you think that polymorphic VT is primarily triggered by ischemia or something else? How aggressive are you about rechecking coronaries before going through all these other therapies? It's a really good question. So we certainly check for ischemia when we see polymorphic VT. There's no doubt about it. Even if it means doing an angiogram just prior to the VT ablation procedure, like on that day, we check to make sure that there isn't something significant that we're missing, especially in the setting of polymorphic VT. And I'm assuming that you're talking about polymorphic VT in the setting of a scarred heart and not necessarily like polymorphic VT as related to like long QT syndrome. So in the setting of basically someone with heart failure who comes in with polymorphic VT, we almost always will check the coronaries unless they've had a very, very recent workup, let's say in the past three months, or there's no evidence of ischemia or anything on their stress testing. In general though, what we found is that once we rule out ischemia, sympathectomy is actually pretty good at treatment of polymorphic VT as well. I showed you the study on the monomorphic VT population because that's where a lot of controversy is. Monomorphic VT is always thought to be related to a reentrant circuit within a scar. And so how can that be treated by sympathectomy? Well, now that hopefully I've shown you all the data about how sympathetic activation can cause heterogeneous activation of that scar and border zone and normal regions, and there's more of an understanding of how it could. But I think for polymorphic VT, at least if nothing else, get rid of the polymorphic and polymorphic aspect of it so that then you can deal with the monomorphic VTs that are left over if there are any. And when you're thinking about sympathectomy, at what stage is it after one failed ablation, two failed ablations, three? Is there any population? I mean, you can keep going with ablations, right? Your 10th failed ablation. So we generally, if it's a non-schemic cardiomyopathy, we basically want to get to a point where we feel like we've done a comprehensive epi and endo procedure, right? So a lot of it ends up being sort of EP-driven, meaning that do you think that you really kind of did as much substrate ablation or what you could do that day? And is there really that much more left for you to do, right? So for us, most of our patients that come in have already had one or two ablation procedures. We generally, if they're non-schemic, like I said, do an epi and endo procedure to make sure that there's really sort of, that they've had a comprehensive procedure and that we've taken out what we can take out. And if they recur after that, we generally send them for sympathectomy. So I would say almost all the patients at our center have had at least one, if not more than one re-tablation procedure. But we're no longer doing the fourth re-tablation procedure, I can tell you that, because sort of like how many times do you keep doing the same thing expecting a different result? Is there anyone that you would consider it first line for, or is there room for a trial, BT ablation versus sympathectomy population? That's a really, that's a great question. We just got the pilot study funded to look at patients who have failed to BT ablation, right? So looking at patient who failed to BT ablation, what happens if you randomize them to sympathectomy versus more standard of care? But we haven't, I don't think approached or been able to get to the fact where, to get to the point where we are yet able to convince people to enroll in a study that only involves, that involves sympathectomy versus BT ablation yet. BT ablation has become the standard of care, obviously, and has made huge advances over the past decade. So I think first we need to show sort of like the AVID trials, that sympathectomy in a randomized fashion works in patients who haven't, who are sicker, who don't have as many options. And then we need to show that potentially it can work further early up sort of in the therapeutic toolbox.

autonomic modulation

ventricular arrhythmias

sympathetic nervous system

parasympathetic modulation

nerve fibers

cardiac function

denervation

neuromodulatory therapies

renal denervation