Hi, this is Eric Pustowski. Welcome to another segment of EP on EP. It's a delight to have with me today a person I've known for many years and who's done such great work in the field of electrophysiology, Dr. Shiv Kumar, who's professor of medicine at UCLA. Shiv, welcome to the show. Thank you so much, Eric. It's an honor to be here. Now, I know this is going to surprise you, but I'm going to ask you to talk about the autonomic nervous system in VT. Wow, I almost guessed that. A total surprise. So let's start with basics. When I first started in electrophysiology, it was really not known how much autonomic innervation there was to the ventricle. Why don't you start the audience with what is the importance of the sympathetic and parasympathetic in the ventricle that might pertain to what we're going to talk next? It's a great question, Eric. When you look at how the nervous system controls the heart, in fact, it controls every cell in the human body, as you know. We call it the internet of the human body. But the heart, for all mammals, it is life or death, how the nerves control it. And the nerves are needed so that the heart can talk to the lungs, and there is proper circulation of blood. And most importantly, the nervous system exists to make sure that at a moment of extreme physiologic stress, fight or flight, as we've heard in medical schools, that response is only possible because of innervation of the heart, so that you'll be able to instantly increase your cardiac output and be able to get up and run. If you heard a fire alarm, or in my part of the country, if you felt an earthquake. So that's perhaps, and that is a survival reflex. And that, of course, profoundly gets altered with disease. In fact, 90% of all heart disease is because of neural signals from the heart to the brain, which has obviously opened up a huge area of science, which is going to help millions of people. And in our own field, in electrophysiology, it's had a very powerful impact on understanding ventricular arrhythmias. So let's go to that, because you've done such innovative and important work in this area by playing around with what was put into our hearts, right? Your autonomic nervous system alterations to help VT. Tell us a little bit about how you do that, and also unilateral versus bilateral, and most importantly, who are the best candidates? A great point. My own inspiration for having done this actually comes from a remarkable study that was published in 1961 at the university where you trained, which is Duke University. And at that time, Estes and Islar published a very interesting paper of a patient who was having incessant VT, in whom they did bilateral sympathectomy. Until then, of course, sympathectomy was being done in the pre-angiography era for angina. I remember that, actually. Yes, and it's interesting. And Duke University's great contribution to medicine. Subsequently, Art Moss and Doug Zipes also published that. And the Europeans started using that, as you know, they did left-sided sympathectomy for channelopathies. And in our own experience in the early 2000s, when we vastly expanded our catheter ablation program for ventricular tachycardia, it became obvious to me, attending your courses in the 90s, and I still remember the interesting observations that come up. Things like sedating a patient and controlled ventricular tachycardia, that shows we see this all the time. And we essentially took two parts of what was known and put it together. So we did the most complex VT ablations, epicardial, endocardial, and a patient was still in VT storm. So out of sheer desperation, we started putting in thoracic epidural catheters. Oh, really? And that was life-saving. And subsequently, we decided we should do surgical sympathectomies, which is how the field was born. The second part of your question, unilateral versus bilateral, for structural heart disease, you always have to do bilateral sympathectomy. So can I stop you just to say, why, in a sense? Because at least a lot of the anatomy suggests there's preferential input to different parts of the heart. Am I wrong on that? Is there not preferential input? It's a good point. I think with increasing knowledge, we have learned in the past two decades that sympathetic input to the heart is almost uniform. It has layers of sympathetic input. Parasympathetic input for different regions, especially the SA node and AV node, is very densely innervated. So the left-right differences really is mainly because of the area of the ventricle. OK. So left sympathetic denervation was used because the LSG controls most of the left ventricle. And for patients with channelopathy, that provides an excellent outcome. So even for structural heart disease, we always start with the left side. But the international collaborative study that we did actually showed that bilateral was life-saving. Yeah, I read that paper. Yeah. So that's why you do bilateral. Absolutely. And the NIH and our tax dollars at work has now funded the pilot phase of the PREVENT-VT trial. And we are hoping that this is a trial that UCLA, Vanderbilt, and Johns Hopkins are doing. My colleague, Dr. Bussegi, is a PI for that study. And we are hoping that that pilot study will set the stage for a definitive trial. OK. So the big question, we all take patients to the lab for VT ablations. Not me, personally, much anymore. So you have a patient who has routine coronary disease VT, and you're going to take him for ablation. I'm guessing you don't automatically, that's a bad word, right? Automatically take care of the autonomic nervous system. There must be some kind of logic flow for you when you do that versus everything else. Can you help us out on that? Sure. It's a great question, Eric. We currently use neuromodulation in two settings. One is when a patient is dying of VT storm, to stabilize them so that we can get them to the cath lab. Oh, to do a routine ablation. Yeah. OK. And we always, always, if there's a substrate that can be addressed, you have to address the substrate. And of course, it bookends on the other side. If nothing else can be done with catheter ablation, you don't want to transplant a perfectly good heart, which could work for the next 10 years. And that's where sympathectomy has a huge role. It could also have a huge impact in something that you and other leaders have talked about for years. And that is, what do you do for patients who don't qualify for an ICD, who the EF is above 35, and they simply, it's hard to show cost effectiveness. Yeah. That's where, that's where, you know, how do we address? We are the heart rhythm society. 22 people die every minute suddenly in this world. It's too high a cost to pay. That's a very interesting observation that someone's going to have to do the study, of course. But so getting back to that before we wrap up, why does it work? And what I mean by that isn't just some philosophical thing. I like to think of a substrate and triggers. I know it's simplistic, but that's how I like to think about it. So if you have a coronary disease and you have circuits in there that you're going to go ablate, why should doing a denervation suddenly stop tachycardia? It's a great question. And the simple answer to that is the signals going from the heart to the brain dramatically amplifies the amount of norepinephrine that's released in the heart. And in fact, we now think when you do S1, S2 stimulation in the heart, the reason why that is induces arrhythmias is if you have a substrate, you get the monomorphic tachycardia. Yeah. Sometimes you get polymorphic VTBF. We called it nonspecific, but it's not nonspecific. It's a lot of norepinephrine released in the heart. And that is because of pacing, because the heart, when it contracts differently, it causes sympathetic excitation, which is why you get pacing-induced dyssymphony, heart failure. And ultimately, you know, this connection, Takotsubo, wherever you see, you now see a new angle for how the nerves interact with the organ. So from what I'm guessing is you're going to say the brain's the trigger. Is that what you're going to tell me? They play hand in hand. Your brain can activate your sympathetic nervous system. You hear a fire alarm, a noise, but a scar in your heart, or if the heart contracts in a funny way, that can also trigger the process, which is why patients with tachycardia sometimes have anxiety. So where's your next move? Where are you? You've already given us a preliminary view into the study, but just in a short kind of moment, where's the next step? Where do you want to take this? Thank you for asking that question, Eric. And I'm hoping that all the trainees and the next generation of people who are listening to us, I can, with no doubts in my mind, state that this is a great area to investigate, because I think we are going to become the neurobiologists of the heart. And electrophysiology is the field that brings science to mechanisms. And people may wonder, we are going to be using things like Botox in the neurons of the heart to control AFib. So the end of electrophysiology should be is going away from pacemakers, away from defibrillators, and away from catheter ablation, but go into biological modulation. But we are still going to be the thinkers that all of us are. And it's a special joy to sit down with a great teacher like you, Eric. Oh, you're so kind. To ask these questions. Well, the nice thing about your research, in addition to all the good it's done, is that you've done what I like to think clinical investigators should do. You've based your research on the fundamental knowledge of physiology, and then you've taken it to the next step of how you can manipulate pathophysiology for the good of the patient. And you should be congratulated for it. It's a delight to have you here, Shiv. No, thank you so much, Eric. I'd probably, you know, be right back at you and tell you that it's people like you, teachers, who inspire us. And as we often quote at UCLA, the start of the team is the team. And the untrammeled joy of working in America is that the future is very bright. I think U.S. is going to help lots and lots of people. And much like you, I'm looking forward to Sheping Nakas seeing all the trainees in our field. Sheping Nakas, listen to this. Shiv, thank you so much for joining us. Thank you so much, Eric. Thank you.

autonomic nervous system

ventricular tachycardia

nervous system control

bilateral sympathectomy

biological modulation