This talk was put together not really focused on the EP audience alone, but really taking into account what we have, the people in the audience who are representing sort of a diverse spectrum of industry experts. So again, my colleagues at UCLA, physician scientists, clinician educators, and scientists to whom we owe so much, and the data I'm presenting comes from the work all of them have put together and our tax dollars have paid. So ventricular arrhythmias are very, very important in the field of medicine, and it's not just something that's unique or a small subgroup of patients. It actually has a profound impact. This image comes from 300 years ago, and this is an initial description of sudden death of a count who comes back after a hunting expedition, and he's given a bowl of cold water by his servants. And of course, the moment he puts his hand into the cold water, he drops dead. Of course, there's more than one explanation of why he died suddenly, but there is a pathophysiologic link of how being exposed to cold triggers bad stuff. And this bad stuff, as we briefly mentioned yesterday, is significant. If you looked across the spectrum, it's estimated something like 12 million people die every year in this world, 22 deaths per minute. And we talked about this yesterday. If you look at the entire population of risk of sudden death and the shaded areas of people who die suddenly, certainly if you have significant heart disease, a chunk of those people are going to die suddenly, die of ventricular arrhythmias. But the shaded area also shows that there are more people dying suddenly who have either minimal or no heart disease. So that immediately tells you that when you look at the pathophysiology of this, it's not just the presence of overt or severe structural heart disease. Yes, that is important. But even small or minor heart disease is not something to be ignored. And we believe that the vast majority of these arrhythmias, especially ones that are preventable, are actually tachyarrhythmias as shown in this panel. And this talk is going to deal with these color images as to what really drives these arrhythmias. So it's a very big topic to cover in a very short period of time. And if you open up any textbook of electrophysiology, cardiology, people would classify arrhythmias at sort of two major categories, something that causes an abnormal impulse to form. Usually your heart should actually have impulses that form in a sinus node, which is the pacemaker of the heart. And there's a sequential activation of this wave front that goes from the SA node to the atria to the AV node, which is in the middle of your heart, and then the ventricles. If any abnormal area decides to take off on its own, that is a disorder of impulse formation. The other reason why you get arrhythmias, like you saw in the case that Dr. Russo presented, there are abnormal electrical channels that are created in the heart. And that is a disorder of impulse propagation, how the impulse travels around the heart. And it turns out sometimes both these mechanisms may be operative. So it's worth spending a minute or two really looking at all these dramatic advances that have happened in the field of basic sciences and translational sciences in terms of arrhythmias. So what have we learned from cellular electrophysiology? This is a fascinating area. And I wish I had borrowed Dr. Andrew Crane's image, which is much simpler. But all of us only wish life were that simple, at least in the real world. It's actually very complex. When you look at each cell, when you look at the entire spectrum of the proteins, the engines that really control ions going in and out of the cell, remember the heart cell has to do two major things. One is it actually has to contract so that it can pump blood. The second part of the heart cell is it's also an electrical conductor. So an electrical wave that passes through, each cell has to talk to its neighbor. So it's fascinating. So in many ways, it's always expected to do two things. And this is, of course, nature has evolved a very beautiful mechanism over the past 3.4 billion years to create this machinery. And until very recently, we had no ways of even studying. I could stand here and say all this happens. What is the proof of that? The proof of that is, again, engineering, electronics. You could actually place a small little electrode on a little cell, and you can watch these little proteins move up and down, which is these electrical signals over here. Many of you are PhDs in the audience, so you know what the patch clamp technique is and why it is recognized by another prize. So this is sort of the building blocks of how electrical activation occurs. So this information now has to be translated to the next higher level, which is organ level electrophysiology. And that's where the entire sort of field of clinical EP is centered around. As it stands, the entire field of the biomedical industry that supports the field of cardiology and cardiac electrophysiology is built around. So organ level electrophysiology is, again, founded on electrophysiologic principles that go over 100 years, if you will. And one of the famous professors in this field was actually George Ralph Mines. Started off in England, went off to Canada, and of course, had died because of self-experimentation, which was very popular in those times. But in his very short life, he came up with three major discoveries, reentry, vulnerable period, and alternance, three concepts, all of which have stood the test of time and were described for the first time by this gentleman. And in fact, long before we had electrical recording systems, even catheters with which we could record electrical activity, the way Mines and his colleagues did experiments, they cut out parts of a jellyfish, and they would stimulate it and watch an electrical wave. You interpret the electrical wave by its mechanical wave that goes around. They also used turtle hearts, and they came up with these kinds of pictures, which showed that electrical impulses can travel around various parts of the heart and re-excite the area from which the impulse started. So, the concept of re-entry, going back to the same circuit, was actually a very fundamental contribution to all of electrophysiology. And subsequently, the other experimental electrophysiologists were coming up with better and better techniques. Electrical recording systems, optical recording systems, this is a 1968 paper for optical recording comes from UW in Seattle. And we could now get electrical signals from tissues without even placing a physical electrode in them. And this has been shown, of course, in 19, this is a citation classic paper in 1976 that came out of University of Pennsylvania, where Dr. Salama actually was able to record an entire action potential, which is shown over here. And this was done without actually using an electrical probe. This was done using light and signals that came out of dyes that were placed into the heart. So, why am I telling you this? Because now, you had powerful ways of studying electrical activity of the heart muscle. And using this, you could start interpreting what was actually happening to electrical impulses as they propagate around the heart. So, we learned how single cells work. Now, we had ways of studying the entire organ and start mapping how waves go through the heart. Now, all this is great when you put it up as an experiment. How does it relate to us as electrophysiologists? Most of the people in this room, how do you create an industry? How do you, the reason you need to have industry is that's the only way you can help millions of people. So, how did the academic private industry partnership occur? One of the big advances, and perhaps we had to thank the Vietnam War for this, a group of physicians who worked in a public service hospital here in New York were able to do these studies and they were able to create catheters. And they threaded this up the heart and they were able to record signals from within the heart. And this is one of the important achievements in the field of electrophysiology. This was, of course, preceded by work that came out of France and so forth. It's like everything else in medicine and science. But the beauty of this is in a patient, in literally an outpatient setting, without massive open interventions, you were able to thread a catheter into the heart and record signals from within the heart. This completely blew the lid off the field because we now could actually use these signals and trace entire arrhythmia circuits. And that has become a completely important, pivotal, central aspect of the field of electrophysiology. And for many years, the field was just doing these types of studies, understanding arrhythmias and generally giving patients drugs to treat it. And this sort of advance in the field also helped people to eventually use the same catheters to start delivering various energy sources and fix arrhythmias. So that is sort of the story of electrophysiology. So what mechanisms have we learned by placing these catheters in humans in the heart? So there's a concept to keep in mind. One is reentry. And this reentry, which was described by Mines 100 years ago, can now be consistently interpreted in the EP lab by placing catheters at various parts of the heart. And if you have a scar or an anatomic barrier in the heart, an electrical impulse can go around that structure. So that is almost like a toy train going around a track, an abnormal electrical track in the heart. So that is reentry. Sometimes you don't need a scar. And there are electrical phenomena in the heart where, functionally, a small region of cardiac tissue can behave like a scar. It's not actually a scar. But that is because of how electrical waves interact with each other. And this can also cause various types of reentry. And perhaps this plays a very important role in certain types of atrial arrhythmias and perhaps components of atrial fibrillation, too. Now, what is new in this field, of course, is the next level, which is regulation of the heart, which operates across all these levels, from single cells to the organ level. And that, of course, is based on how nerves control the heart. And this is a big area. All of us have known this. Here's an example where you just stimulate a nerve, the stellate ganglion, which is far away from the heart. If you just stimulate that little ganglion in your neck, what you see over here is a completely normal heart can go into fibrillation. So that actually shows the power of nerves that control electrical waves in the heart. And we now have techniques. The reason that happens is because if you actually use this probe in the heart, you can directly measure. In this case, I'm showing an example of norepinephrine, which is a neurotransmitter released in the heart. But you can virtually sort of record the exact concentration of peptides or any other biological compound that is released in the heart. So these are ways in which you can now really understand why arrhythmias occur, why certain regions of the heart are more prone to abnormal electrical activity. And once you have that type of information and you overlap the electrical maps over here, then you can start understanding why certain regions are the regions from which abnormal electrical impulses are triggered and why you actually have catastrophic rhythms such as fibrillation. So this is sort of the next phase of trying to relate not just cells and organ level, but putting it in the context of patients. And we do this all the time in the EP lab. And we try to mimic this phenomenon by infusing isopryl, which is structurally a chemical that is very closely and acts through almost the same pathways that the body's own neurotransmitter norepinephrine works. It works through the same cellular receptors. So that's why we infuse isopryl in the EP lab, for instance, to recreate these phenomena and increase the proclivity for generating arrhythmias. And it turns out the science and the scientific instrumentation in the field has come a long way. We now can go to a very detailed level of mapping the hearts. This is an experimentally created infarction. And you're going to see the clinical equivalent of this in one or two images. Here is an intentionally created infarction. This is a diffusion tensor MRI image in the left lower part of the screen. And you can merge these images. And then using high density electrodes shown over here, you really can understand how electrical waves go around the heart. And it's because of these techniques that we have learned that nerves and other ways and metabolic phenomena and inflammation play a very important role in arrhythmias. So after all this, why should we care about pathophysiology? Because it actually has big implications on how we map and fix problems in patients. So the what if questions. So focal arrhythmias can occur due to problems in a small region of the heart. It may be something that you're born with, like you heard in Dr. Crane's talk yesterday, you know, congenital channelopathies. And of course, some hearts, when one of the coronary arteries is tied off or there's reduced blood flow, that's essentially a structurally normal heart that can develop arrhythmias. So the reason why that is important is, of course, if you can understand mechanism. And there are some rare examples, such as channelopathies. Here's one example. The details of this particular channelopathy is kind of a nerdish thing. It's very interesting for some EPs. But there are some very specific mutations where we fortunately can use drugs to target and control arrhythmias. Here's a type of arrhythmia which was controlled and managed by this medication called flecainide, which works on a specific part of a channel. And it turns out that this was one of those examples where in Holter studies, people were able to show that this particular type of bidirectional VT was controlled by a molecular target. And it turns out it is already an FDA-approved drug. And it was repurposed for managing this arrhythmia. So this is one example of how, at the level of a cell, sometimes understanding a mechanism works. But then you also heard yesterday in Dr. Haynes' talk that drug therapy has sort of not done too well because we've never been able to get very precise targets. And this link of molecules to arrhythmias became somewhat weak. But a small region of the heart, if it's consistently a source of an abnormal rhythm, such as a focal arrhythmia, PVC, we said focal PVCs can cause heart failure, right? So these types of focal arrhythmias can, of course, be very effectively targeted by placing catheters in the heart, mapping them, and zapping that region. So that's a big success story for ventricular arrhythmias. And in fact, one that we are very fond of targeting because you can actually prevent heart failure. So that is a big advance in our field. And again, you know, we tip our hats to the industry for giving us these technologies to use in our patients. But what about the actual mechanisms of focal arrhythmias? This is a good friend of ours, Professor Yance, who all the EPs in the audience know very well. It's important to highlight that we still have very minimal understanding of why a small region of the heart electrically can cause arrhythmias. So I'm going to just plant that seed so that, you know, you should keep your eyes open because we are still in the very early stages of understanding mechanisms of these arrhythmias. Now, all of these sort of focal arrhythmias, especially even channelopathies, ones that we cannot ablate in the end, an interesting regulatory therapy has worked for over 100 years. And in fact, if there are children with CPBT or long QT, ultimately, if a drug doesn't work, ICD is not the treatment for them. We actually cut the nerves going to the heart. So isn't that amazing? You're using a regulatory mechanism to control a problem in the heart. So file that away. The next part is structural heart disease. This is a nice segue to the exact presentation that Dr. Rousseau just made. And that is a phenomenal success story in the world of EP. We know that all of structural heart disease, a fundamental driver of arrhythmias is scar. And thanks to medical technology and industry, we can actually map scars incredibly well. Here's an example of an experimentally created infarct and a confocal image where these are lasers that generate high-res images. And you can see that this is normal myocardium, this area is scar. And within the scar, you see all these little strands of muscle that are alive. And those are the culprits. Those areas harbor abnormal zigzag conduction that causes arrhythmias. The joy of this is you can actually target that with catheters. There's a huge experimental literature to show that within the scars, you can pick up these little abnormal potentials, which are the circuits through which these electrical impulses propagate. The beauty of that is you can map that and control that. It's also important to remember that once you have a scar, depending on how the nerves and how the electrical impulses propagate in the heart, you get VTs. And Dr. Russo showed a nice example of how you can pace within the heart and recreate VT morphologies, which is shown over here. And sure enough, if you use catheters, electron atomic mapping systems, many of your companies here make this, we can get a 3D display, tag these points, find out what drives these circuits. And of course, hemodynamically stable VTs, we can terminate the VT. And even if a patient cannot tolerate a VT, we can go look at all the potential problematic areas and fix them. So finally, that component of how VT is managed has been well worked out. The entire field of mapping is a huge success story, which we should relish. And we now know, based on multi-center evidence, that catheter ablation of VT is lifesaving. Here is a multi-center effort that came from many centers in the world that do large volumes of VT ablation. And this is the first time we identified there's a 30% one-year mortality of drug refractory ventricular tachycardia. And you can sort of save these lives by actually performing VT ablation. And a repeat slide from Dr. Rousseau showing that several studies have also shown that there is mortality benefit for catheter ablation of VT. So having this information, I'll leave you with one last thought, and that is we're going beyond the heart. And going beyond the heart is important because this is kind of where cardiology, electrophysiology relates to cardiology and other fields. When the heart is injured, it sends signals to the brains and other parts of the nervous system, which is why heart failure progresses. And we now know that if we can interfere with this pathway, either by giving beta blockers, the drugs that are needed to block the ill effects of the heart sending signals to the brain, you can actually prevent arrhythmias and heart failure. And the same phenomenon in extreme cases, if nothing else works in the heart, you've tried VT ablation and nothing controls VT, you can actually go back to the same toolkit and use autonomic modulation to control arrhythmias. And in fact, in patients with VT storm acutely, you can do stellate ganglion block or thoracic epidural anesthesia. And of course, you can also surgically remove the stellate ganglion, which is the nerve that controls the heart. And that, of course, has increasing evidence over the past decade. Several centers now have fully established programs where we surgically cut out the nervous tissue that controls the heart. So these are the stellate ganglion tissues in humans. And we now know that if you can cut both stellates, you can get good outcomes. Not just stellates, you can also go to the renal arteries. Yesterday you saw the renal denervation study for AFib. Renal denervation, again, is a bailout method which works in patients who have refractory VTs. And in fact, it even works in a subset of patients in whom stellate ganglionectomy has failed. So this is data that just came out in HeartRhythm. And that leads me to the final word. And just a fun fact for all of you, only one-third of the heart is muscle. Two-thirds, the bulk of your heart cells are not muscle cells. It has all other cell types, including nerves, blood vessels, lymphatics. And it turns out that better on science. There's going to be a lot more interesting science that's going to come our way. We're going to get new treatments. And for sure, the myobed industry is going to have much better and interesting targets to go after. And I'm going to stop here. Thank you, colleagues. Thank the HeartRhythm Society of the Haines and the Bassman for this opportunity. Thank you so much. Thank you.

ventricular arrhythmias

medicine

abnormal impulse formation

abnormal impulse propagation

pathophysiology

catheter ablation