Phillip S. Cuculich, MD, of Washington University School of Medicine in St Louis, describes the noninvasive therapy used to map and treat arrhythmia that has potential to change the process for resolving heart rhythm problems.
Good morning to everyone and thank you for joining us this morning for cardiology. Grand rounds. Tryry to 1st September 2021 pleasure to be presenting dr Phil coe college uh this morning to prevent our to present a grand rounds. Um and special thanks to him waking up earlier probably 5:30 to give this uh grand rounds since he's one hour behind us in ST louis And it's currently six them over there. Dr Philip kuka, which is a clinical cardiac electrophysiology and associate professor of Madison and radiation oncology at washoe in ST louis. And in addition to coming up with new ways to treat rhythm disorders inside the body, DR cook a lick leads a team of investigators for pioneering and entirely non invasive way to target and treat abdominal heart rhythm. And this process focuses on focus radiation to treat abnormal scarred areas of the heart in a similar way to treating cancer. The first report of this collaborative work was published in the new England Journal of Medicine and results from the first prospective trial on the James Wilson Award, the best paper and clinical science in circulation In 2019. But the cookie, which is the cold director of the Center for Noninvasive cardiac radio ablation and is widely considered the world leader in the field of non invasive cardiologist. Now from a personal perspective, I think I was a trainee when this project started with Washington University in ST louis and feel, if I remember correctly, I think I was a clinic fellow. And this started so it's really been amazing to see and weakness, the genesis and evolution of this project which has, which culminated in this high impact paper In 2017 and now with intense and international recognition in the use of noninvasive radiation to treat malignant arrhythmias. This has led to development of both national and international consortium. So it's really been uh fulfilling to have dR quickly joined us this morning. So from the physicians and cardiologists at santa and the affiliate faculty members of the VMS. Thanks to DR Kubelik joining us this morning of which, your doctor Coca Leaf, thank you for that kind introduction after all Associates. Um, it's really, it's an honor. It's and I really, you know, coming from you. Having this invitation come from you means a lot to me. So thank you. Um, and it has always been great to work with you and I hope to continue to be able to work with you. So for those who have taken the time to be here, I hope this is a A fun 45 minutes for you. I hope it's both entertaining and informative because it's really outside the box. We're talking about treating VT with cardiac radio ablation and I put my partner's name. Cliff Robinson on the opening slide because this really has been truly a partnership in this cliff is the um, the radiation oncologist with whom I work and um, this doesn't get off the ground with his without his support. I just wanted to recognize him in this as well. Um, these are financial disclosures, much of the work that you're going to see here supported either by NIH grants or american heart association grants or uh, generous donors along the way. And we will discuss some off label use of linear accelerators that are outside their current intended use. I always like to try to start with something that captures your imagination. This is a picture that was actually drawn by Walt Disney back in 1954. So while soon talks about this idea that the genesis may have happened in our clinic Seven or eight years ago, really walt. Disney was thinking about this 50 years ago. So this was uh, an illustration from a book that was trying to demonstrate the positive power of nuclear energy coming at a time of Cold War. Fear of what nuclear energy was capable of from a destruction standpoint. But walt Disney partnered with a german physicist and created this book and then a series of television shows to really show the positive effects of radiation. And you know, here clearly is an example of radiation to the heart to treat VT right? So today in ST louis we treat VT in under seven minutes non invasively without catheters. We don't do it for everybody. But we're increasingly doing it for people who have treatment refractory VT. So let's kind of walk through how we got there. The top two killers of humans are heart disease and cancer. And I like to use this slide to poke fun at my oncology friends to say that we on the heart disease standpoint. The cardiologist on the green line Have done a lot in the last 20 years to really change the natural history of heart disease and in cancer. The blue line, you can see that that continues to escalate though. I think we take some cues from each other and I think importantly, with the advent of all of the great work that we're doing to open arteries early in heart attacks and get potent medicines on board that help restore or stabilised injury to the heart. In many ways we're turning heart disease into a chronic disease. People are living longer after their heart attacks. They're living better. And that has some implication for what we do as electro physiologist because as people no longer die acutely from their heart attack and no longer die semi acutely from their heart failure. We see them 10 years down the road with sustained monem or fic VT. So let's dive into this a little bit deeper. If you don't mind what we're talking about today is going to be ventricular tachycardia. So for the uninitiated on the call that usually is a scar in the heart and electricity moving through around through around that scar. And so that reentry circuit creates a heartbeat that's too fast to pump naturally and patients will die of sudden cardiac arrest Now an E. P. We don't have a whole lot of armamentarium here we have defibrillators that can help try to rescue patients if they do go into ventricular tachycardia. We have medications like amiodarone and we have invasive procedures such as catheter ablation and a catheter ablation is a procedure that we go in through veins and arteries, often in multiple places to try to identify where the scar is within the heart and then heat up the tip of the tissue or tip of the catheter to heat up the tissue and render that circuit no longer electrically active. These are the three options that we have. This is about it and increasingly were using catheter ablation and I want to point out this plot on the right. It's overall survival for catheter ablation. If you have VT and your overall survival really tracks with the other comorbidities that you bring to the table. For example, ejection fraction if you fail to prior catheter ablation and the type of cardiomyopathy. And based on that we can stratify patients as low risk medium risk and high risk. The low risk is in green. The medium risk is in yellow, the high risk is in red And this is the overall survival over the course of one year. And you can see in the best case scenario if you have a catheter ablation and you're considered a low risk patient, your one year survival tracks along the 85-90% range. But if you're a higher risk patient, your survival tracks closer to 50% at one year. And we've started to look closer at the patients that we get referred because our referral base tends to be even higher risk than what's published in the literature. So, for class for heart failure patients who have recurrent VT despite catheter ablation and despite medicines, The one years survival for these patients is closer to 25%. So it's quite a range between 90% and 25% 1 year survival. And I want to dive deeper into that slide here. Because if you look at this, The biggest changes in the slopes of these four lines happens in the 1st 90 days, doesn't it? That if you look at, if you look after 90 days, the slopes are relatively similar. But it's really the impact of the 1st 90 days that really changes the trajectory. And this overall survival curve looks awfully similar to this survival curve, which is non small cell lung cancer done by its TNM groups, the things that we learn about in medical school. And so there's some parallels here between VT and cancer that we're starting to see Now in those 1st 30 or 1st 90 days after a catheter ablation patients are very much at risk for mortality. That's because when we take an honest look at our procedural complication rates, it's in the 7-10% range of a procedural complication, doing Evita ablation. I would posit is the most complex of the procedures that we do in clinical ep In the in hospital mortality ranges from 3%. If you have relatively reasonable heart failure capacities to 41%. If you're a class for heart failure patients, let me say that again. If your class for heart failure patients, you have structural heart disease and you have record BTU undergo a VT ablation of a 41% in hospital mortality. That's not trivial. And I have to wonder if when we look at the curves here in the first one, first three months, if it's not so much the disease process, but maybe the treatment itself that may be contributing to this more rapid decline in people's survival. And that's because invasive VT ablation are tough on patients. takes us about 45 minutes in our lab to set up for the procedure, we insert 345 different ivs into the veins and the arteries. We insert catheters into a hard and we make a very detailed scar map. This is a picture of what a scar map might look like each of those white points points sampled from the tip of the catheter and then we assign a color based off of the size of the electricity of the side is the electra graham. That probably takes about half an hour to create a reasonable scar map. Purple is normal. Read his scar and then we induce the VT. And of course when we induce the VT many times, patients don't seem to tolerate that from a human dynamic standpoint. And so this induction of VT can be a bit of an insult for a patient's thermodynamic system. Now, if the VT is tolerated, we can maneuver are catheters around and we can look at the timing of the electra grams and really try to find where the electricity is moving through and around a scar. So it goes red, orange, yellow, green, blue back to purple. And it's this reentry circuit around and around. That gives us a clue where we may want to put our catheter to identify that corridor of electric signals. And we look for that diastolic isthmus and then we do some pacing maneuvers to confirm that that's indeed the important part of the circuit. And then we heat up the tip of our catheter and we get an immediate but limited effect. I say, limited because the tip of the catheter is only 3.5 millimeters big. And we know that the thickness of the heart can be 12, 15, 18 mm thick. The depth of our heat really is only on the order of about five, sometimes six deep. So it's a relatively small tool to do a full thickness ablation. Now, if we're successful in obtaining the first VT, we redo this whole process again to look for more circuits and oftentimes we find a second and a 3rd and 1/4 circuit. And so by the time you add up all of the time that it takes to go through an invasive catheter ablation, it adds up to about a five to sometimes eight hour procedure. Remember we're doing this on patients with severely reduced ejection fractions, advanced cardiomyopathy. Oftentimes with general anesthesia. So this can be particularly difficult on patients and this is why the 30 day survival for this is only 95% 5% of patients who undergo a catheter ablation for VT die in the first month. And I showed you this map, which is a beautiful voltage map. But increasingly we see these sorts of maps as well. This is a pretty incomplete type of a map. This is a patient who was referred for a redo catheter ablation. We looked at their map and you can see big areas where the operators don't sample with a cat because to do this procedure requires a fair bit of dexterity and and the reproducibility of this procedure is therefore limited to the skill of the operator. That is, if the operator can find and maneuver the catheter to all of the different points in between. Perhaps we'd have a better map here and perhaps we'd have a better outcome. I told you that the tip of our catheter is a bit limited, shown here on this image is a beautiful shot. This is the green shaft of the catheter, you can see the silver tip of the catheter buried in a tissue and this tissue runs left to right on the screen with a ruler. We're heating up the tip of that catheter and you can see the oblate of thermal effect around it in a kind of a tan color. And that's the actual heating and the desiccation of the tissues. But if you look most of the tissue is still red because the thermal energy that we apply here is limited in terms of how deep it could send the heat and therefore how deep of an ablation that can be performed. And so there are limits biophysical properties of heat transfer which will limit our ability to give deeper catheter ablation. And this has been investigated more recently that when we do all of our catheter ablation studies, we tend to do it in animal preps. We tend to do it in healthy tissue. And when you have healthy tissue and you heat up the tip of the catheter, it creates a very beautiful looking lesion, a beautiful looking ablation region. But the fact of the matter is shotgun and I put our catheters into scarred tissue with collagen and fat, not homogeneous muscle and when we try to oblate in that type of a tissue, those other cell types, the fibrosis, the adipose tissue act as insulators. And so therefore when you oblate and scarred myocardial um the resistive itty, the tissues are different And so therefore the tissue injury. The heat transfer is greatly reduced. This curious, really important weight in our field because if we're a blading in scar and we can't create heat in scar, What are we really doing? This is an autopsy taken from a patient who has a scar. You can see it here. If we zoom in closer, you can see the the epic cardio surface here at the end of cardio surface here, you can see some of the tan and white scar. And one can imagine a electrical circuit that might move around and through this mid myocardial scar. Now look at these tan circles. If you look at these tan circles here where I put the red dots, that's where we did our catheter ablation. And you can see that those catheter ablation is don't reach the depths of where that scar is. Because what we really want to be doing is we really want to be applying energy full thickness to render that tissue electrically inert but structurally intact. And this is really the basis for what we're going to talk about here with non invasive radio ablation. Because if we really want to be honest and we really want to build a better mousetrap here. If we want to start from the ground floor and say, what is a better patient experience? I want to make VT ablation safer? I want to make VT abrasions more comprehensive and totally non invasive. So what if we didn't need the catheters. And so I'm going to show you some data that says perhaps we don't need catheters to find out where VT is. And then I'm going to show you our workflow that says, we don't need catheters to treat the VT. This is a tough picture. Usually if we're in a group, I might say, does anybody recognize this? Difficult to recognize what this is? But this is a picture from the Hubble Space Telescope back in 1994. Now. Fast forward 15 years or so. And this is what that same pick Sure looks like. And if you fast forward even just five more years, this is what that same picture looks like. I'm showing this to you because I believe in cardiac imaging And you can see planetary imaging changing just as quickly as cardiac imaging. Over the course of 20 years, we went from that pixelated picture on the left to a very high detailed picture on the right and the same sort of renaissance is going on right now in cardiac imaging that we have some spectacular tools to help identify where the scar is. Because if I can identify where the scar is, I have a head start to figure out where the VT is coming from. This is a picture from one of our ultrasounds, the intra cardiac ultrasound? You can see the heart is moving through here. But look at the white stripe of scar associated with that, a kinetic segment of the heart. So we can see without even putting catheters in without having to create this three dimensional map. We can see where the scar is. We can see where that white stripe is increasingly. We're leaning on CT and MRI. And when you really start looking at some of the high resolution CT shown here, we can start to color code based off the thickness and thinness of the tissue and so the the variations between the thick and the thin tissue provide ideas where the corridors are moving through the scar. So here we're looking at the variations in topography of the scar. To give us an idea where the tissue might be able to conduct electricity better. And this is being validated in several centers across both europe and the US. And with a single picture using contrast ct we're starting to get an idea where within the scar, the electrical signals may be more important. This has also been shown in MRI. So this is a short axis or a stack of short axis and looked at in cereal sort of radial screens. So from 100% down to a 10% radius. And on the left is a reconstruction, looking where the scar is in red And as we move towards the inside, we can start to see where there may be some corridors through that scar. This is through an MRI. And you can really see that we're able to dissect out some of these corridors again without having to put catheters in. This is with contrast enhanced MRI No, We also need to be thinking about this in electrical way and I would say don't throw out the century of data that we have from 12 VDCGS. We keep looking at 12 VdC Gs at VT. To get a great idea where the exit site may be coming from. That is where the VT is starting from. And so we can lean on a wealth of information that's been published again over the course of last century to give us an idea of where in the heart. VT may be coming from simply based off of a smart analysis of a 12 lead EKG and this is the cardio cardio insight system. This is a noninvasive mapping system that we were part of the development here at Washington University is now commercially available and a patient wears a vest of electrodes so on the chest and on the back to take a panoramic picture of the heart and in a single beat, we can reconstruct the electrical potentials from the body surface down to the surface of the heart. Here's just a still snapshot of VT in one of my patients and you can see red, orange, yellow, green, blue. You can see where the VT may be coming from. In this case we're looking behind the patient, The mitral valve is here. The troika spit valve is here and the atria are removed and we can see the earliest activation from the basil septum between the left ventricle and the right ventricle. What we would call the crux, the inferior crux of the heart. This is a difficult spot for us to be able to get catheters in heat into this tissue and this patient had failed several catheter ablation and I can understand why. Once I see this location, but with a single bit of VT wearing this vest, we can reconstruct this image. And so we have the tools to be able to see scar and we have the tools to be able to see the electrical circuits of VT. So how do we put it all together? Here's a patient who had a beautiful MRI, you can see the scar here along the lateral mitral angelus that's from, I'm going to say two o'clock to four o'clock and the basil metro Angelus. We induce the VT. And this is a picture of the cardio insight, noninvasive mapping system and you can see red, orange, yellow and then it comes back into this lateral mitral analyst. This is a similar picture where we've removed the atrial. We're looking from the back of the patient. This is the mitral valve and so we can see that, oh we can't even show, I'm going to show you a video of this. This is the mitral valve. This is the lateral edge of the mitral valve. This is inferior. This is over towards the septum. We're going to see three beats of VT in real time here. So this is ventricular tachycardia. Starting from that lateral mitral annulus sweeping around back into that scar. And now you'll see during diastolic we'll start to see some activation through that scar and ouch underneath the mitral ambulance. This pattern repeats through all of those beats of VT. So with two pictures with the MRI to find the scar, with the non invasive map to see where the VT is coming from, we already have an idea where this VT circuit is. This could help me tremendously if I want to put a catheter into that spot again, I'd have to put it on both the inside and the outside. Or let's think about doing non invasive treatment. So I'm going to introduce this concept of stereotype Actiq oblate of radiotherapy or stereotype Actiq body radiotherapy. These are saber or SB artie This is something that's done in the basement of many hospitals. It's a standard workflow and has really revolutionized the way that oncologists can treat patients with us. The picture I'm showing on the left is a patient with a lung tumor and the CT scan identifies this color density. This color density is the differences of radiation doses described in gray and the patient lays on a table and you see these yellow sweeping arcs around the patient. The gantry moves around the patient in these sweeping arcs and delivers thousands of little beam litz of energy. Each of these beam lets itself is relatively harmless. But where they come together, where they coalesce deposits higher doses and sometimes very high doses of energy. And that high doses of that photon energy will create a blade of effects on tissue. And so this, as I mentioned, has revolutionized the way we treat lung tumors. So this is a lung tumor that's being targeted and this is the the target volume, the planning target volume. The PTV is shown here with that red circle and the colour coding where it goes from red to green to blue is the rapid fall off of the energy to the surrounding structures. So one of the beauties of this is that you treat the entire tumor with a blade of energy and then there's a rapid fall off to the surrounding healthy tissue. Friends, this is exactly what we want to do in the heart. So here is an example of that patient with the lateral mitral isthmus, VT. And we asked the radiation oncologist instead of treating the tumor on the left to simply treat the lateral mitral isthmus shown here and again, you can see the red circle is the oblate of energy and the rapid fall off to the healthy tissue around it. So we can be full thickness. We can be gap free and we can do this all in a non invasive way. So show me the data. If you're if you're thinking about this, you probably I hope you're approaching this in a skeptical way because we've learned from decades of treating whole chest for patients with Hodgkin disease. That may be high doses of radiation would be bad for the heart. And I think that's true. I think we've all seen patients who have had advanced valvular disease, advanced pericardial calcifications. We know that radiation to the chest can't be a good thing for survivors 2025 30 years down the road, but we know far less about focused radiation to just a portion of the heart, particularly if it's a portion of already diseased and scarred heart. Let me show you some data about dose finding and the preclinical studies where different doses were given to the cabo trick hospital isthmus of a pig. You could see that at doses of 25 grey and above. We started to see more and more fibrosis that was being induced. So there's a dose dependent response to that radiation. Now, the first in man was done at Stanford University in 2013. It was a patient who could not tolerate another VP ablation, had an inferior in far and they tolerated the inferior wall and you can see the months from treatment before and after. And so there was certainly a fair bit of VT episodes before the procedure with a reduction though not cure for about 6 to 7 months and then some recurrences at eight or nine. This patient ended up dying of cardiac cardiac and pulmonary diseases and did not have more WVT storm. But this first inhuman gave us, you know, some ideas of what we might expect. And so when we looked this is really beautiful data that came out last year from the mayo group about what the time frame is for radiation. You can see a cross section of the heart. This was an induced infarct here and this is the beam delivered to 30 grey next to the infarct. And when you look at it an MRI, you can see the infarct that was created and you can see this full thickness Ablation that occurred at that 30 grey using in this case using protons. Now the timing of this, they did the treatment and they followed the animals with serial MRI. And it's difficult to see, but this is four weeks, eight weeks, 12 weeks, 16 weeks. And this is the volume of scar. And the conclusion here is that The oblate of effect of radiation didn't show up on MRI until about eight weeks after treatment. And it seemed to stay over the course of 32 weeks. So it's a durable ablation. Um but it doesn't show up till about eight weeks. And and that might have some implication for us treating patients. I can't quite wait eight weeks and somebody who has V. T. Storm. So I'm just gonna take a second and pause to say we've got a portion of this procedure. If we're going to try to put everything together there's a portion that the cardiologist does. Which is we have to think about where in the heart of ET is coming from. And then there's the treatment part that's the part that the radiation oncologist does and that's the actual delivery of energy. And this this requires a partnership between E. P. And radiation oncology. And so when we think about our workflow the patient selection, the mapping the determination of potential VT circuits is done by the heart rhythm doctor and the treatment. The segmentation, the planning and the delivery is done by the radiation oncologist. And this is a shared responsibility. The closer this partnership is the better this works and I think the safer it is for patients now that workflow I'm not going to go into too much detail but it's very similar in terms of motion management strategies and targeting and segmentation to what the standard workflow is for lung spr T. So this is not a deviation in their workflow in just about any way. Um This is Cliff Robbins that I mentioned him on the opening slide. He's the radiation oncologist with whom I work. Cliff and I got together in 2013 to talk through this possibility. And we treated our first patients in 2015. Um This is our first public the first poster. So you can see the late efficacy and toxicity after eP guided noninvasive cardiac radio ablation. We submitted this to Astro, the American Society of Radiation Oncology and we thought for sure this was going to get a talk right. We were bold and brave and this was really some important work and we did not get a talk. We got a poster session. Okay. We got a poster, we were pretty proud of that. And we found out that the poster session was in the non oncology section of posters which they have different sections the lung tumors, the breast tumors, the brain tumors. The non oncology section is perhaps the least popular space at a radiation oncology meeting. In fact, if you look at the era, we are sitting next to a poster for Herpes disaster on the buttocks. I'll blow that up over a cliff shoulder there. So that's that's what Astro thought of our work. And yet we were still laughing and smiling because we knew that what we had was working for our patients. And in fact, two months later, we had our new England Journal paper published, this was five patients who had recurrent VT. All of them had been imaged for scar. All of them have been imaged non invasively to figure out where the VT was coming from. We delivered 25 gray in a single treatment Over a mean time of 14 minutes. This graph shows each of those five patients the monthly burden of VT. So the number of times that the OECD had to be called in to rescue whether that was shocks or pacing events to get the patient out of the T. This is before treatment. And then this is what happened to those patients after treatment. We were pretty aggressive in trying to reduce the anti arrhythmic medicines. I wanted to see if this effect was because of the anti arrhythmic medicines or because of the treatment. And in fact it seems to be due to the treatment importantly, one patient had a stroke about a month after treatment, she had a chance to vast score of seven, which is extremely high for risk of stroke. She had atrial fibrillation. She couldn't take blood thinners because she had a prior brain bleed. She was kind enough to give us her heart when she ultimately died after the stroke. And we looked and we did not see any empathy, illegal disruption or any reason to think that there was clotting in the heart after treatment. Nonetheless, you know, this I think has made us want to give blood thinners after radiation for at least a month just to try to prevent that sort of complication if it was radiation related. But the remaining for patients continued out survived a year and had very little VT. So we empowered by this. We went on to create a phase one, Phase two clinical trial. We said, let's do this in a prospective way and we thought this was going to take us about 3.5 years to enroll. It took us just over one year to enroll. There's a lot of patients with Refractory VT out there. The patients that were brought into this study had Monem or Fic VT or they had a lot of PVcs that were causing a cardiomyopathy. They had to at least tried one anti arrhythmic medicine and had at least one catheter ablation and they had to have a fair bit of VT of your PVCS. When you looked at the adverse events, we declared what the serious adverse events were going to be at 90 days. And we set our efficacy was going to be any reduction in VT burden looking the six months before and after treatment And on balance, we needed 19 patients to achieve those endpoints. When you looked at our patient population, the range was from 49 to 81 years, most were men, most were white, Half were ischemic and the median ejection fraction was 25 Most of the patients, 53% of these patients came into this with VT storm and most of the patients were class three heart failure. In fact, three quarters of the patients were class 34 heart failure. So that's a pretty sick group. We induced anywhere from 1 to 5 Vts in our patients And the treatment, the actual treatment size that I wanted to target was 25 ccs. So a golf ball is about 45-50 CCS. If that gives you an idea of what the target is that I wanted to target. So just underneath the size of a golf ball was my ablation volume. By the time you expand that volume to account for motion to account for uncertainties and set up, the average size was now the size of two golf balls. So it's a pretty sizable ablation volume when it came down to the actual treatment. But what became very obvious to me was after patients get treated, they get up, they walk out. So if you look on the left is one of our patients who had his cardiac radio ablation. That's it. There's nothing inside him. He's going to get up, he's going to go home. Uh He goes and has lunch on the right is one of our patients who had conventional ablation. So afterwards he's still intubated. He still has central lines. When you look at the safety end points in the 1st 90 days, we had one patient who had pericarditis at eight day 80 and that resolved with predniSONE. So, we had one toxicity that was likely related to radiation in the 1st 90 days. This is the follow up out to pass two. We're at two years now. In terms of our patients, If you look beyond 90 days, we've had three patients that have had severe toxicities that could be related to radiation or are related to radiation. Two patients had pericardial effusions. 2.5 years. Ouch. I tapped both of those. Sorry, jumped ahead there. I tapped both of those. Yeah. There we go. And they were benign effusions. We managed both of those with culture scene. This is a known sort of complication from thoracic radiation particularly reported in left sided breast radiation. So pericardial effusions are something that we are looking out for and I think is easily treated with culture scene. We did have one patient who had a gastro pericardial fist do officially 2.5 years after treatment. And I do think that's from something that we did. This is a picture of where we treated. This patient had a very large a pickle aneurysm and you can see the treatment volume was pretty large and it ran down towards the stomach underneath. And that is the picture inter operatively. This patient showed up with um Apologies station showed up with abdominal pain and we took him to the operating room same day after a cT scan demonstrated a connection here between the stomach and the pericardium. This was repaired. The patients spent two days in the hospital and recovery and went home and it gave us an important thought about how we might target and changed the way that we treat some of these inferior in a pickle types of treatments. So subsequently we've changed the organs at risk priorities. Prioritize protection of the stomach and the esophagus because of this. And we have not seen any complications in a similar way. If you look at our survival from quite sick patients, remember most of our patients were class 34 heart failure at six months, 90% of patients were alive at 12 months. About 74% of our patients were alive. When we look at the modes of death on our patients, it tended to be heart failure, although three patients had non cardiac path when we looked at our ejection fractions over the course of time, there was not a significant change however, and what most people want to know is, does it work? So on the left is a bar graph of the six months before treatment. And on the right is the bar graph of the six months after treatment. So each patient went from having a lot of VT too much less VT. And you can see we did not cure the patients, but 94% of patients had less VT. Now we followed this out over the course of time. So the first six months, the next six months, the next six months. So shown in blue here is the median VT episodes in the population who makes those six months. And you can see that VT remains suppressed over the course of time though. Again, not a cure for everybody. We're not seeing those same high levels VT as we did before the treatments and I showed you the overall survival from the first year, but now we've taken it out to three year survival. The I think importantly, we've been doing this while we're reducing doses of anti arrhythmic six in particular, high doses of amiodarone. So we've been able to really drop down, particularly the high doses of Ambrogio deron for our patients. It's interesting we try to get patients off of anti arrhythmic entirely, but when they have three or six months of not getting shocked, they don't want to change anything. They're so happy with the way things are. And they say, why do I want to rock the boat with the reduction in VT. We've seen quality of life improved in a number of modules at the six week and six month time point in particular. And so the SF 36 modules are the things that we use it. It looks at some of the social health, some of the mental health and some of the physical well being of patients. And interestingly, the five modules that improved were largely in the social and mental aspects, but not necessarily in the physical and that makes sense, patients are getting shocked. So, they are more confidence in going out there more comfortable in social situations, but it doesn't fix their heart failure. They remain limited in terms of what they can do physically. So, I think that the SF 36 modules really mirrored what we were seeing in clinic I was very worried that focused radiation was going to cause the ejection fraction to go down and friends that just simply isn't the case. This is our cohort pre treatment three days, three months and longer term. And you can see largely the ejection fraction remains unchanged from those time points. So I think this is really important from my standpoint to feel comfortable moving forward with this. And to summarise our longer term follow up as we push out to four years with our longest survivors. We've not seen any damage to coronary arteries yet. We've not seen any damage to frantic nerve. We've not seen any heart block even with ablation at the proximal septum. We still haven't seen heart block. I told you about the to late cases of pericardial effusion in the gastro pericardial fistula and almost everybody seems to enjoy a substantial reduction though not a cure in VT. And certainly we've seen deaths and that's mostly due to heart failure but without changes in ejection fraction. So this I think uh to me this is the most important clinical study I've ever been involved in. We had rigorous and complete follow up on our patients the I. C. D. S where the recorded events. So there really was great collection of data and you know unfortunately it's a smaller sample size, right where this was the first go around. And so it's the 19 patients that I'm going to report. And I think for me the biggest limitation is that um, it's difficult to know and patients who bring a lot of comorbidities how much the radiation could be contributing to changes in heart function. And you won't know that until you do a clinical study randomized clinical trial against other therapies, really understand the impact of radiation alone on these quite sick patients. So, we've built out a center for noninvasive cardiac radio ablation and that's included a large group of people shown here. We've reached out to our radiation oncology. Friends are radiologists, are cellular biologists, are software developers. It's been quite a large group that we're building out at this point, because what we're really trying to do is we're really trying to understand the role of cardiac radio ablation within the right patient population. What's the biology of the radiation? What's the right patient for this? What's the right time course? What's the right imaging that we should be looking at? And I think this provides a reasonable place for us to stop. I have more slides that I could share. But I think this is a good opportunity for us at least take some questions and have some discussions before we wrap up here for the morning sugar. And if you wanna uh sort of moderate those questions for me. Sure, thank you. Doctor Kubelik, fascinating, brilliant. Um, really appreciate the lecture and just how you've pushed the boundaries of what we're doing clinical cardiac electrophysiology, really appreciate it. Pretty succinct lecture. I have a question here from dr uh Hill gentlest. You may remember him, You met him at VT symposium About three years ago. Yeah. Good morning. Great, great name. By the way, I really appreciate your time this morning and Sharon, what's really uh clearly ground breaking work and something that, you know, we've been, many of us have been tracking for a while, not only in this but in other arenas as well. And looking at animal modeling and um, you know, for for Rachel arrhythmias and hear what you've done with, particularly with me. It's hard not to imagine this as being the really the future where we're going to head, as you mentioned in terms of advancement in imaging computer powering and being able to really sort of find you where we are and your picture of the patient, you know, walking in and out speaks volumes as to why that would be, certainly from a patient selection, um our patient preference, but I guess where we are right now, one of the things I know she june and are incredibly interested in how reproducible is this, you have a, you know, and it's taking time, but you've developed a tremendous team there in ST louis, you know, how do we hear in the Hampton roads area. How how do we reproduce this? You know? And obviously first steps are getting in, getting engagement with our radiation oncologists and and working through um, you know, imaging and so forth. But is it reproducible is you know that I guess what I'm curious about. I think that's an awesome question. Thank you for that. If you come to, if you come to ST louis and if you're unfortunate enough to have a VT, you know, some cardiac arrest and have VT, you'll go to five different hospitals and you'll get five different VT ablation with catheters, right? Yeah. Um what we do with catheter ablation is highly not reproducible. Um, the fact that we can really take this process and and turn it into something that is reproducible and really be able to share methods and learn the same methods I think is critical to this moving forward. So very astute observation. I put my slides back on because I think this might help answer this um in this center that we've put together, we call it conquer center for noninvasive cardiac radio ablation. There's different arms, there's the biology arm, the clinical arm. And in particular the population arm. Because I think this is where the reproducibility can happen. And I'll show you we hold uh symposium for for non invasive radio ablation that we called snow rad. We thought we'd get 50 people to show up and you know, we got close to 100 and 50 people show up. So there is certainly a global interest in this? And when centers like yours are interested to get started in this, we just open up dialogue and we actually have a process by which we can give you the information that we've learned. And importantly, so you don't make the same mistakes we made right and be able to do this in a similar reproducible sort of way. So what we do is we open up a shared box folder, we give you a set of resources for imaging tools for a radio biology workflows uh for you know, sort of almost a it's not a how to pamphlet but it pretty much is similar to that. And with this we've been able to reach out to or other centers have reached out to us and we've been able to help now 57 centers across the globe get started with their programs. And so I'm really hopeful that if you have an interest in this, all you have to do is get your get an E. P. Champion which sounds like you have several, get a radiation oncology champion and and then reach out to us. The conquer website is a great place to start. We open up a dialogue. We open up that shared box folder. Um And it's done in a consistent way. The last thing I'm going to point to you is we do it in a 17 segment model. So it really doesn't matter what your imaging tools are Um whatever you're good at whatever data you have can be used through the 17 segment model. So, for example, you know, some centers are fantastic at Cardiac MRI and others are not. Some are fantastic at nuclear medicine and others are not. Some have really terrific cardiac cT programs. Others do not so work with your strengths. And so this is an example from Tokyo University, one of our early collaborators, they have this beautiful MRI. You can see the beautiful CT scan, you can see the calcification that the big typical aneurysm here on the left. A couple of different Vts that were induced. We analyze those VTS and said the exit sites are coming from these segments. The scar is in these segments. And when we put it all together we can create a target probability a heat map. So Phil we can actually say um I want to oblate segment seven and segment 13 And we can make segments seven and 13 show up on that CT Scan and the radiation all colleges can use that as a target and build their plan around it. And so highly reproducible when we're not trying to mesh mapping systems or mesh imaging systems. When you and I can simply have a conversation and say, I think this is coming from segment seven and 13 and we can show where that is on that patient cT scan. We can deliver a target to the radiation oncologist. And so I think this really democratizes our idea of VT ablation is tremendous. Thank you have a no line question here. The question is, how does ablation volume differ from our f ablation? How those cardiac volume on average? How much cardiac volume on average are we treating during our trip ablation versus excellent question, yep, excellent questions. So, in our clinical trial, I showed you that I'm generally targeting about 40 CCs or one golf ball worth of volume And by the time you set, take setup uncertainties into account your up to about two golf balls of volume, so about 90 ccs of volume. Um, and how does that compare to catheter ablation? Well, that completely depends because catheter ablation is done in such a unregulated way. Some operators might go in and do three or 4 abrasions and each of those abrasions might give you a volume of uh somewhere in the order of 7 to 12 CCs of ablation volume. And some might just do a couple little spot shots of that and others. Um, as you know, uh shotgun, you know, the idea of a blading the entire scar of homogenizing all things that are scar related means that we're doing 80 or 90 or 100 catheter ablation lesions in the scar and around the scar. And I don't know how much that actually creates because if it's in scar, I don't know how much actual tissue is being heated up because of the scar characteristics. So, it's completely unknown when we do our catheters, how much or how little we're actually destroying or treating in this case with radiation. We know exactly what we're targeting. We know exactly the volume. So I hope that I hope that answers the question. Yeah. Thanks. Still have a question for you. Has you know many centers or any study have looked at using radiation ablation in the atrium for atrial arrhythmias or S. E. T. I know it's dealing with a different uh tissue characteristics here in terms of thickness and whatnot. But you know if there's any any data or any studies looking at that, I'll have to look at that. Yeah. Great question should go And obviously that sort of feels like the Holy grail. Right? That's what um There's far more atrial fibrillation in the world than ventricular tachycardia. So the answer is yes. Uh It's been looked at in animal models. And in fact 25 grey starts to create fibrosis around the pulmonary veins and create isolation. It probably requires more like 35 grey to really get a more consistent isolation of the pulmonary vein. So yes it can be done in animals. Yes. It has been done in humans. So there's two patients that were reported in Mexico who got treated with radiation. I think it was in a cyber heart unit. Um And um one of those patients um continue. I think both patients continue to have a fib there's really very little data that's um published about those two patients. There was a small trial in Japan of patients who had terminal cancer and also had atrial fibrillation and they treated those patients for a fib and wanted to see if they went away. Yeah so nothing that's been rigorous and scientific but a couple kind of small case series that we don't have really great data to follow up. Good. I'm just going to say this. I think we know we know that radiation can be harmful to the heart. Let's not overlook that. And we have we have decades of cancer survivors who have shown us that. So I take this very seriously. I don't think it's trivial. And atrial fibrillation is not a life threatening disease right now right so I don't want to take the risks. The unknown risks of radiation to the atrium for a disease that is not life threatening. Um When we have our conversations with patients who have V. T. You know a 75 year old guy with an E. F. Of 10% who's been through two catheter ablation and he's getting shocked every week. And we have a conversation. Well I don't know if radiation is going to hurt you. It might cause Um you know scarring in your heart. It might cause your valves to not work 15 years from now. And these patients look at you like you have two heads. They say well look I'm getting shocked now. I'm dying right now. I'll be happy for you to do a tavern 15 years and get me through this but I'm struggling right now. And that same calculus just doesn't apply to atrial fibrillation right now right? It's not life threatening. It's it's a procedure that we have new newer tools to try to treat it and I just don't think the risk is worth it yet. Give us 10 years, 15 years to really figure out what the best doses and how to do it as precisely as possible. And then we can start to take a look at that. But to me the risk doesn't seem worth the reward in that patient population. Thank you. Sounds like that makes sense. Most common radiation in the atrium. Have a question for one of my advanced heart failure partners. Doctor Battier's who I was curious to know if regulation has been used to treat V. T. And L. That patient. I really think either last year or so. I may have reached out to you about a patient we had here who had Elvin and you said it may have been uh maybe one or two folks who talked for you. You reach out together from um I believe he was either Connecticut or colorado. But what was the experience like with radiation ablation in elderly patients, yep. So the short answer is yes it can be done and yes it has been done. Um There's the nice part is the radiation doesn't um uh You don't have to worry about, you know the full thickness ablation with radiation? I think with with catheters. It's obviously difficult to kind of, you can't get up a car deal anymore after an L. VAD at least it's very difficult to. So the nice part is you can you really not limited by the anatomy so it can be done I'd say the hardest part ends up being some of the imaging just because L VAD artifact can make things a little bit more difficult. So from a radiation oncology planning standpoint, um there's a lot that goes into planning based off of the C. T. Scans that are done and the type of tissue. So the artifact itself can interfere with some of the planning. But she soon has been done now that we know what we've participated in a couple. Um I know of a few more. So at least four patients with L. VADs have been treated. And then the emery group published their advance. Their results from their pretty advanced heart failure patients. I was in heart rhythm and I think that group had an additional three or four patients who had L've answers or mechanical support. Who can be done. I have one question. So every one of the challenges you face when in terms of delivering radiation was cardiac gating. I think back then is able to target the tissue displacement of the specific tissue you're targeting? You have to do a respirator gating. What's the status of that? Are we still working with primarily restaurant gating? Or there's been some improvement in trying to do cardiac gating. Yeah. Great question. Um, the pope is slide that kind of I think demonstrates that if the radiation oncology folks are on, they have motion management strategies that they've been doing for moving targets like lung tumors all the time. Um, the one we do is the one on the left, which is when we take the pictures of the heart for treatment that's called a simulation cT scan. We do it in a free breathing for D way that is. We take pictures of the heart as its insistently and diastolic. We we take pictures of the heart as the patient is free breathing, so full inspiration, full exhalation. So I know the entire motion envelope of the heart. I know where it's going to be insistently diastolic, breathing in breathing out. And so when we choose to target a part of the heart will create that target and then we'll account for the breathing and the cardiac motion. So again, there is no getting in the way that we do it. We treat the entire motion envelope knowing that at any point in time the heart tissue that we want will be subjected to the radiation dose that we wanted to. And the value there is that we don't have to gate, which takes time. And for heart failure patients to lay flat, time is valuable. Right? So the longer a patient lays flat particularly if they're short winded they're going to start fidgeting. They're going to start breathing differently and the target will no longer be where you want to be or where you expect it to be. So we do this it's called the I. T. V. So we don't actually gauge we don't wait for a respiration to target just at the top of motion and then not treat through the rest of the motion. So I hope that that kind of makes sense. We we actually don't want to get we actually treat the entire motion envelope. Yeah that makes sense. So dr cooking time is about up uh really appreciate you joining us this morning and it's Levine um and like me to see how much work has evolved to this point and how much the work continues to go on uh from our uh park here we're really interested in looking into this. And obviously we're reaching out to you again. Thank you again for joining us this morning. Um And thanks everyone for calling me and appreciate it. Have a good day. Thanks again quickly
