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EP Fellows Curriculum: Cardiac Ablation Without Ca ...
EP Fellows Curriculum: Cardiac Ablation Without Ca ...
EP Fellows Curriculum: Cardiac Ablation Without Catheters
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Great. Thank you, Nishan. Thank you very much for this opportunity and Brad and Will and everybody for putting this together. This is really a tremendous venue to be able to share. So, thank you so much. I really appreciate it. I want to at least start with disclosures shown here. Importantly, we're going to talk about some off-label use of linear accelerators. This is outside their current indicated use in the FDA. I like to start with the thank yous, because the team is becoming quite large and there's a lot of different people to say thank you. So, in particular, I just want to acknowledge Cliff Robinson, who is my partner in radiation oncology here, who had the courage to move forward with this idea. There's a number of people in the Center for Noninvasive Cardiac Radioablation shown here with asterisks who are playing really important roles and are changing the way that we think about radioablation. And then funders on the bottom, which I think are always important. We've had some generous donors and we've worked hard to get AHA and NIH money to help support this as well. So, in the next 45 minutes, I want to talk about these five questions. Why would we want to ablate without catheters? How is it done? For whom is this most appropriate? Is it safe and does it work? And then, what's next? I really want to focus on sort of new horizons. What's coming down the pipeline here and how can we do this better? So, let's start with the why. You know, why do we want to do these things? When I was a chief resident in medicine at Northwestern, the program director, the then program director, Diane Wayne, would frequently say, if you're not moving forward, you're falling behind. In this case, I think we need to think about how we can push the field forward. And it turns out that you can look backwards. This is a piece of art that was in a book from the late 1950s, illustrated by Walt Disney. And this is from the book called The Atom, Our Friend. This was in the time of World War II and Cold War and concerns about what the nuclear bomb, the atomic bomb, could do. And this was really a picture in a series of pictures in a book and then a television show that really tried to show the beneficial powers of radiation. And you can see that Walt Disney, in 1956, clearly thought about non-invasive VT ablation. Here's a picture of somebody sitting there comfortably with a beam of radiation going into his heart, clearly fixing his VT. And so, if I want to try to capture your imagination and capture your interest here, I'll tell you that here in St. Louis, we ablate VT non-invasively in under seven minutes. And so, that's what this is going to be about. We're not just doing this to be different. We're doing this to solve problems. Because if we really want to take an honest assessment of where we sit with current catheter ablation for VT, I do the procedure regularly. I enjoy it when it goes well. It's super satisfying when it goes well. And I think it's highly effective for patients when it goes well. But you'll notice that I'm always throwing the caveat when it goes well. Because catheter ablation, if we're going to be honest, is risky for patients. And I'm super proud of our field for looking at, the IVTCC has looked at, the early incidence of death after VT ablation for patients with structural heart disease. And I think this is really staggering to see that the cumulative mortality from days from the procedure gets up to 5%. And that line looks like it's continuing to go. And I'm kind of surprised that most of the death isn't in the first day or two, that this is actually a continuum of mortality. That is, and I think if you've seen enough patients with structural heart disease undergoing VT catheter ablation, you realize this, we can limp people along for days, weeks, but maybe they just never leave the hospital after their procedure. And we have to think, why is that? Why is it that people continue to be at risk? Some of that is the disease that they bring along with them, the comorbid conditions. Some of it may be what we actually do to them during the procedure. I'm also going to say that VT ablation is not as effective as I want it to be. I'm going to show this, and this is from a prominent German group. These are the one-year VT freedom numbers for ischemic and non-ischemic. And you will recoil and say, my center does better than this. Somehow everybody's center seems to do better than this for ischemic cardiomyopathies. But the fact of the matter is, when you do look at real-world data for all the centers, not just the high-end referral centers, to have a 57% one-year freedom from ischemic cardiomyopathy VT is a reasonable number. And particularly for some of our more advanced non-ischemic, to see a 40% success rate is common from the centers that we're interacting with. And catheter ablation for VT is quite challenging. This is Will. Will, you look very handsome. He enjoys doing catheter ablations. He's skilled. He's smart. Here's a picture of him doing a VT ablation in the Brigham lab, and really just a tremendous job that he and his team do. And here they are working on VT1. And then soon after this, he'll be working on VT4. And later in the afternoon, he'll be working on VT7. And with each subsequent VT that they induce, you know that that's an additional half an hour to 60 minutes of mapping and an additional maybe 15, 20 minutes of burning. And this is what Will looks like. Paul sent me this picture. This is what Will looks like after VT7. And he's walking home. He used to be a really tall guy, but you can see that after wearing lead for that long and after being beaten down, this is kind of what he looks like coming home. So not only is VT ablation hard for patients, it's difficult for us to perform well. And perhaps most importantly, VT ablation is not reproducible. The results, the execution of the procedure is different in each hospital. And it shouldn't be. We should be doing things as similarly as possible. But if you have VT in St. Louis, you go to six different hospitals, you'll get six different approaches to catheter ablation for VT. You'll get six different endpoints. You might get six different ablation strategies. You can use 30 watts. You can use 50 watts. You can use it for 30 seconds, 120 seconds. What's your endpoint? Are you going to look at impedance values? Are you going to ablate all the VTs, some of the VTs? There's so many variables to the way that we do catheter ablation for VT that it makes the results not reproducible. And at the end of the day, we talk about survival and we talk about living. And this is, again, data from the IVTCC looking at low-risk, medium, and high-risk groups stratified by ejection fraction, prior catheterizations, type of cardiomyopathy. Overlaid is Wendy Zhao's data from the IVTC of the most advanced patients, the recurrent VT and the class IV heart failure. And you can see that the one-year survival probability can get quite low. And friends, this mimics what non-small cell lung cancer looks like. It's as if you had stage one, two, three, and four lung cancer in terms of your one-year survival. And if you were to look at the shape of these curves, where do the curves diverge most? Where is the most difference in survival? It's actually in the first month or two after a VT ablation. That's where the curves diverge. And again, this could be because we have sicker patients versus less sick patients, or it might be that we're working in a different way than we might for the sicker patients than we might in the healthier patients. Or it just might be that the sicker patients don't do well with our current tools to map and ablate VT. Now, survival is important. And I do want to put that out there. We still owe the field, the pivotal study to show that catheter ablation saves lives in a prospective, randomized way. We've not yet proven that in a prospective way. We've looked at it retrospectively, right? This is Rod Tung's data from IVTCC. That is, patients who were able to control their VT seem to live longer. So this is transplant-free survival at one year, and it's dichotomized by the patients who don't have VT and the patients who do have VT that recurs in the first year. So there's an association with VT suppression and survival, for sure. It remains an association. I want to prove that in a prospective trial still, but I think this is what we hope to see, that if we can control VT, we can affect mortality. This becomes super important. So how do we control VT? And how do we take an honest assessment of where we're falling short with our catheter ablation? And I want to point this out. This is a picture with a small catheter shown here, a four millimeter tip that's heating. And you can see the rim of tissue change. And you can see the full thickness of the heart here. And delivering thermal energy with the hopes of ablating at the tip of a catheter will always be limited by the biophysical properties of heat transfer. We will learn different ways about how to transfer that heat deeper into tissues, maybe wider into tissues, but we will always be limited by the biophysical properties of heat transfer. And this becomes crucial as we think about where we fail. Rod Tong published this or posted this on Twitter, really a humbling picture. This is a heart that was removed. You can see a mid myocardial stripe, a common sort of substrate that we go against with catheter ablation. This is the septum. This is the left ventricle. Over here is the right ventricle to the right. We have a mid myocardial stripe. This patient underwent four catheter ablations at two different academic medical centers. You can see the latest of the catheter ablation. I think I can see some healed catheter ablation here as well. 50 watts, half normal saline. And you can see the depth at which we're able to create ablations. And it is not nearly the depth that we need if we think about trying to put heat or ablative energy in the mid myocardial septum. The tools that we're using right now for catheter ablation are really helpful for superficial things. They're really helpful for accessory pathways. We can actually link it together in lines for flutter. And we've gotten pretty good with AFib and isolating pulmonary veins with these tools. But when you start thinking about the enemy here, you start thinking about the thickness of a 15 millimeter, an 18 millimeter, 22 millimeter septum that's scarred. It's difficult to get the ablative heat further into that. What we really want to do is apply energy to that area, render it electrically inert, but structurally intact. And that's what this picture is. I want to look at a CT scan. I want to identify where that mid myocardial stripe is. And then I want to apply ablative energy to that region. So the why, the first of the five questions that I wanted to answer today, why would we think about doing cardiac radial ablation? Because we want to create a better patient experience for our patients with VT. I want this to be safer. I want the ablation to be more comprehensive. And I'd like it to be totally non-invasive so that we can get these fragile patients through a VT treatment in a safer way. So this is one way that we can do it. If we're looking for full thickness ablative energy to be applied non-invasively, this is being done in our basements right now. Actually, not right now. They don't wake up this early. So usually the radiation oncologist will roll in maybe eight or nine o'clock, but this is non-invasive, full thickness, gap-free ablation, stereotactic body radiotherapy. The idea is that we use sweeping arcs of photons that are shot into the patient in different angles and different shapes and different sizes to focus ablative radiotherapy to the areas of tumor, in this example, with rapid falloff of energy to the surrounding tissues, in this case, the healthy lung and the chest wall. This has revolutionized the way that cancers are treated. This has worked well in several disciplines with surgeons who might want to remove those tumors or might want to work with the radiation oncologists to remove those tumors. This is something neurosurgeons work with radiation oncologists, thoracic surgeons work with radiation oncologists on a regular basis. What we are simply asking the radiation oncology colleagues to do is shift that target. If I can show you where the diseased part of the heart is that's harboring the BT circuit, can you apply the energy to that area to render it electrically inert? There's a number of preclinical studies. I want to show you Oliver Blank's preclinical work here because this is really, I think, so carefully done. Oliver is a very careful scientist. He looked at regular vein structure here. This is a control animal that had not been radiated. We're going to see the staining. This is with 25 gray. Gray is the dose of radiation that's given. With 25 gray, he can see mild fibrosis on the trichrome stain here with what we'll call an intermediate dose. As we increase the dose to 30 gray, one can see more moderate fibrosis. As you keep going higher, 32.5 gray gives us confluent fibrosis up to 40 gray where we get this full transmural circumferential fibrosis in all of the animals that were treated. There's a dose effect to the changes that happen on a macrostructural level. This has been shown not only in Oliver's lab but in a number of other labs. I'll show you some of the data in a moment. We always have to be open to the possibility that radiation can cause harm. We know that it can cause harm. At what doses and how does it cause harm is what we need to be looking for. This is one of the animals from Oliver's experiment that got 37.5 gray and developed a bronchial fistula in an area near the high dose region. It's important to think about these dose-related effects and location-related effects. One of the patients that got high doses, 40 gray near the AV node, developed a AV block six months after treatment. When looked at that, you can see full thickness confluent ablation in that region. If we take the totality of the preclinical data, that's going to be shown on the bottom here, we actually have over a decade of preclinical data in this space. I showed you Oliver's work. Some of the earliest work was done by the Cyber Heart Group published in Heart Rhythm in 2010. Finding a similar dose response, you can see this s-shaped, the sigmoidal-shaped curve looking at escalating dose and the intensity of fibrosis. That sweet spot seems to start at 25 gray and continues up to the 35-40 gray. Now, I want to point out Doug Packer at Mayo and colleagues and collaborators across Europe have done some tremendous preclinical work with carbon ions and now more recently with protons and with photons like we've been doing as well, taking organs that have been removed from animals and then closed chest models as well. It's really a fantastic story and it continues to show a similar sort of structural response that starts around 25 gray and becomes more pronounced in the 35-40 gray. We've seen that both in acute AV node, chronic AV node, and some beautiful MRI studies in the ventricle as well. On top here is the first in human and the human experiences. So the first in human shown here, the Stanford group working with the Cyber Heart Group, so Billy Liu, Paul Zai, Amin El-Ahmad, showing the very first in person, first in human, and in the Czech Republic shortly around that time, CVEC and colleagues, they were using a CARDO to try to register a location for non-invasive radio ablation. These were the first in humans, right around 2012, published in 2014-2015. Our first case series, I'll go over this data a little bit more in detail, was done in 2015, published in 2017, showing a dramatic reduction in VT in five really end-stage patients. This experience has now been replicated in at least three centers worldwide with publications coming out of Emory, out of Austin, and a large study coming out of the Czech Republic as well. And all of these are showing similar results, that is we're controlling VT but not curing VT with the current methods that we're applying for cardiac radio ablation. And importantly, when you look at the preclinical and some of the clinical work, the EP effect is thought to be related to apoptosis, that a programmed cell death induces a fibrotic response. This is the thought, the working physiologic explanation that's being really looked at, particularly in the preclinical studies. Now at WashU, we've taken kind of a full, this is our workflow, where we're identifying patients, particularly patients who have been refractory to medical therapy, refractory to catheter ablation. We've been putting them through a workup, and I'll go over this in a little more detail, because this is where the EP effect becomes important. This is where we have an input and do the targeting for this procedure. And then the workflow is very similar to something that might happen if a patient had lung cancer. That is, they lay on a table, they have some type of a limiting device that's placed that limits the depths of breath to try to keep the heart and the chest in a similar location throughout the course of a simulation scan. So a CT scan is performed. And I sit down with the radiation oncologist. In this case, I sit down with Cliff Robinson. We identify the location that we want to target for ablation. And then he and his team go through a set of criteria that they apply to figure out how to deliver the dose of radiation that we want to these structures and avoid the nearby structures with different dose constraints. Ultimately, this is delivered in a single fraction, that is a single dose. And then we watch closely in the clinical trial for the VT outcomes and the toxicities. I want to acknowledge Cliff and his group, and really acknowledge his courage for doing this. You have to realize that in 2015, when 2014, when we started talking, the field of radiation oncology thought it was absolutely wrong to treat the heart with radiation. They have textbooks written to avoid the heart for breast cancer and lung cancer. Cliff's most recent publication prior to us meeting was about the toxicities of radiation to the heart and the dose-dependent toxicities in patients with lung cancer. We sat down, we learned to talk each other's language, and had to explain that we don't want to treat healthy heart. We really want to treat diseased heart and really keep it focused on the diseased heart. Ultimately, our first five patients were published. About a month or two before the publication in the New England Journal, we had this poster at the American Society of Radiation Oncology. We were put way back in the corner in the non-oncologic section. This is a very poorly visited section in a cancer meeting. It was us and a couple other people back there. They thought so highly of our work that they put us next to this herpes zoster poster that you can see over Cliff's shoulder. Let me blow that up, what we have next to us there. There's a good picture of what Astro thought of us in 2015 when we were ready to publish our paper. But nonetheless, these were five patients who had very high levels of VT. They had failed catheter ablations. They had failed multiple medical therapies. We gave 25 grain a single fraction. This is the number of VT episodes each month before treatment. Then this is the number of VT episodes each month after treatment. You can see that the effect wasn't immediate. Patients oftentimes still had arrhythmia in the first month, but oftentimes went away by about six weeks. You could quantify that after the six-week blanking period over the course of the next nearly 10 and a half months, the four long survivors here had a total of four VT ablations, and we were able to wean off antiarrhythmic medicine. This pioneering group, this really brave set of patients told us that indeed radiation works. Now, is there opportunity to optimize? Is there opportunity to do it better? Sure, maybe, but they showed us that this effect is there, that we could control VT. Emboldened by their results, we asked this question in a formal way. In patients who have VT, who have failed conventional therapies, does a single noninvasive radiation therapy safely reduce the VT burden? This was the basis for our ENCOR VT prospective trial. This was published in 2019 in Circulation. I want to go over this with you because it's the only prospective trial of cardiac radio ablation to date. We took patients who had monomorphic VT or PVC-driven cardiomyopathies. Their EFs had to be less than 50%. They had to have tried at least one medical therapy and at least one catheter ablation or be contraindicated for catheter ablation. They needed to have at least three VT episodes over the prior six months, and you'll see soon that that was a lot more for most of these patients. We were pretty inclusive. That is, we didn't throw out a lot of patients. We excluded patients who had very advanced heart failure. If they were on inotropes or had LVADs, we excluded them, but short of that, they were included on the trial. We included people with renal failure. We included people outside of everything else with the exception being prior radiotherapy to the chest or if they had VF as their primary arrhythmia, polymorphic VT as their primary arrhythmia. We didn't think that it was fair to include those people if we were trying to understand the mechanisms of radio ablation and really needed to know more about the VT circuit before we could actually do the radio ablation. It was a fairly inclusive group, and it turned out to be a pretty sick group. We looked at safety and efficacy. We were looking at serious adverse events using this standard way in radiotherapy, the CTCAE way of scoring adverse events, and then efficacy at six months. We compared the patients six months before treatment to the six months after treatment with a six-week blanking period to allow for biologic effect of the radiation. To power this appropriately, we needed 19 patients to get a safety signal up to 20% serious adverse event and an efficacy as low as 40%. You've seen a similar workflow where we take the images to do the targeting. I want to spend a little bit more time talking about what that looks like. As an EP community, we need to think this through a little bit more. One option is to say, I need to find out where the VT is, so I'm going to put catheters back into the heart on these patients and map around all of their different VTs and put them through another long invasive procedure, but then now to apply the actual catheter ablation with the radiofrequency ablation. That to us seemed like an incomplete way and not the safest way to take care of our patients. We worked very hard to structure a way to non-invasively figure out where the VT was coming from. That involves taking electrical information and merging it with anatomic information in our heads to identify where the critical isthmus and the target of the VT might be. In particular, if I can make it as simple as possible, we use the 12-lead EKG to figure out where the exit site is, and then we use the anatomic scar maps to find the VT-adjacent sites. We targeted those VT-adjacent scar sites for radio ablation. To show that in a different way, step one is find the VT exit site. That can be done with analysis of a 12-lead ECG. This is what we do all the time in person when we walk around with ECGs. This is done on Twitter all the time. Where's the site of origin? We happen to have CardioInsight. For the case of our clinical trial, we used the research version of ECGI. This is Yoram Rudy's work. We did a non-invasive electrocardiographic image map. Shown here is two VTs. If you look at the lateral view, you can see the activation maps. It starts coming from the lateral wall towards the lateral base in the inferior version of it here. You can see almost a re-entry as it moves around and through this area. I put a little asterisk near that. That was VT1. VT2 was originating a little bit more superior on that basolateral wall. Again, you can see red, orange, yellow, green, and blue meeting through here. These are two non-invasive images of VT, and this is captured in a single beat. Once we find the VT exit site, we can look at the adjacent scar. In this case, it was a fairly focused scar. I'm showing you images from a perfusion scan, and you can see a dropout here on the basolateral wall that corresponds with the two VT exit sites. Then we target the VT adjacent scar. We're not looking specifically at the exit sites, but we're looking at the scar next to the exit sites. Sometimes this can be very large, and I'll show you an example of that in a moment, but this, I think, illustrates a very focused version of what we do. If you look at the Oncor VT trial and the people who came into it, the demographics are shown here. Half the patients were in VT storm. Two-thirds of these patients were class III or IV heart failure. The median ejection fraction was 25%, and about half the patients were ischemic. Half were non-ischemic. You looked at the number of VTs that we induced. It was on a median of two, but up to five VTs that were induced and targeted for radioblation. The median gross target volume, that is the target volume that I put on a CT scan in conjunction with the radiation oncologist, the median was 25 cc, and to give you an idea, a golf ball is about 45 cc. We're targeting full thickness, endocardium to epicardium, of about half to two-thirds of a golf ball in volume. That ranged from 6 cc all the way up to 88 cc. Now, when you account for the motion, account for uncertainties, that becomes much larger, and the actual treated volumes become much larger, about the size of two golf balls, when you're thinking about the motion and the uncertainties of setup. The median beam on time was 15 minutes. Undoubtedly, one of the lessons that is hard to capture in the metrics of designing a study, but becomes super obvious when you look at the patients, on the left is a patient who had cardiac radioblation, and he's done with his VT ablation, and he walks out. On the right is somebody 10 minutes after ablation who still is intubated and has additional lines in as well, and is going to stay in the hospital for several days thereafter. If you look at the safety endpoint, we followed our patients now past two years, and in the first 90 days, we had one patient with a treatment-related toxicity, graded three or four, and that was a pericarditis that happened at day 80. It was likely from our radio ablation. It resolved with a short course of oral prednisone. We had two patients who, I'm sorry, we had one other patient who had an admission for heart failure during this time as well. Difficult to know if that was treatment related or not. That responded to IV diuretics. I want to talk beyond 90 days because this is new data out there. So we had three patients who developed probable or definite grade three or four toxicities over the course of those two plus years of follow-up. We had two patients who we diagnosed pericardial effusions with shortly after about two years during their follow-ups. We did tap them. We saw that they were bland, they were acellular, and they both responded to colchicine therapy. But something to consider, and this is known data, very consistent with what we would see for left-sided breast cancer, to see pericardial effusions in the 10 to 15% range. And so this, I think, is an expected type of a safety thing that we should be expecting and we should be looking for. In the future, I think we would manage these medically without having to put a needle in and tapping them. But because they were on trial, we thought it was important for us to try to investigate whether this was, what the etiology of those pericardial effusions were. Importantly, we had one gastropericardial fistula that showed up about two and a half years after. He ended up being one of our biggest wins from a VT suppression standpoint. In fact, he'd never had any VT in the, now three plus years after the treatment, but he showed up with abdominal pain. We got a CT scan and noticed the gastropericardial fistula. What I'm showing you on the left is the treatment plan. This gentleman had a very large anterior apical and then inferior scar. And this was the region that we targeted for radioablation. He had a number of VTs that were coming throughout the scar. We had to make a decision about whether we wanted to target just the anterior portion of the scar or the entirety of the scar. This is somebody who we did a rather extensive scar homogenization with radioablation. And you can see how close to the stomach this ends up being. This is an intraoperative picture during the repair of the gastropericardial fistula shown there. This is not surprising. This is why we follow our patients. This is something that we learned from, and this is very consistent with how radioablation was used and developed in cancer treatments. Patients were treated, we were following very closely for adverse events and then altered the way that we treat the organs at risk. And so we've modified our approach to radioablation based off of these type of findings. And we changed the organ at risk priorities for luminal structures like esophagus and stomach as a result of this. And as a result of that, we've not seen any more of these types of fistulas. Survival is really important. The six-month, 12-month, and 24-month survival is shown here. Again, remember, these were mostly class three and four heart failure patients in substantial BT storm. We can talk about the ways that these patients died after this talk, but it's important to know that most of them died of advancing heart failure with about a third of patients dying of non-cardiac death as well. If you look at the efficacy endpoint, this bar graph is sort of the waterfall plot that we're used to seeing for the ThermoCool VT trial results. So each one of these bars represents the number of VTs for each patient in the six months before and then the six months after. Now, if I layer on subsequent six-month periods of time, you're gonna see a more complete view. On the left is six months, on the right is 24 months of follow-up. And you can see some of these people, in fact, I would say most of these people, will have some VT in follow-up. And it's pretty rare to have a cure of VT for 24 months in this advanced VT population. But if you look at the primary endpoint of any reduction in VT, 78% of the patients continued to meet the primary endpoint of less VT than they started. And this is 24 months of time. This is also getting off of antiarrhythmics or reducing antiarrhythmic medication. To show this differently, if you look at each six-month time period, I'm gonna show you the median VT episodes for the patients who are in the six-month time period before the first six months, the next six months, and beyond. And you can see for the patients who survive out to 12, 18, 18 to 24 months, the median VT burden remains low. So it seems to suppress VT, though it doesn't seem to cure VT. And I think that's a fair assessment of the data. We had some predetermined secondary endpoints, which I think are really important from patient standpoint. Freedom from ICD shock was seen in 78% of patients. If you use the Vanish combined endpoint of freedom from death, shock, storm, 62% of patients met that endpoint. Almost everybody had a 50% reduction in VT. About 2 3rds of patients had a 95% reduction in VT. So I think these are important ways to be able to share data with patients. Importantly, we were able to reduce the medical exposure, particularly to high-dose amiodarone. And we had improvement in five of the nine modules of the SF36 quality of life metric, which I think remain important. So some of the strengths of this ENCOR VT trial, very rigorous follow-up. We had no dropouts. We had vigilant and consistent endpoints, and a very thorough evaluation for any adverse events, now out to almost three years on our patients. The downsides is that it's a small sample size, and it's inherently difficult to attribute risks in patients who have such advanced cardiomyopathy. And there's a bias, of course, to any of the survivors that might limit the benefit and risk discussion. So the conclusion of this prospective trial is that a single non-invasive radiotherapy treatment did safely reduce VT burden in a very advanced group of patients who had failed prior treatments. And this effect seemed to persist for two years. Serious toxicities were low, but they still could occur after two years. So we really feel very strongly that long-term follow-up is still needed. And we think this is currently best suited for patients who have failed conventional VT treatments. We don't see this as a first-line therapy yet. There's still much to learn. So let's finish up with what's on the horizon. Let's talk about what we see coming up. And I keep harping on the long-term toxicities, long-term safety. We really wanna continue to follow these patients, and it's difficult to do off of a protocol. So centers who are doing this currently for their bailout treatment patients are generally doing it off of a protocol that allows for long-term follow-up. So we're working with FDA and other funders for a randomized controlled clinical trial. So I'm unbelievably excited about the idea of having a cardiac radioablation versus redo catheter ablation clinical trial done in a randomized prospective way. We expect this to be enrolling in early 2021. I'm thrilled to be able to be a part of that. So more to come on that. I think from this group, I think one of the interesting things is to think about how are we targeting VT without catheters? You know, our traditional way of doing things is to put catheters in, obtain all of the data from the tip of the catheter in the 3D maps, and then make decisions in the EP lab based off of that data that we gather. But we're on this brink, as you heard from Jeff Winterfield just earlier this week, we're on this brink of an imaging renaissance. We have these beautiful cardiac images that now tell us the scar architecture, particularly for ischemic VTs, and can start to direct us towards regions that might be of more interest without having to put catheters in, or using catheters to confirm what we see on the imaging. So what are the most constant and consistent ways that we can use this imaging to develop a target for radioablation? And I'm gonna, I underline that because this is something that's super important for us as we think about how we can develop consistency from one center to the next, how we can do things the same from one center to the next, how we can interpret the data as a group, as a global community, and be able to react to that data and improve the procedure for our patients. And I'm gonna finish up with a little bit about do we need to keep destroying more? Is catheter ablation moving to radioablation moving to a pan-destruction of the ventricle? Is there a limit to how much we should use these weapons of mass destruction? And is there more to this than simply more destruction? And this, I think, is a really cool story. So I'm gonna finish up with these two stories. We need to do this the same way every time. When you look at how cancer is treated, there are a number of steps and checks that go into quality assurance that provide end-to-end testing from the very beginning of the treatment to the end of the treatment, looking at the quality of the plan, looking at the reproducibility of the plan, looking to make sure all of the margins of a cancer are covered, make sure that the organs at risk are appropriately accounted for. And this process reduces the error and has shown to give good outcomes. In cardiac radioablation, the single biggest source of variability is us, is us determining where the VT is coming from based off of interpretations of 12 leads, interpretations of MRIs and CT scans, based off of interpretations of catheter maps that have done previously. So in an effort to try to reduce that variability and improve the quality and reproducibility, we've been spending a lot of time thinking about how we can target in a consistent way. Everybody's first thought is I want to take my CARDO map or my NAVX map and import it into the CT scan. I want to import all of these data points and bring them into the CT scan for us to target our non-invasive radioablation. And it's a difficult task, one that is oftentimes fraught with errors. We've always had a hard time with registering things in the EP space. And many of the images that we acquire, 12 EDCGs, MRIs, many nuclear scans, don't come in an axial plane. They're very difficult to co-register with the CT scans that are needed for cardiac radioablation. And while the first method may be, hey, let's bring everything together in the CT scan, that error is too big on a regular basis and it will hinder us being able to do things similarly. So one thing that we've discovered is we need to be able to talk the same language. When I say anterior wall, that's really the superior wall, right? When I say the posterior wall, we might be talking about the inferior wall. There's a lack of communication between the radiation oncologist and the cardiologist because of our language differences. And to find a common ground model that can help interpret all of the available cardiac scans, that can help us take a cardiac MRI or interpretation of a 12 EDCG and put it on a common model, we can make use of the American Heart Association 17-segment model. This has been used in MRI, it's been used in nuclear scans, it's been used in echo interpretation, and now increasingly is being used in interpretation of 12 EDCGs as well. And if we harness this, we can start to speak the same language and we can start to apply energy in the same way, in a consistent way. And I'll show you an example. This is an example of a group that we helped in Japan. Mari Amino's group had a patient who, you can see on the bottom left, this is a CT scan, a contrast in the hand CT scan, very large anterior apical aneurysm with some calcification that's really beautifully seen here. Another image shown here on the bottom right, you can see the calcification on this very large aneurysm. They induced two different VTs on their non-invasive program stimulation shown here and here. And by working together with Mari and her team, we were able to use the 17-segment map to say, where do you think the exit site is coming from from VT1? And she marked it here. Where do you think the exit site is coming from from VT2, marked here? Where does your radiologist think that the wall thinning, the scar is on this CT scan, shown here? And where is the calcification in that CT scan is an area that might be of particular interest as barriers for conduction, and that's shown here. And you can take these 17-segment models now and blend them and merge them and get something that gives you a heat map, if you will, a target probability that says, if you look at where the VT exit site is and you look at where the scar is, the VT-adjacent scar, we can, instead of targeting two thirds of this patient's heart, we can target the area that is likely to be most arithmogenic for those two VTs. And instead of targeting the entirety of this scar, you can see on the bottom left here, we target the anterior portion of the scar and don't need to target the apical and inferior regions because they're not currently causing any VT. Now we can have philosophical debates about whether we wanna be doing full scar homogenization or not, but the data will show that the larger the radiation field that we treat, the more chances of risk. And so it does still matter for us to be physiologists, for us to interpret the interaction between scar and electricity. And so here's a patient who was treated just in this region based off of our being able to bring everything together in a common language. The last story I wanna show you is really important. This is what the patients have taught us. This is a ICD interrogation. You can see all the different VT. We treated this patient. We kept him in the hospital a couple of days so he didn't move here. We got him off maxillotine and off amiodarone relatively quickly. And friends, his VT went away almost instantly. That's not what I would expect when you radiate a heart. We certainly know that when you radiate a tumor, the tumor doesn't disappear immediately. The biology takes some time for that tumor to change and shrink and stop growing. But we have seen now time and time again that VT suppression can happen on the order of days to weeks, not months, like we would expect fibrosis and apoptosis to occur. And this is data that our fellow, our super fellow Rachita Navara has put together looking at the ECG changes at day three, week six, month three, month six, month 12 for the Oncor VT patients. And if you look at where ECG changes occur, almost all of them occur within the first three days after radiation. Again, well before you would expect apoptosis, fibrosis pathway to occur. And when you look at the type of ECG changes, I would have expected delay, scar causing widening of the QRS, causing prolonging of the PR interval. In fact, more often, we saw shorter PR intervals, shorter QRSs and shorter QT times, which was very surprising and very curious to us. And we've been fortunate enough to have great collaborators. And this is work from Stacy Renschler and her team that have looked at heart tissue from hearts that have either been removed at autopsy or at transplant for patients who have been treated with radioglation. And shown here are the trichrome stains showing non-targeted and targeted regions of the heart. All of these patients are non-ischemic cardiomyopathy. You can see the type of scar that moves through these non-targeted regions. And you can see the treated regions have slightly more blue cells, slightly more fibrosis. Shown for reference is an area of RF ablation done in this patient. And you can see far more fibrosis, far more blue cells. And you can quantify this level of fibrosis. So shown here is the targeted and the non-targeted regions and the percent or burden of fibrosis in those regions. What strikes me is that the areas that we radiobladed did not give us full thickness fibrosis. We do not see full thickness blue cells here. And yet in all four of these patients, VT went away very quickly in the first month of treatment. And these patients had no more VT for at least six months and beyond. So we know that radioblation did something to the VT burden, but it wasn't full thickness ablation. So fibrosis alone cannot account for this degree of VT suppression. More to come here in Stacey Rentschler's lab, and she's the right person to help us figure this out. So the five answers to the questions that we started this hour with, why do we ablate with catheters? To create a safer, more comprehensive ablation. How is it done? We're currently doing it with stereotactic body radiotherapy which is focused radiation. For whom is this most appropriate treatment refractory VT patients? The longer term results are pending, but the short term results certainly look very safe from this procedure. And it does seem to reduce the VT burden, but it's not curative in just about everybody. So what's next? I'm excited about the randomized clinical trial against redo catheter ablation. And I'm really excited about the careful study of molecular pathways, both lethal and non-lethal that lead to VT suppression. A quick shout out to my group, the Center for Noninvasive Cardiac Radioablation, where we're targeting each of these various arms, each of these different questions, looking at the biology, looking at the way that we should be running this out in a clinical trial, thinking about how this can extend access to care, setting up a global registry for this, and thinking about how we can determine the critical arrhythmia sites and improve the process for our patients. Last slide, if you're interested in learning more about this, if you're interested in being part of this global community, here's our phone number, our contact information. Caitlin Moore is our center director, and we're happy to help move the field forward together. So let's stop there. We've got about 10 minutes to take some questions. I hope this will have a nice discussion afterwards. So Ashant, if you want to lead the discussion afterwards, I'd be happy to answer questions. Yeah, that is great. I mean, amazing work. You should be congratulated on everything you've accomplished. First question, I'll let Dr. Zhai have the first question here. He said, more and more centers are starting these programs on their own. What would be your advice to centers that are now starting? Yeah, so excellent question, Paul, and it's really important. I point out that right now with catheter ablation, you get so many variations on endpoints and so many variations on the way that people are ablated with catheters for VT. We really stand in an opportunity to almost approach this with a clean slate, that if we all are doing this in a similar way, we can learn from this. By delivering radio ablation, it takes out so many of the variables that go along with catheter ablation, the contact force, the energy, the duration, the substrate that we're working against. All of those variables with catheter ablation can be minimized with cardiac radio ablation. And so we have this opportunity to work together to be able to learn. When centers try to do this on their own, they miss the opportunity to contribute to the greater good of understanding this. They also miss the opportunity to learn from the mistakes and the things that other centers have learned along the way. So I think it makes sense that as groups are interested in being part of this, to reach out and become part of this global community. Paul and I are working together on a number of projects, but most importantly, this randomized clinical trial. I mean, this is really gonna be an important step for us to be able to see where's the value. So I would, I'm somebody who's a team person. I think we can move the field forward together much better than individually. Great. Along those lines, you have a recent kind of systematic review that was published in Heart Rhythm. So you've reviewed the data from a lot of these other centers. Is there anything you've gleaned that maybe you think your center is doing differently that has led to improved outcomes compared to some of the other centers? I don't know if it's improved outcomes. It's nice to think that, but I think if you were to take a step back, we learn from prospective trials much more than we learn from retrospective trials just because the biases that are built into that. We learn a lot more from retrospective series than we do from case reports where biases are very strong. We have a publication bias to show the one case that we did with a good outcome, but we're very resistant to publish our bad outcomes, particularly in a case report. So it's difficult to make deep judgments on the limited data that we have. But I think overall, we're starting to see a similar picture that's evolving. That is in just about every center, we're seeing a relatively quick and relatively dramatic reduction in VT burden in patients who otherwise were refractory. Some of the worst patients are getting treated and the VT seems to be going away. It doesn't seem to cure VT. It doesn't seem to be durable forever. And whether that VT that recurs is a different VT or the same VT is very important. So there's a lot to learn here. I think, as I pointed out, the biggest source of variability is in the targeting. And so for us as EP community to come together and figure out how do we wanna approach the way that we ablate in a consistent way, in a way that we've proven to be safer, in a way that we've proven to be more effective, I think that's really the key to this. Great. There's a question here about whether any special equipment is needed by the radonc department or is this stuff that they already use routinely and probably already have? I would generally say that if you have a linear accelerator and a cancer group that treats with focused radiation, with stereotactic body radiation, that you can generally perform this procedure. There are nuances to each of the different types of equipment and there's different ways that the radiation oncology teams will manage motion. For example, or deliver therapy in different arcs, different number of arcs, different ways to manage the setup uncertainties. So there are a lot of different subtle differences that become ultimately very important in the execution of the plan that the EPs wanna put forward. So in general, the tools are there. In general, this doesn't require a huge capital expense to be able to do these types of procedures. And this carries a great deal of impact if that's the case because you can start to think about many centers across the world who don't have catheter mapping systems, who don't have access to the expertise that's needed for VT ablation, but may have a radiotherapy unit in their hospital. And so this really opens up access to VT care if we can show that this can be safely delivered with a minimal data set in a structured scientific way. This allows VT ablations to happen across the globe and really opens up access to this type of care. And there's a question here about, I guess, creep in a way. What concerns do you have about people applying this more broadly maybe to patients with idiopathic PVCs and paroxysmal AFib and atrial arrhythmias? What are your concerns? Yeah, great question. I started out by saying, if you're not moving forward, you're falling behind, right? And so I think pushing envelopes is important, but I think pushing envelopes for the right reasons is important. So just doing things to do them doesn't make sense. If we're doing something to make it a better experience for a patient, we wanna make it safer, faster. If there's some value in thinking of a full thickness ablation versus a catheter ablation, I can understand wanting to do that. I think because we don't know the long-term safety of radiation yet, I would caution against doing this in patients who are generally healthier. I think the place that this seems to make the most sense right now from a risk benefit standpoint is in patients who have advanced VT, who have failed standard therapies. Their longevity is very limited, right? The chances of somebody with class IV heart failure and VT storm living 10 years is low. But if we can buy them several years of VT freedom or VT suppression, that's a value proposition that's great for them. They're not gonna live 10 years to find out the radiation effects downstream. But if we start treating patients, we will refer to a 20-year-old woman who had idiopathic VT, LV summit PVCs, not VT, LV summit PVCs, and had failed multiple catheter ablations. But I'm nervous about taking this woman and offering her high-dose focused radiation because I have her penciled in for many decades to come. And until we know what the risks are many decades to come, I would be slow in offering this to the healthier patients. And then a very optimistic question. Do you think we'll get to the point where we never do catheter ablation again? No, I don't think so. I think the role for catheters, we've evolved a really terrific way of treating arrhythmias with catheters. The evolution of catheter ablation has been extremely exciting and has revolutionized the way that our field is practiced now compared to where we were 30 years ago. And we've certainly sunk a lot of resource into doing catheter ablation better and better. And I think our outcomes and our procedural results speak to that. I think if you take a step back, you'd say that catheter ablation is well-suited for some things. We do great with accessory pathways. We do really nicely with atrial flutters. We do very well with thin-walled structures and we're learning how to deliver that heat energy better and better to those regions. But if you think about what we need for VT and you think about the substrates that we oftentimes go against for VT, it's not the right tool. Catheter ablation is not the right tool with the things that we have right now. There may be other tools that deliver thermal ablation deeper. It's very exciting to think about other energies, but ultimately we need to think about those other energies to fight the battle of VT ablation.
Video Summary
Dr. Jeffrey Winterfield delivered a presentation on the topic of cardiac radio-ablation. He explored the use of non-invasive radiotherapy to treat patients with ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Dr. Winterfield discussed the limitations and risks of current catheter ablation procedures and presented the potential benefits of radio-ablation. He highlighted the ability to target specific regions of the heart with focused radiation and the potential for safer, more comprehensive ablation. Dr. Winterfield presented data and insights from preclinical studies and clinical trials, demonstrating the effectiveness of radio-ablation in reducing VT burden. He also discussed the importance of standardizing and optimizing the targeting process and the need for long-term follow-up to better understand the safety and long-term outcomes of radio-ablation. Finally, Dr. Winterfield shared future directions for research and the potential for a randomized controlled clinical trial comparing radio-ablation to catheter ablation.
Keywords
cardiac radio-ablation
non-invasive radiotherapy
ventricular tachycardia
heart rhythm disorder
catheter ablation procedures
focused radiation
preclinical studies
clinical trials
long-term follow-up
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