All right. Hello everyone. Can you guys hear me? Okay. So, my name is Piotr Futyma. I'm from St. Joseph's Heart and Rhythm Center, Rzeszów, Poland, and it's my pleasure to chair this session about latest approaches to VT management. And I would like to invite the first speaker, Dr. Yoshihiro Harano from the University of Tsukuba. Okay. Thank you for introducing, Mr. Chairman. Today, I'm going to talk about the clinical impact of daily application of steroid ganglion phototherapy for refractory ventricular arrhythmia. That is incredibly strange. It should be. The autonomic nervous system is involved in controlling the cardiac function and heart rate. The sympathetic nervous system is associated with the occurrence and maintenance of VT and VFs. Therefore, the neuromodulation therapy for refractory VT and VFs have been performed. And these are the well-known neuromodulations. The steroid ganglion is one of the sympathetic ganglion which located at the surface of the neck by indicating right figures. And by targeting this ganglion, the steroid ganglion block have been performed as one of the neuromodulation therapy. These are the previously reported effect of the neuromodulation therapies. They demonstrated a significant reduction in ATP and DC therapies and suppression of electrical storm. So when we see this result, we want to apply this treatment for such patient with drug refractory VTs. However, these procedures are more or less invasive and require appropriate procedural skills. Therefore, the application of these neuromodulation therapies in the outpatient setting is limited. As a result, it is challenging for us to manage such patient with refractory VT who receive ICD shocks once or twice a month but do not experience electrical storm. Steroid ganglion phototherapy has been considered one of the non-invasive neuromodulation, usually by using this machine called SuperLyzer, which places its probes on the patient's neck and applies near infrared light. In fact, several article reported its effect in suppressing electrical storm without any adverse effect. This approach may have potential advantages of non-invasive and easy-handling nature. However, the effect of phototherapy is considered transient and the application of phototherapy in outpatient setting remains limited. Since 2022, the University of Tsukuba has been using a portable device we call the SuperLyzer Mini that's applying the near-infrared light for the patient with refractory ventricular arrhythmia. So, as you can see in this slide, this device is easy to use for each patient. This allows patients to receive neuromodulation therapy at home every day. However, there is no reported evidence that this portable phototherapy approach can prevent ventricular arrhythmia in outpatient settings. This study aims to evaluate the efficacy and feasibility of daily portable-use SGP in suppressing VTs burden in patients with refractory VTs in outpatient settings. This is a retrospective single-center cohort study conducted from January 2023 to April 2025. We included the patient who had the refractory VTs treated by daily portable-use SGP and structural heart disease, which means they are not struggling with the idiopathic VT. And also, they had attended a device outpatient clinic for post-ICD or CRTD implantation. When the patient experienced the frequent non-sustained VT episode or ATP or DC shocks, the daily portable phototherapy was introduced at the device clinic or an outpatient basis. The patient then self-applied the SGP for 10 minutes bilaterally using the device. By using a device record and remote monitoring system, we evaluated VT burden and ATP or DC therapy burden one month before and one month during the SGP. So a total of 27 patients were evaluated in this cohort study. Of these, 20 patients were male, and the median age was 67 years old. Half of them experienced the prior heart failure admission, and one-third had a prior VT abrasion. Most of them were taking beta blockers, and many of them were taking amiodarone or sotralol if the patient had amiodarone side effect. The seromon BNP level was high, and left ventricular ejection fraction was 40%, which means they have a structural heart disease with chronic heart failure. This is one of the key findings of this study. The number of ATP or DC therapies were evaluated before and during phototherapy. The light figure shows the number of ATP and DC therapy burden for each patient in the month before and one month during the SGP. So you can see that many patients experienced frequent ATP or DC therapies, but after starting the phototherapy, these ICD therapies were significantly reduced. The right panel shows the significance. More than two ATP or DC therapies were suppressed to zero after starting phototherapy. This is another key finding. The number of all VT events, which includes the sum of non-sustained VT and sustained VT, was evaluated one month before SGP and one month after SGP for each patient. The blue bar shows the non-sustained VT burden, and the red bar shows sustained VT burden. Although some patients did not decrease the non-sustained VT burden, but all VT burden was decreased during the SGP period. And the right panel shows the significance. And there is a sub-analysis of changing each non-sustained VT and sustained VT burden before and during SGP. Interestingly, while non-sustained VT burden was not significantly reduced, but sustained VT burden was significantly decreased during the phototherapy. In terms of the safety outcomes, there was no adverse effect during the phototherapy. Furthermore, no patient experienced additional therapy, such as radiofrequency aberration or changing anti-arrhythmic drugs during the phototherapy period. Now move on to the discussion. These are the study summaries. ATP or DC therapies and all VT events were significantly decreased during the phototherapy, and no patient experienced adverse effect or did they receive additional therapy for suppressing VTs. Therefore, this photovoltaic use SGP demonstrated the efficacy and feasibility of non-invasive neuromodulation at home. The findings of suppression in the ATP or DC therapy and sustained VT burden, not in non-sustained VT, may indicate how SGP reduced the VTs. So prior study in animal models have demonstrated that disturbance in autonomic nervous system can sustain and modulate ongoing VTs, indicating that these disturbance did not merely act as trigger for ventricular arrhythmia. Compared to the findings of other neuromodulation therapies, daily portable SGP has also demonstrated a reduction in ATP or DC therapies more significantly than in the occurrence of non-sustained VT. That is, SGP may have a greater effect on VT maintenance than on triggering ventricular arrhythmia. Furthermore, compared to other neuromodulations, this daily portable SGP demonstrated its feasibility to be performed in an out-of-patient setting without special skills and complication. Therefore, the novel approach may become a game changer for the management of refractory VTs in the out-of-patient settings. However, there are several limitations to this study. First, VT events were counted based on the ICD or CRTD record, thus VT events not detected by this device, such as slow VTs. Second, because this study is an observational cohort study with a small number of patients, it cannot demonstrate a causal relationship. The research in this area is needed to overcome these limitations. So this is the conclusion. Daily portable SGP may represent a non-invasive therapeutic approach for suppressing refractory VTs in patients with a high-power device. Thank you. Thank you very much. I was initially informed that the online Q&A application doesn't work, but it appears to work. So if there are any questions you would like to submit, you can write it down and we can read it. Otherwise, I don't see any questions so far. But there is one from the floor. Hi, Peter. Hi. Thank you. Come closer to the microphone. Thank you very much. Excellent presentation. So can you tell me a little bit more about the machine? How expensive is it? How often do you use it? Not how often, how long? How long are the periods? And how fast do you see the effect? Do you have immediate effect during VT storm, for example? So thank you for your question. So this machine costs like 4,000 grand, and it's sold in Japan. So made by Tokyo Iken, Tokyo. And usually this device was made for the pain control in anesthesia area. And so your question is, how fast the effect? Right. And how long? Right. And how fast? Okay. So usually in this study, so we lend the device for two months, and they usually use the two months for suppressing the refractive VTs. And the effect is sometimes some patient represent immediately after attempt applying the phototherapy, but the others demonstrate a little bit VT or VF the first 10 days or half a month. But after that, they are going down to the decreased VTs. How long does it take to perform single daily session using this device? 10 minutes. 10 minutes bilaterally. Okay. So 10 minutes and 10 minutes. Any other questions from the floor? There is one question. Any changes in ventricular tachycardia cycle length? Did you notice any of these? Actually, I didn't see all the cycle lengths of the VTs, but so usually the cycle length does not change from my seeing the ICD record. All right. Thank you. Very interesting. Because of time reasons, we need to go further, and let me introduce Dr. Jana Haskova from Institute of Clinical and Experimental Medicine, Prague. Jana. Thank you. Thank you for introduction. Hello, everyone. I would like to present, but just I need to start it. I would like to present our randomized trial named STAR-VT, which compared radiotherapy with repeated radiofrequency ablation in a patient with a scar-related ventricular tachycardia. Hope it's here, yeah, okay. And it is a randomized trial named STAR-VT. For the beginning, I want to talk just briefly about some Czech history of stereotactic arrhythmia radiotherapy. In 2014, the very first published case report was published. It was published from Czech Republic from Ostrava, and described some case about an older lady with dilated cardiomyopathy and ventricular tachycardia with previous fat radiofrequency ablation. The same group of patient, the same group of people or physician continue with this study, and they reported this 10-case series in 2019, and they achieved a reduction, significant reduction, I don't know why it is this thing, significant reduction, it was 87.5% of ventricular tachycardia, be careful on this, be careful there, please, thank you, reduction of ventricular tachycardia events, and they achieved mortality 30% in this cohort, and they referred the side effects in two. A patient was a progression of mitral valve regurgitation, and one patient underwent mitral valve replacement. Then, we published last year the larger cohort from Czech Republic, we cooperate two centers there, and we describe efficacy and safety of radiotherapy in a patient with scar-related ventricular tachycardia. As we can see here, we divided this cohort onto the efficacy and safety due to new coregistration system, I will talk about it in the next slide. That's why we assessed just the 17th patient for efficacy cohort, and here we can see on the graphs that we achieved ventricular tachycardia reduction and ICD intervention reduction, and we compared, but ATP reduction wasn't so statistically significant as ICD shocks, but if we can see here, the blue perpendicular line show us the time when was radiotherapy made or performed, and the red spots shows us repeated radiofrequency ablation in this patient, that means that the patient had around 5.9 procedures to achieve these results. That's why we think there is some synergic effect of these two modalities for treatment of recurrences of ventricular tachycardia. If we look at the safety cohort, which is very interesting, we assessed 32 patients with follow-up more than six months, and we noticed 12% of adverse events, several adverse events, and eight patients had progression of mitral regurgitation, three of them had mitral valve replacement, and we had one deadly complication, it was bleeding due to esophageal pericardial fistula. Here, I would like to present our new, more precise system of co-registration between 3D anatomical map and CT scan, and with this co-registration, we improved targeting of radiotherapy, and it was described in 2020, and if you remember, I mentioned it before that in our cohort, we divided this cohort onto the efficacy, just on the 17 patients, those patients had this planet target volume determination, that's why. Okay, let's move to our START VT randomized trial. We initiated this study in June 2020, and we finished in January 2024. Again, we cooperated two check centers, randomization was in two arms, active arm was radiotherapy, and redoablation was as a control arm, randomization was in a one-to-one fashion, and we used for radiotherapy treatment a cyber knife system with a single dose of 25 grays, and in this patient, we used a planet target volume, this new type of co-registration. Repeated radiofrequency ablation was performed according to the new guidelines. Our study endpoints were recurrence of sustained ventricular tachycardia, and repeated ablation for ventricular tachycardia. Here, we can see on this table some demographic data and some basal clinical data of our patient. We see it wasn't significantly different in this both cohorts. We enrolled 22 patients, 11 in each arm, 77% were males with a predominantly known ischemic cardiomyopathy, and with the depressed ejection fraction of left ventricle, and the patient had around 3.1 previous radiofrequency ablation before this randomization. Here, we can see the results. As you can see, it was really slow enrollment. We just enrolled around 3% of this patient, which were indicated into the BT ablation. Study terminated after four years, and the follow-up was 18 plus minus 12 months. Eight patients had crossovers from the start, from the radiotherapy to radiofrequency ablation cohort, and two had crossovers to opposite side. Two patients in radiofrequency ablation arm couldn't be crossover due to incisional ventricular tachycardia and hemodynamic deterioration. They underwent another radiofrequency ablation. And here, we can see results in a graphic view. As we can see here, the patient in radiotherapy cohort had non-significantly higher risk of ventricular tachycardia compared with the radiofrequency cohort, but they had significantly higher risk of radioablation or repeated catheter ablation after radiotherapy. If we can see, if we look at the patient outcomes, we see that seven patients are already died. Heart transplant underwent three of them, and implantation of ventricular device system, two of them. We don't have some adverse even, but we again see some progression of mitral valve regurgitation that should be problem of this modality. And in a conclusion, let me say that in this highly selected cohort of patients with structural heart disease-related ventricular tachycardia, despite several previous radiofrequency ablation, recurrences of ventricular events were frequent in both radiotherapy or redo radiofrequency ablation. However, the risk of repeated radiofrequency ablation was higher in the patient after radiotherapy compared with the radiofrequency ablation. Prognosis in this population was and still is very serious, and this randomized trials cannot support the idea that STAR should be as a first line of therapy or should be as some equivalent of redo radiofrequency ablation. Thank you for your question and for attention. Thank you very much. We actually have some questions from the app, so let me read the first question. Can you expand on why eight patients crossed over from radiotherapy to radiofrequency ablation? Yeah, it was due to ventricular tachycardia, due to incisive ventricular tachycardia and storm after radiation. Yeah. We cannot wait to the effect, yeah, due to bed station. Any other questions from the floor? There is one question, please. Thank you for the presentation. I have a question regarding the endpoints, too, actually. So the first one is, you do not adhere to a blanking period. I think, and I were actually, if I was looking at a couple of meters, the radiotherapy arm, there were, I think, roughly 35, 37% recurrences within one week, I would say. So would that instantly make the treatment failed? That's actually my first question. My second is, the patients had no recurrence of catheter ablations prior to the treatment of three, I think, so they are sort of refractory to these treatments. Do you think in these patients, time to recurrence is the most meaningful endpoint, or is possibly VT burden reduction a more meaningful endpoint for these patients? Okay, for the first question, thank you. I think the blanking period is maybe more important in another studies, not here, because after radiation, the patient was in a storm, we cannot wait, we need to count it that it's some problem there. Okay, if we do it that some six weeks, as several study had six weeks of blanking period, we maybe achieve the better better results, but we want to treat the patient, and we want to know if this therapy is good to recommend to them, because it's less invasive. Okay, I understand that it should be nice, but the patient had an electric storm or incision ventricular tachycardia very, very early after radiotherapy, and we cannot cover it over our eyes of this view. Okay, but it's a good point, of course. And our second question, maybe I lost the whole, if we can't, excuse me, sorry. If in these refractory patients, time to recurrence is the most meaningful endpoint, or should we use VT burden? Yes, maybe the patient had radiofrequency ablation, you mean after radiotherapy? Yeah, it wasn't time to wait, yeah. They had amiodarone, they had ganglion stellatum blockade, and they were very often in a general anesthesia, but they still were in a rhythmic storm or some very incision ventricular tachycardia, even they were slowest, yeah, and it started to develop ventricle or heart failure, that we don't wait, we don't usually wait of this patient, to wait it, yeah. That's why the huge volume of radiofrequency ablation, yeah. And we indicated the patient in a really really bad condition, it means that we try to do radiofrequency ablation as a first, yeah, we more believe this modality than radiotherapy. The radiotherapy is for us as a by-law treatment modality, that's why the patient had ablation, ablation with both endocardial, epicardial approach, and if it cannot to give this patient more, we try to less invasive modality radiotherapy, and we see in some cases it helps, yes of course, but we see these results. Yeah, you're welcome. Thank you very much, and because of time reasons we need to proceed further, so let me introduce Dr. Lingguo Xu from University of Pennsylvania. Here is the screen and... Good afternoon, everyone. Today I'm going to talk about the geometric characteristic of the ventricular tachycardia corridors in patient with ischemic cardiomyopsy. Let's review the VT re-entry requirement. First, it require the presence of analytical obstacles and circuit dictated by adequate size of the obstacles and their circuit. Slow conduction velocity, adequate refractory period of duration of action potential. Second, the presence of the unidirectional block. Third, the preservation of the impulse current as it traverse the disease path. Electrophysiologist has a clear interest in understanding the obstacle and circuit tissue property. Recently, it has been hypothesized that a hyperboloid corridor can explain the lines of block on the surface mapping during the basal rhythm but conduction during the ventricular tachycardia rhythm. Two type of longitudinal section can be generated by cutting through the center and the peripheral of a hyperboloid. It generate a central hyperboloid and peripheral hyperboloid. Lines of block in the central hyperboloid can be found at the two lateral sides and the current can go through in the middle. Lines of block in the peripheral hyperboloid can be find at the forward direction or exhibit as a U shape which will block the current going forward. The 3D hyperboloid model for the re-engined VT circuitry has been supported by the electrogram mapping but has not been validated on imaging. The purpose of the current study is to reuse the real world late gadolinium enhancement cardiogram imaging in patient with ischemic cardiomyopathy to characterize the geomagic feature of the viable corridors that participate in the VT circuitry. From about 2,400 patients that underwent the left ventricular mapping and ablation at the Hospital of the University of Pennsylvania from the end of 2018 and the middle of 2024, we retrospectively identified 45 ICM patients who underwent the LG images before the ablation and identified 125 VT exit in the mapping. We also identified five patients with ICM with the prior LG images and identified 11 VT entrances during the mapping. All patients underwent electroanaphytic mapping. VT re-entry was identified as a concealed fusion with short post-passing interval or 12 ECG morphology mapping matched to the VT morphology and with non-indisability of this site after the ablation. When possible, such sites were further classified as the entrance, the isthmus, and the exit. LG images using the software ADAS, we semi-automatically control the sub-endocardium and the sub-endocardium. Then the myocardium was divided into nine layers equally. The myocardium then was categorized as three type of tissue. The healthy myocardium with less than 40% of the maximum signal is color-coded as the blue in the 3D-LV shell. The borosomal tissue between 40 to 60% of the maximum signal is color-coded from the white to the orange area. The dense LG region with more than 60% at the maximum signal is color-coded as the red area in the 3D-LV shell. Then based on these three type of tissue characterization, the corridor was computed automatically by the software ADAS. Then based on the following criteria, first the corridor must go through the borosomal tissue, and it must connect it with a healthy myocardium at the two end, and protected by the dense LG region at the two sides, and the length of the corridor should be no less than five millimeter. Then the borosomal tissue and the dense LG region and the corridor that derived from the LG images was then co-registered to the EM data. We identified three type of corridor, the funnel-shaped corridor, the cylinder-shaped corridor, and the hyperbolic-shaped corridor. Two type of longitudinal section can be generated by cutting through the center and the peripheral, which will generate the central plane and the peripheral plane. In a scenario of the hyperbolic, it will generate the central hyperbolic and peripheral hyperbolic. This is a schematic plot to explain how we characterize the geometric feature of the VT corridors. As we mentioned, the myocardium was divided into nine layers. Here, from the layer number one to layer number three, and layer number seven to layer number nine, no corridor was detected. Therefore, they were classified as peripheral. Therefore, they're classified as the peripheral. And then from the layer number four to layer number six, the corridor was detected and registered the VT axis. Therefore, they were classified as central hyperbolic. In a central hyperbolic, we measure the corridor length, the corridor width, and the corridor thickness. More importantly, we measure the angle of the corridor osteum at the VT size, as well as the angle of the object osteum. Among 46 patients with ICM, the mean age is 68 years old, with 95% male, 85% has documented heart failure, 98% with ICD presence, and 72% with amiodarone use. The mean LVEF is 28%. From 45 patients with ICM, 125 VT axis was identified from the mapping, and then registered to the corridors that derive from the LG images. Among these 125 VT corridors at the VT axis size, 4.8% of corridor exhibit as a funnel-shaped corridor, 1.6% exhibit as a cylinder-shaped corridor. Most prominently, 94% of the corridor exhibit as hyperbolic-shaped corridor. From five patients with ICM, 11 VT axis was identified from the mapping, and then registered to the corridors that derive from the LG images. 100% of the corridor finally exhibit as a hyperbolic shape. Therefore, in the context of ICM, most of the VT corridors align with a hyperbolic model. Here we use the real-world LG images to showcase the 3D hyperbolic model of the VT corridor. As we mentioned before, the myocardium was segmented into nine layers. Here from the layer number one to layer number four, no corridor was detected. Therefore, they were classified as the peripheral. And then from the layer number five to the layer number nine, the corridor was detected and registered to the VT axis size. Therefore, they were classified as a central hyperbolic. Then from these five central hyperbolic, we extract the corridor area and then reconstruct the corridor area into a 3D model. Here it exhibits a hyperbolic shape. This is the view from the first layer to the ninth layer. This is from the ninth layer to the first layer, and this is the lateral view. The red 3D structure here corresponds to the dense LG region here. Finally, we quantify the geometric measurement of the VT corridor at the central hyperbolic. There are five central hyperbolic here. We take one layer, for example. We use the digital projector to measure the angle of the osteum at the VT size, which is a 91 degree. We measure the angle of the opposite osteum, which is a 51 degree. We perform the same measurement in all the central hyperbolic, and then the mean of all the measurement from all the central hyperbolic will be used to represent the 3D hyperbolic model. As we mentioned before, there are 125 VT axes identified from the mapping and then registered to the corridor. The angle of the corridor osteum at the VT size has a mean of 103 degree, which is substantially larger than the angle of the opposite osteum with a mean of 83 degree. Therefore, in the hyperbolic model, the exit osteum typically has a larger angle than the entrance osteum. Then we try to explain why the VT corridors exhibit a hyperbolic shape. I use the source and the sink mismatch theory. If the corridor exhibit as a cylinder shape when the current going through the corridor, and then at the interface, it will be the small source connected with a rapidly enlarged sink. This rapid transition will result in current degradation into the multiple directions and substantially slow down the conduction velocity and finally induce the impulse block. By contrast, if the corridor exhibit a hyperbolic shape when the current going through the corridor and then at the interface, it will be a small source connected with a gradually enlarged sink. Therefore, this transition is much slower, which will help to maintain the current preservation and facilitate the impulse propagation. Imitation, the sample size of the current study was modest. External validation with a larger sample size may help to refine the result. A median resolution error remain to be 3.3 millimeter. However, this is not going to have differential impact on the exit versus the entrance. Conclusion. The VT corridor shape that derived from the LG images commonly exhibit an asymmetric hyperbolic model. Funnel and cylinder shape can also be observed, but with a much lower frequency. Finally, the VT exercise was associated with a larger angle osteum than the entrance size. Thank you. Here I would like to thank my postdoctoral mentor, Dr. Simone Nazarian. Thank you for his dedicated mentorship. Also like to thank all the faculty member, colleagues and lab mates at the EP department at the University of Pennsylvania and thank you for all your attention. I'm ready for questions. All right, so because of time reasons, let's proceed with one question. When were the MRI scans acquired? Before ICT implantation or with already implanted ICD? Do you have information about this? Oh, yes. So we actually, yeah. So most of the patient, so they has documented matricular tachycardia and in 98 of the patient has ICD presence. Yeah, but the issue is that, you know, the presence of ICD can have some impact on the quality of MRI scans, right? And sometimes you have, you may have like a large number of artifacts and stuff like that. So the question is, if there were any scans obtained before implantation or after, do you have any information about that? I think that's a very great question. Yes, you were right. The ICD presence will cause a certain artifact on the cardiac MRI images, but very fortunately, the artifact there from the ICD devices actually has a pretty minimal effect on the LG images. It has a lot of impact on the CT images. And also we actually have a long flowchart that we filter the patient and what the criteria it is, we identify those patients who has those EM data and also have the pre-procedural cardiac MRI. And those which has a poor quality already excluded. So before we perform the data analysis, yeah. Is there any special protocol required from the company in order to obtain such reconstruction to proceed with any special MRI protocol before sending the data to projection of 3D images or is it like a regular MRI scan? Oh, so I think this is a more regular scan, but for the images from our center, I think it tend to be a little bit higher resolution. So the in-plate resolution, I think it is one millimeter times one millimeter. And then a very important feature about data, it is we have almost 60 to 72 slices. So which means that the thickness of the slice, it is small. It's about a 0.4 millimeter, which is substantially smaller than the convention, which is the slice is eight millimeter and then the inter-slice gap is two millimeter. So ours is substantially smaller than the conventional one, yeah. Thank you very much. And because of time reasons, we need to go forward and let me invite Dr. Konstantinos Siontis from Mayo Clinic. Thank you. It's my pleasure to be talking today about RADIATE-VT. Let's see if our slides show up. On behalf of my co-investigators, this is a presentation of the study design protocol of RADIATE-VT, a trial that will be looking at the comparison of cardiac radio ablation and repeat catheter ablation for refractory ventricular tachycardia. Disclosure slide. And so RADIATE-VT is a Pivotal International multicenter IDE randomized control trial that will be randomizing and is randomizing one-to-one repeat catheter ablation versus cardiac radio ablation for patients with refractory VT. The goal of the study is to assess the safety and efficacy of cardiac radio ablation with variants CRA system. The system consists of three components, the Avira targeting application, which identifies the target, the Eclipse treatment planning system where the treatment plan is created, and ultimately the TrueBeam radiotherapy system that delivers the photon radio ablation. The study scheme I've shown here, it's a one-to-one randomization, as mentioned, between CRA and catheter ablation, redo catheter ablation. The planned enrollment is 380 patients. After the last patient is enrolled, there will be a one year of additional follow-up and primary analysis will be conducted at that point with a plan for another five years of long-term follow-up beyond that. The key inclusion is that patients have to have high-risk refractory VT, we define that as ischemic or non-ischemic cardiomyopathy with an EF of 49% or less. They have had to have a previous standard of care catheter ablation for VT, at least one, and they have to have recurrent sustained VT, monomorphic VT in the previous six months after the catheter ablation. They do have to have an indication, a clinical indication for repeat catheter ablation procedure and they also have to have failed or not be tolerant to amiodarone, meaning they had recurrent ICD therapy or sustained VT while on amiodarone or they had to stop amiodarone because of a side effect. There's a number of exclusion criteria. The key ones is that if there's a contraindication to catheter ablation, patient cannot be enrolled, it's a 50% chance they will be randomized to catheter ablation. There will be a VT ablation done within the last two weeks would be a contraindication for enrollment. Pleomorphic VTOVF as a primary arrhythmia would not be inclusive in the trial. And if you have a lot of VT morphologies on the ICD electrograms or in the NIPS procedure, that would also be an exclusion. Few other things, LVAD patients or patients who are scheduled to get an LVAD or a transplant would also be excluded. There's two primary endpoints. There are co-primary endpoints. One is a safety endpoint that includes freedom from treatment attributed serious adverse events. That is events that are probably or definitely attributed to the treatment in the first 12 months post-treatment. And then an efficacy endpoint, it's a composite of freedom from death, appropriate ICD shock and VT storm. The mortality will be counted from randomization through the 12 months for shock and storm. There will be a 30-day blanking period post-randomization to allow a little time for patients to actually receive the treatment, especially for CRA, which can take a little longer, or scheduling the ablation procedure. A few secondary outcomes, there will be quality of life assessments at six weeks post-treatment, and a VT burden assessment as a secondary outcome, which will include assessment of a six-month pre- and post-randomization period for evaluation of VT events, anti-tachycardia pacing, and shock. A few exploratory endpoints, there will be catheter ablation-specific and CRA radiation-specific outcomes. And we're gonna be particularly interested in the outcomes and characteristics of patients who undergo repeat procedures, second procedures, either as a repeat catheter ablation in the CA arm or as a crossover from CA to CRA, from ablation to radiation or vice versa, from radiation to catheter ablation. As you can see, there's no repeat CRA. Patients are only allowed to receive a single treatment as part of the trial in the CRA arm. A little more about the specific arms and interventions. The catheter ablation will be a uniform ablation protocol per standard practice, standard of care for catheter ablation that will include VT induction and mapping, whether it's activation mapping or substrate mapping. They will be encouraged by protocol to do post-ablation inducibility testing unless the patient's hemodynamic status does not allow that. Only irrigated radiofrequency catheters are allowed in the trial, so PFA systems and other off-label, like bipolar, for example, alcohol, those types of approaches will be not allowed in the trial. In the cardiac radioablation arm, there is a treatment simulation that is done with a contrast-enhanced, respiratory-gated CT. For treatment planning, the ablation volume will be identified based on the scar information and the VT exit, the VT morphology information. And a patient-specific target will be defined in the treatment planning CT. The treatment consists of a 25-gray single fraction with photons using the TrueBeam. The study governance includes five committees, the usual clinical event committee, as well as the Data Safety Monitoring Board, and specific and unique to this trial, the EP eligibility committee that reviews all patients to ensure that they meet criteria for enrollment. It's particularly about the appropriateness of the first or the previous catheter ablation procedure and the completeness of that procedure. And then the targeting committee in the CRA arm that reviews the target creation in Avira, as well as a radiotherapy committee that reviews the treatment plans for all patients. The study is open and enrolling currently in nine sites in the United States that are shown here, with several more to be activated in the next few weeks and months, and a few more sites also in Europe, and more to come on that in the next few weeks. Thank you very much for your attention. Happy to take any questions. Thank you very much. Looking forward for results of the study. There's one question, I guess, for this presentation. How many ablation for structural VT do you have each year? At your center, I guess. This is what I have. Oh, yeah. I'm interested how many ablation procedure due to ventriculotorhicardia in a structural heart disease do you have in your center per year, approximately? I will have to look up the number. Probably something at Mayo Clinic, but this is not a single center trial, right? So this would be a multi-center and there's high volume centers like, you know, Mayo, Penn, Vanderbilt, and a few other places. I think, I can speak for Mayo, probably we do about 250 structural VTs a year, maybe 300, something like that. Because we have a stop-storm consortium in Europe and it's many centers there, a huge volume, and we cannot achieve this other target. That's why I will hold the finger if this 380 patient will be done. Okay, that's what I was asking. We hope to meet that goal as well. Thank you. Yes. Yeah, I just wanted to know, you've got this review panel for your targets, but is there any standardization in what imaging is being done to inform that targeting process? Or any standardization on what imaging can be used for pre-procedural catheter ablation as well? Like something like an in-heart scan, is that eligible to be used on either the catheter ablation or the pre-procedural arm? Yeah, so the assessment of the scar and defining the substrate is, and defining the substrate is obviously a key component of both invasive and non-invasive ablation, but even more so non-invasive ablation. So we rely on the usual cardiac MRIs and previous maps that might be available to us. CT and other imaging information, a little less so. In-heart and other imaging segmentation modules and software are not part of the trial. We rely on a proprietary method that I mentioned, the Avira software and the Eclipse treatment plan that accounts for a lot of the structural information, but not third-party vendors as part of this. And is any of the insights in the Avira software accessible for pre-procedural planning of the catheter ablation side, just to have that knowledge of the substrate before you go in catheter? Yeah, for regulatory reasons, I can't go into too much detail about that, but I can tell you that the data that is fed into the treatment planning software is equal to both CA and CRA arms. Yeah, so in that sense, the operator has access to the comprehensive information. Okay. If there are no questions, let's proceed further. And let me invite Dr. Mike R. Harris from Vanderbilt University Medical Center. All right, good afternoon, everyone. I'm delighted to be here today. My name is Majdal Harassas. I'm a second year EP fellow at Vanderbilt, and I'm excited to present to you the results of our randomized control trial evaluating the use of the ryanodine receptor inhibitor dantrolene for treatment of ventricular tachycardia. So we know that sudden cardiac death accounts for up to 20% of deaths in the United States, and that ventricular tachycardia and fibrillation is a common cause of sudden death in those with structural heart disease. Despite this, there have been no new antiarrhythmic medications that have emerged for VT in over 20 years, as you can see from the timeline here, that demonstrates many of the antiarrhythmics that we use today clinically were evaluated back in the 90s. So a lot of people had been really thinking critically about the pathophysiology of VT and how we can leverage this to develop new drug targets. We know that in structural heart disease, there is alteration of the ryanodine-2 receptor that results in calcium leak from the sarcoplasmic reticulum. This causes delayed after depolarizations that can facilitate reentry and therefore be proarrhythmic. Dantrolene is a medication that blocks the ryanodine receptor and is already FDA approved for the treatment of malignant hyperthermia in humans. And it does this effectively by blocking the ryanodine receptor in skeletal muscle. Dantrolene has been shown to have antiarrhythmic effects in animal models, but the effects in humans are not well-defined. So we performed a randomized, double-blinded placebo-controlled trial with two-to-one randomization of dantrolene to placebo. We stratified patients according to coronary disease with prior infarct, amiodarone use within the prior 21 days, and LVEF less than 35%. We included patients who were referred to our institution who were 18 years or older and who were undergoing catheter-based VT or PVC ablation and had evidence of structural heart disease, which is defined as you can see on the slide. Patients also needed to have a mechanism for backup cardiac pacing with an implanted permanent pacemaker or transvenous defibrillator. These are our exclusion criteria. Briefly, we excluded patients with severe heart failure, severe liver disease, kidney disease, or respiratory neuromuscular disease. Patients underwent their routine VT or PVC ablation as per usual standard of care. This is an example of a typical timeline for a VT ablation where patients came in after vascular access, we did a baseline EP study with induction of VT, we then performed an electroanatomic voltage map, ablated the clinically relevant VT, and then repeated usually an attempt at VT induction. At this point, our study protocol commenced. We performed a measurement of conduction and refractoriness, hemodynamics, and attempted to induce VT. The patients then received dantrolene or placebo as an intravenous push over three minutes, followed by a 20 minute waiting period where we continuously monitored ECG parameters and hemodynamics. After this waiting period, we then repeated our measurements of conduction and refractoriness, hemodynamics, and attempted to induce VT once again. Over the course of about three and a half years, we screened 527 patients for enrollment in our study, and we enrolled 69 participants of which 51 ultimately completed the research protocol. Of these patients, 29 received dantrolene and 22 received placebo. I'm gonna draw your attention to some key baseline demographics. Our median age at enrollment was 68.4, and this was roughly similar in both groups. About 60% of our patients had coronary artery disease, and again, similar in both groups, and about half of the patients had received amiodarone within 21 days prior to the ablation. Median LV ejection fraction pre-procedure was 35.5%. And I'll also draw your attention to the fact that these were long procedures. Our median duration of the procedure was 5.8 hours, and on average, our research protocol added about 60 to 90 minutes to what was already a lengthy procedure. We had three aims in this study. We wanted to evaluate the effect of dantrolene in patients with structural heart disease on inducible ventricular arrhythmias, hemodynamics, and conduction and refractoriness. So what did we find? For VT inducibility, we had a standard induction protocol where we attempted to induce VT. We defined patients to have met the primary inducibility endpoint if they had monomorphic or polymorphic VT or VF that lasted for 10 seconds or more, or if they had two or more episodes of non-sustained VT that lasted between three and nine seconds. And this is an example of a patient who received three ventricular extra stimuli, after which we induced a monomorphic VT. We found that in patients who received dantrolene, there was a significant reduction in VT inducibility. 41% of patients actually met criteria for the primary inducibility endpoint pre-study drug compared to 13.8% of patients post-dantrolene. And as you can see, there was no significant change in those who received placebo. In a logistic regression model, the odds ratio for meeting that primary inducibility endpoint was 0.23 in those who received dantrolene, and this was statistically significant. From a hemodynamic standpoint, all of our participants had a pulmonary artery catheter and an arterial line for hemodynamic monitoring. We measured heart rate and blood pressure every minute for 20 minutes. We also looked at change in pressors and inotropes. We measured cardiac output by the FIC method every five minutes, and also evaluated right atrial and pulmonary artery pressures pre and post-study drug. We noted that there were no significant changes observed in any of these hemodynamic parameters. From a conduction and refractoriness standpoint, we used our baseline voltage map to identify an area of high voltage, such as the area here in purple, and an area of low voltage or scars, such as the area here in red. We then placed a mapping catheter, which was usually the decanav catheter, and we did a standard protocol where we gave a drivetrain at 600 milliseconds, followed by a series of decrementing single extra stimuli, and measured the time from the pacing to the recording electrode. And from this, we were able to construct a conduction restitution curve, and we derived the value denoted A, which is the baseline conduction time, as well as the value denoted by B, which is the curve inflection point. We performed these measurements in the high and low voltage regions, pre and post-study drug, and we found that dantrolene did not alter the effective refractory period or the conduction curve restitution properties in both the high and low voltage areas. A member of our study team also did a blinded measurement of ECG parameters, such as the PR interval, QRS duration, and corrected QT interval, every two minutes for 20 minutes, averaged over three consecutive beats, post-study drug. And we used a mixed effects model to evaluate the changes in these parameters over time, and we noted that there was no significant change in any of these ECG parameters with time. Our secondary outcomes, in conjunction with our anesthesiology colleagues, we also set out to evaluate the effect on neuromuscular twitch height amplitude, the need for respiratory support, and respiratory mechanics including tidal volume, respiratory rate, and minute ventilation, as well as arterial blood gas parameters. The results of this analysis will be reported separately, but overall we noted no drug-related serious adverse effects during the duration of our study. So in conclusion, we found that in patients with structural heart disease immediately post-VT and PVC ablation, dantrolene reduced VT inducibility significantly post-ablation compared to placebo. There were no effects on conduction or refractoriness that were measured at a rate of 100 beats per minute in unablated tissue. Weather effects occurred in more diseased tissue, in ablated tissue, and at different pacing rates warrants further study. But overall from our initial feasibility and safety randomized controlled trial, our findings support a potential antiarrhythmic effect for ryanodine receptor inhibition in humans that warrants further study. Potential applications include as an adjunct antiarrhythmic in VT storm or in the cardiac arrest setting. I'd like to thank and acknowledge the project program and project principal investigators, Dr. Stevenson and Dr. Shoemaker, as well as the rest of our members of the research team and to the American Heart Institution for funding this research. Thank you. I'd be happy to take any questions. Thank you very much. Any questions from the floor? There are two questions, so please. Go, go. Hi, Shovik from Australia. Great talk. Really liked it. What's the half-life of dantrolene? And is the idea mainly to see if it's an acute setting drug or how is it planning to be used? Primarily in an acute setting drug because the half-life of the IV formulation of dantrolene that we used was 10 hours. The time-to-peak effect was about 0.5 to five minutes, so primarily it would be used in an acute setting. So if the half-life was 10 hours, did you guys, following day, did you guys look at any particular parameters? Yeah, so we did a few things afterwards. We measured the grip strength two hours after the procedure, and then we also measured, for the first 48 hours after the procedure, serial blood tests for the concentration of dantrolene to do a pharmacokinetic and pharmacodynamic analysis, which will also be reported in the manuscript. Great talk, thank you. Thank you. Thank you. So, thank you. Pieter Postma from Amsterdam. Great study. So, if it doesn't have any effect on ERP and conduction velocity, directing this only to Ryanodin is quite challenging, maybe. One question. And the second question is, this is also already available as a tablet. Are you already investigating the use of this? Yeah, so both are very good questions. To answer your first question, for the conduction and refractoriness, we didn't find any in our particular data set, but we were measuring it in particular areas of the ventricle, whether it has effects in more kind of disease tissue, in ablated tissue, and again, at different pacing rates, because again, it was all done at like 600 milliseconds for the drivetrain. That just requires additional work, but we were kind of just reporting the data as we found it here. But certainly, it's interesting more of like as a mechanism per se for VT inducibility, which is the main reason that we're going to be looking at it clinically. And then to answer your second question was, there is an oral formulation of dantrolene that is available. Currently, it's really indicated more for chronic muscle spasticity, so patients with cerebral palsy, multiple sclerosis, and things like that. So it's not been evaluated for the arrhythmia setting. The oral formulation of dantrolene primarily is used in the neuromuscular setting and has some side effects associated with it. Yeah, just as a line of thinking, it's nice to have one of the neurology drugs into cardiology instead of the other way around. Yeah, exactly. All right, so we are two minutes over time, which is not that bad, I guess. So thanks all the speakers and all the audience for this fantastic session. Thank you.

ventricular tachycardia

steroid ganglion phototherapy

refractory ventricular arrhythmia

STAR-VT trial

radiotherapy

radiofrequency ablation

late gadolinium enhancement

cardiovascular magnetic resonance

ryanodine receptor inhibitor

dantrolene