Good afternoon, welcome to Heart Rhythm TV. My name's Oliver Monfredi, and I'm delighted to welcome my co-host, Jessica Mornix. Thank you. It's great to be here. I'm excited to talk about the studies we're going to hear about to sound really interesting to me regarding treatment of ventricular ectopy or VT, the IN EURO study, specifically looking at how CT can be used to guide our treatment with ablation, which is phenomenal when you think about the centers and the access to CT being so large. Absolutely. Historically, we either used no imaging for these procedures or we had to rely on MRI imaging. Precisely. And the availability, widespread availability of CT should really open the door for better management for these VT patients. It's great news for our patients. I'm super excited to hear about the BRAVE trial, where they discuss Brugada syndrome patients and approaches for VF ablation in those particular patients. It should be a real breakthrough for those patients who've been underserved, I think, historically, Jessica. And we're also going to hear about the TREAT-PVC study using transcutaneous technology to treat ventricular ectopy. That's completely phenomenal to me. Absolutely. Save a few people an ablation. That can't be a bad thing, right? I mean, you're the EP doctor. And then last of all, the MAP-IT-CRT trial, where the authors discuss using special CT imaging of the cardiac conduction system to guide the positioning of the right ventricular and the CS lead to guide better outcomes is really exciting and could be a real game changer in terms of how we adopt these new technologies and how we approach these procedures. Better pacing is better for our patients, right? And now it's time for your late-breaking clinical trials. Good afternoon, everyone. And thank you for joining us for this late-breaking clinical trials and science randomized clinical trials session. I'm Sana Al-Khatib. I'm an electrophysiologist from Duke University, the program chair for HRS 2025. And I am delighted to be joined by my colleague, Dr. Andrea Natale. And we have four sets of clinical trials that will be presented today. I guarantee that they're going to be very interesting and informative. Just as a reminder, this is the QR code that we'd like you to use to enter questions. And I'll pay attention to the questions that are coming in. We'd love for this to be interactive, including with questions from the audience. So it is my pleasure to invite the first speaker, Dr. Frédéric Sacher from France. He's going to be presenting computed tomography-guided catheter ablation for ventricular tachycardia, the in-your-heart multicenter randomized clinical trial. Thank you very much, Mr. and Mrs. Chairman, dear colleagues. It's really an honor to present our study in your heart, the computed tomography-guided catheter ablation for ventricular tachycardia on behalf of the co-investigators. As you know, VT ablation is a complex procedure, generally performed in highly experienced centers with various strategies, and heterogeneous strategy. And we and other groups have tried to develop image-guided ablation to aid for this complex procedure. And basically, the idea there is to try to standardize and simplify the procedure. And I have to acknowledge the huge work of Pierre Jaïs, Hubert Cauchy, and Bruno Sauret, who really were at the beginning of that. Basically, what you are seeing is a color coded on wall thickness, dark red being the sinus port, and the light yellow being 5 millimeters. And what has been shown is the area between the sinus port collocates with VT isthmuses when mapped during VT ablation. And the idea under that is that this dark red area, the sinus port, were acting as boundaries. And the strategy is there to connect these boundaries to each other and to anatomical boundaries when it's close by. So this is the goal of the study, to compare conventional VT ablation versus city-guided strategy in terms of procedure duration, efficacy, safety, and cost. So this is, in your heart, is an institutional multi-centric perspective signal blinding randomized clinical trial. It has been funded by the EITLs, which is a EU organization in charge of innovation in health. 14 clinical sites have been involved. Of note of these 14 sites, 11 were naive to this workflow. So it's important to keep that in mind for the dissemination. So these 11 centers did not use that in a routine. And we just asked them to get at least one blank procedure before hiring people just to make sure that there was no problem with the workflow. We included 113 patients in these 14 centers across Europe. And actually, the inclusion criteria used were pretty classical for de novo VT ablation, prior mucolar infarction. We are dealing with patients with prior mucolar infarction, in this case, with kind of VT, number of VT, which actually were the criteria used for VANISH2 VT episodes. In terms of exclusion criteria, nothing really unusual, neither. We add the chronic kidney disease and exclude patients with DFG under 30 milliliters per minute, just because those patients need a CT scan, and then with the injection of contrast. So in case of renal failure, it was not feasible. So all the patients get CT scans. This is part of our clinical workflow to route enterocardiac thrombus and other contraindications. And then, once this was the case, they were randomized either to conventional VT ablation without imaging or to CT-guided imaging. All CT scans for the CT scan of all patients were uploaded on the in-heart platform, and model was created. But only those randomized to CT-guided ablation were released. The model of patient with CT-guided ablation were released on the platform, and then can be downloaded by the participating centers to be integrated in their 3D workflow model and 3D ablation system. So they were importing the images, merging. And merging here is key, because this will make the procedure accurate. So this was an important point. And then, ablation of the identified, what we call, isthmus, this area in between a thin scar. And the idea was to render this area non-capturable anymore, using at least a contact force catheter with at least 10 grams, 40 to 50 watts, for 45 to 60 seconds. And once this was done, we did a study in this CT-guided arm. If it was negative, with passing from RV, LV, up to S4, and down to 200 milliseconds, we stopped there. If there was a VT inducible, then we go and ablate for it to render it non-inducible. So this is the flowchart. We had, basically, 114 patients at the beginning. One did not go the procedure. So we ended up with 113 patients. And as I mentioned earlier, 11 of these sites were not used to the procedure. So eight did not receive the procedure. Actually, they received both procedures, because they had a full map, which was not recommended in the protocol. So here is the population. Pretty classical. So their initial MI was 15 years ago. So pretty long after the first MI. EF, LVF was 35%, and 40% of the history of electrical storm. In terms of procedure, use of high-density mapping was present in 91% in the commercial VT ablation arm, which was quite kind of logical, because of the VT mapping and substrate identification and mapping, and 25% in the CT-guided VT ablation group. So the CT-forced catheter, whereas it was required, was not used in every patient. But it was the same in both groups, 91% of the cases. And we obtained, in the CT-guided group, non-inducibility in 65% of the patients, meaning that in three-fourths of the patients, we stopped the procedure after isthmus connecting this scenario. There was an adverse event during the procedure, a major adverse event during the procedure was the same in both arms. And concerning primary endpoint, which was procedure duration, and the definition was the time between first catheter introduction to last RF application, we had a decrease in 19% in the CT-guided group of procedure time. When the protocol was followed, per protocol, it was 28%. Procedure time is good, but efficacy is important too, and this is the main goal. So absence of VT recurrence was present in 67% of patients in the commercial arm versus 66.8%, but this was not significant. We had a reduction of VT burden by 90% in the CT-guided group, the blue bar, versus the commercial group. So finally, concerning the absence of unplanned cardiovascular hospitalization, cardiovascular death or VT events, this was obtained in 59.6% in the CT-guided arm versus 48% in the commercial arm. And finally, concerning procedure cost, and we can discuss that, it was based in French public health system, and we are not paid very much, but in the manuscript we'll have much more detail depending on countries. Without general anesthesia, without housing either, and assuming cost for image modification of 1,250 euros, we had a reduction in 10.6% of procedure cost using this approach of CT-guided versus commercial VT ablation. So to conclude, ladies and gentlemen, this digital twin based on the wall thickness as a surrogate for infarct scar and the channel to guide the VT ablation allows a reduction of procedure duration by 90% and 28% when the protocol was followed without increased procedural risk with a one-year VT-free survival of 76.8% versus 67.3% in the commercial group, although this was not significant, and a reduction of procedure cost by 10.6%. So I really want to thank all the participating clinical site because this could not have been done without them, and this is a huge effort for all of them, and I really thank everyone for their participation. Thank you very much. The commentary will be provided by Dr. Jason Bradfield. Thank you. Well, first I want to congratulate the authors on a really impressive study. I'm not typically terribly impressed by, you know, many VT studies, but I think this one has real potential to change the way we ablate VT. I mean, I think for many years we knew that procedure duration affects outcomes for these patients. The longer the procedures, the more complications, and when we started doing a lot of imaging, and we've done it for years, a lot of that was helpful to have a general idea of where the scar was, and the authors have been instrumental in providing better imaging data for us, and there's a cost to that data, and it's always been a question of what that cost is and how beneficial it is in the long term for outcomes, but also for the, you know, how you can justify that to your institution. I think now we're getting to the point with this data where we can not only just see pretty pictures, if you will, but clear targets that can help more and more people perform VT ablation. Perhaps less experienced centers will have data that's provided to them that they might not have known before, and that can ultimately benefit patient care, expand the availability of VT ablation across the world, and I think the, you know, the cost information it sounds like will be in a different manuscript, but I think that's going to be interesting as well because, again, at least in the states, when we have to justify an upfront cost of imaging, if you're actually saving money on the back end because of needing other fewer of the other tools I think that's beneficial. Obviously as a VT ablationist that hurts my heart a little bit to think about not doing multipolar mapping during a VT ablation and how they decided that in the study I'll be interested to see in the manuscript but I think could be very beneficial for patient care and outcomes. Thank you. All right thank you very much. We have a couple of minutes for questions and I'd like to ask you Dr. Sacher a couple of questions if I may. The first one is I'm intrigued by your choice for the first for the primary endpoint. Did you consider making VT recurrence a primary endpoint and if so what sample size would you have needed to look at that particular primary endpoint. That's a very good point and this is of course the reason of this endpoint. I mean for calculation it was a bit hard because we just have pilot study and this is a good start to get a bigger study though. But from what we had we anticipate more than 500 people. So make it pretty unrealistic at least as a first step. So that was one of the reasons why. That leads me to my second question which is are you planning to do another study looking at those endpoints. Yeah. So I have backup slides to the future and I think yes but with also different ablation strategy and different tools for ablation and not with our single or small tip RF catheter but with larger tip this could be achieved even easier and probably with better result on long term. So we are working on both ablation part but also the imaging part with new imaging modalities such as photoconting CT with better spatial resolution tissue characterization that could even we can even learn more on the substrate itself and be more specific on the targets. I have a couple of questions. How do you explain that the group undergoing conventional have less radiofrequency ablation time the other one. I would expect the opposite. Yeah. So that's a very good point. So the strategy in conventional arm was led to the so I suspect that some are doing more just well they have to do substrate ablation but some were maybe less inclined of doing more more substrate and more focusing on VT mapping. And this is probably one of the reason but we have to we have the map of all of the patients and we have to compare that. Yes. Then ask you. I just want to ask you one question that is there in both the arms VT induction wasn't required at all and baseline is that true. Yeah. So it was in the in the commercial group but it was not and it was not perform in the in the city. Yeah. Yeah. So it's when the city guy who is mostly so it's it's mostly a substrate based ablation in one group. Yeah. It is a substrate based ablation. Yeah. Yeah. I had the same question. I thought that would be more ablation in the conventional group than the targeted group. And then the reduction in cost which is kind of contrary to what Jason just said we're all worried about increase in cost I believe is two things one avoiding mapping or the multi electrode catheter and to procedure time which adds to lap time and the cost of the procedure. All right. Yeah. That's correct. What can I have to move on. But I just want to say just to put a plug in please enroll try your best to enroll more women in the next trial because I saw that the number of women was pretty low. So thank you so much. Thank you. So we move to the next trial is the brave Brugada syndrome ablation from the for the prevention of the presenter is not the money. Thank you very much. Dr. Nathalie. Dr. Carty. Good afternoon. Ladies and gentlemen. This is my discourse your slide and catheter ablation of electronic subject areas in symptomatic Brugada syndrome patients has emerged as a promising therapeutic approach for preventing ventricular fibrillation is used also has grown globally particularly in lesion where community is unavailable as an alternative therapy. However prospective random mind control try data has been lacking to address this gap. We initiate the in 2017 we initiated the breadth study among the center prospective randomize try conducted in Thailand. The bread try experience a significant delay due to the COVID-19 pandemic resulting in a pause lasting approximately three years. We couldn't do anything unfortunately. Fortunately we resume and completed the study following recommendation from the data safety monitoring board which terminated the try in December 20 to 24 due to compelling interim efficacy result. I'm pleased also that the bread try data today and that I'm presenting today and delighted to announce that it our manuscript had been accepted by heart with him and will be published simultaneously after the embargo today following this presentation and it will be available open access. Therefore I will not be reading about the participating center and investigator detail could be provided in that manuscript brave is a month descent center study that aims to assess the efficacy and safety of abrasion therapy for a VF invention in patient with a symptomatic Brugada syndrome. The study is conducted across Thailand featuring one to one random might decide comparing abrasion versus control eligible participants were symptomatic Brugada syndrome patient who either had existing ICD or had experienced at least one appropriate ICD shock within the past five year passion that younger than 18 or older than 17 as well as those who had a combined Brugada and crown QT syndrome were excluded. Those who were randomized to ablation would under when we underwent electro anatomy called mapping both endocardium and epicardium in both ventricle electrophysiologic study as malign administration to highlight subject and then underwent ablation with the ablation employ as an elimination of the all electrophysiologic subjects and secondly employ is non inducibility of VTVF and how normalization of the Brugada ECG pattern as you can see here I would not bother the interest of time but you can see the fact that the signal in the red area where we ablated the study employ the primary employees will be F event and detected by ICD or death and a second a point normalization of Brugada ECG pattern the study had a plan interim analysis when the patient 50 patients were randomized with the stopping criteria of leg for fertility and efficacy and a subtle study termination criterion had to be significant different in the hazard rate but that rejected the null hypothesis of no different this flowchart illustrating allocation of an outcome following the randomization we screen 67 patient 10 decline randomized session but opted for ablation outside a study and 5 decline both randomization and ablation of the 52 patient randomized cases 625 were allocated to the control group no ablation and 27 to the ablation group two patients initially randomized to the ablation declined immediately before the procedure and withdrew leaving 25 patients of the ablation group during the follow-up of 18 of about 1,000 day mean thousand day 18 patient experience at least one VF recurrence 13 in the control group and 5 in the ablation group a cases of that had VF experience the control group crossover baseline characteristic of the patient were pretty balanced notably 96% of the abrasion group had either VF event detected by ICD or about a sudden cardiac death as an event overlapping early depolarization of Brugada syndrome is very important and were common in both group observe 32% in the abrasion group and 22% in the control group prior randomization 70% of the patient have VF event detected by CD and the distribution of the VF event with respect to the frequency of ICD discharges were comparable between the board group this is the captain my compelling ablation and control after first ablation to detect the VF probability of recurrent and you can see clearly that the ablation has a much better outcome than the control with the hazard ladle ratio of 0.288 and with this finding the data safety monitoring board chaired by Dr. Peng Cheng had decided to stop the tribe because the stopping criteria require the heart rate has a ratio to be less than 0.342 the only one complication in the abrasion group is the hemopericardium without consequence sequelae and then for ICD discharges both in in two in both group the we want to understand a little bit more about the variable that dictate the recurrent of after first ablation so we look at the combined three group cross over registry and the randomized group of total 42 patient the demographic as you can see here 80% of the patient have VF detected before the during the index event and you can see here that very drastic that if you look in the patient who had pure Bugada syndrome without overlapping ER we have almost no recurrent the one that had one patient that recurrent in the the Bugada pure Bugada group is a patient who whose EKG is still having a Bugada ECG pattern whereas the patient that concomitant ER has a significantly higher recurrent rate this is the patient this the effect of the ablation after the including the repeat ablation three patient did not want to have any repeat ablation because they were doing fine most of the shock have happened at night and you can see here that drastically the ablation is very effective so therefore Mr. Chairman and Ms. Chairman ladies and gentlemen this is our breadth study is the first randomized clinical trial in symptomatic Bugada syndrome and prevention of VF and the catheter ablation is safe and effective predicting factor for success is combined ER and Bugada ECG pattern is a show that they had a high risk of recurrent and a normalization of the Bugada EKG we believe that catheter ablation is an important therapeutic modality for Bugada syndrome patient and will likely to become a primary treatment for VF prevention and the future direction we have to refine the technique and then especially in the patient who have overlapping syndrome and this is the one that I would like to do the most is that the catheter ablation to select certain subset that catheter ablation can be standalone therapy for possible elimination the need of ICD. Thank you very much for your attention. The commentator is Dr. Tandri Arikrishnan. I really want to congratulate the authors, especially Dr. Natamani, for his fantastic effort for this paper and this study. And this is not just one study. You really have to see the journey of where this all started and how this came to fruition. Here's the first publication by Dr. Natamani. It was just nine patients, patients with Bregada syndrome, type 1 Bregada pattern. I think the whole study had about 13 patients and nine made it to the ablation arm. If you look at it, VF ablation has already been there. Michelle Hazegar's group had actually shown ablating Purkinje potentials for VF, but no one had actually looked at right ventricular epicardial outflow tract as a potential target. What they found with these long potentials in the right ventricular outflow tract, they targeted, and once they did target these abnormal electrograms on the outside of the ventricle, they abolished the Bregada type pattern. It was sort of magical at the time. Many didn't believe that this was really results were true or not. Small group of patients may be carefully selected, need more studies, but they were already planning for a bigger study. As you can see, this is the epicardial outflow tract at the right ventricle. It does require quite a bit of an extensive ablation to abolish the Bregada type pattern. Once you do that, you do see a substantial change in the Bregada type of ECG pattern, and that was associated with improved outcomes. Now, the second one was Bravo, Bravo study, and then really looking at this is, again, not a randomized study. Again, Dr. Nanamani is right there with Michelle Hazegar's group. Now if you actually look at the distribution of substrate, now they find the substrate not just, well, 100% of them had some epicardial RVOT fractionated late activation in there, but in addition, you also tend to see this sort of a petty valvular distribution. Now here, there's a little bit of overlap between other arrhythmic syndromes. You have this basal RVOT substrate and some substrate in the lateral LV, but the results are staggering. Not randomized, but a good case series where you do substantial reduction in VF events post-ablation. Now, this sort of, again, tells you if you do the ablation, if you still have the persistent Bregada ECG pattern, you had a less effect compared to when you were able to abolish. And now, again, this study, again, shows about if you do have some early repolarization left, you still have less benefit compared to if you're completely able to normalize the ECG. So maybe early repolarization has slightly a different substrate compared to pure Bregada ECG alone. Now this study is fantastic because it has a control group. It's randomized, very close follow-up, well-defined ablation endpoints. And of course, if you look at the history, it's reproducible. It's been done one, two, three times in the same way, the same group of people targeting the same substrate. And I think it's very commendable, and how many studies are actually stopped because of efficacy is rare, right? Only 25 patients enrolled in both groups. Future directions, we'd like to see what these new ablation modalities will help. Is cryo coming out? Pulse fields coming out? And we'll have to see how this is going to play out in this. And of course, they have addressed the need for ICD. We'll probably need a braver study to address if they can eliminate ICDs in this patient population. Thank you. Can I ask you a question? Can you elaborate a little bit about what is the difference between the patient that continue to have the pattern and the one that didn't, and was the pattern assessed by repeat Ashmalin challenge, and how far after the initial procedure? Thank you, Andre, to ask the question. We repeat Ashmalin testing. In Thailand, we have Ashmalin available. So we do it three months, because we have the data that sometimes there's a late effect of the ablation. And we published in the paper that sometimes takes three months before normalization occur. Now, interesting that we have several patients in whom the pattern remain that they did well. But many of our recurrences is when we did not successfully normalize the pattern. And that is, if we were going to do a patient that don't put an ICD for prophylaxis, we have to make sure that that pattern is normalized, especially if it's normalized after the Ashmalin or sodium channel blockade. Thank you. I have a couple of questions, actually. One of my questions will help answer a couple of the questions that came from the audience, which is basically, if you look at these patients, if you look at all patients with Brugada, the prevalence of early repolarization is about 10% to 12%. You showed here the higher prevalence of early repolarization. I suspect that's because of their presentation with VF. I mean, these people are presenting with VF. And so most likely, the results were biased or subselected those high-risk patients. Is that your explanation for it as well? Probably, yes. In Thailand, for some reason, especially in the northern part, a lot of these patients come from Chiang Mai. We also published the variant that we have, we call it RE5, it's the inner intron. And the three patients that we did that had this variance that is regulated in the sodium channel had this combined syndrome, and two of them were seen in this study. And I didn't have time to present. Frederick told me that in Europe it's about 10%. But in Thailand, for some reason, if we have, for example, a patient coming with the early repolarization, when we keep aspirin, we could see the combined syndrome. So for some reason, in Thailand, we have this much more than the European patients and here in the U.S. And last question from the audience, which is an excellent one. What are some of the limitations of your trial? Some of the limitations of your study? Well, our limitation, obviously, is the sample size is small and the delay. But with that, the outcome is pretty clear. So anything that... And one might want to see even longer follow-up than the three years. Great. Thank you very much. So we're going to move on and Dr. Sunny Po from the University of Oklahoma is going to share with us results from the transcutaneous electrical vagus nerve stimulation to suppress ventricular premature complexes, the TREAT-PVC randomized clinical trial. It's my great honor to present the results of the trial on behalf of the eight study centers in Nanjing, China. The study on neurostimulators were provided by Paracin. We know that PVC quite often are fueled by adrenaline and vagal tone is anti-adrenergic and anti-inflammatory. Previously, we used a low-level transcutaneous vagal stimulation to treat paroxysmal a-fib. Low-level stimulation means vagal stimulation does not slow down the heart rate or AB conduction. The tragus of the ear has auricular branch of the vagus nerve, so that side is used for active stimulation. In contrast, the earlobe of the ear doesn't have vagus nerve, so it's used as sham stimulation. After daily stimulation for six months, the AF burden in paroxysmal a-fib patient was significantly reduced. However, after we published the results in 2020, we created a problem for the field. Patients can easily Google and find out which arm he or she is assigned to. We cannot blind the patients anymore. The question and hypothesis of this trial is can daily transcutaneous stimulation of the tragus suppress PVCs? This is a double-blind sham-controlled multicenter study. Patients we believe are appropriately blinded to treatment assignment. China doesn't have Google. We took the keyword for tragus stimulation in both Chinese and English to use their search engine to see if we can find the assignment, and we could not. The study center does that every two months to make sure patients cannot find out that there is a treatment assignment. Inclusion criterias include symptomatic PVC burden over 10% based on 10-day monitoring. PVCs are refractory to at least one antiarrhythmic drugs, including beta and the calcium channel blockers, aged between 18 and 80. So major exclusion criterias include EF less than 45% unless it's proved to be PVC-induced, arrhythmias related to structural heart disease, PVC ablation within three months on amiodarone, or change of antiarrhythmic drugs in two months, and reversible causes like excessive caffeine consumption. We used the same paracetamol device as we did in the AF study, active stimulation on tragus and sham stimulation on ear lobe. We screen the patient and collect information at the baseline, three months and six months. We deliver one milliamps of stimulation below the discomfort threshold, and one hour every day. Primary outcome is reduction of PVC burden at six months. We calculated the sample size based on 11 patients not in this trial. We found a 16.4% relative risk reduction at one month, assuming 40% relative risk reduction at six months from a baseline of 15%. We expected to recruit 90 patients, considering dropout, we elected to recruit 100 patients. Secondary outcomes include the heart rate variability, plasma inflammatory markers, pain-sympathetic activity, quality of life, treatment compliance, and adverse effects. We screened 207 patients, 100 were randomized, 48 patients in each group finished the study. The baseline characteristics were balanced between the two groups, except the sham group had more patients with either right or left ventricular outflow tract PVCs. After six months of tracheal stimulation, the PVC burden was significantly reduced from a median of 18.7% to 12.5% based on linear regression analysis. It's a 33% relative risk reduction. However, the sham group also showed similar reduction. So the relative risk reduction in the sham group is 27%. There was no difference between the two groups. The time domain heart rate of variabilities didn't show any difference within or between the groups. There was a significant increase of the low-frequency domain in both groups and a significant increase in high-frequency power in both groups and significant reduction of the low-frequency to high-frequency ratio in both groups. There was no difference between the groups in any of the three matrix. For other secondary outcomes, the plasma level of inflammatory markers like interleukin 1 beta 6 or TNF alpha didn't show any intra- or between-group differences. We do see a trend of improvement in skin sympathetic activity that was measured by a device very similar to the one Dr. Pengxian Chen's group used. And we also see an improvement of the quality of life in the assay. But there was no statistically significant difference in the group or between the groups. Treatment compliance was similar between the two groups in the high 80% range. Four patients in each group had some mild skin irritation. So in this study population that we believe is appropriately blinded, we observed an increase in the parasympathetic activity based on higher power of the high-frequency domain. We also observed a possible shifting of the autonomic balance toward more parasympathetic dominant based on a lower low-frequency to high-frequency ratio. Both active and sham stimulation yielded parallel results, suggestive of placebo effect in action. Let's not forget about the results of the Simplicity Hypertension-3 trial. The sample size calculation was based on 11 patients. They got active stimulation. So when we calculated the sample size, we were not aware of this placebo effect. So the sample size is probably too small to detect if trigger stimulation actually can suppress PVEC. If you look at the paroxysmal a-fib trial, the trial was driven by the patients progressed from paroxysmal to persistent a-fib. That means their a-fib burden increased to 100% at the end of six months. For a disease like a-fib, that potentially can progress rapidly. We were not able to detect the placebo effect from that trial. But in this one, PVECs are usually not rapidly progressing. We actually see a substantial placebo effect. So what did we learn from this trial? Future neuromodulation trials must include appropriate blinding measures. If we had not blinded the patients correctly, this trial may turn out to be a positive trial because the treatment effect can be amplified by the difference between positive expectations from patients who knew they were assigned to the active stimulation group and the negative expectations from patients who knew they were assigned to the sham stimulation. So appropriate sample size for all the neuromodulation trials must consider the placebo effect. From what we see in this trial, the parallel effect and a pretty significant placebo effect, the future trials probably will need to have a very large sample size to be able to detect the difference between active stimulation and sham stimulation. I think this trial is a negative trial, but it said that the standard for future neuromodulation trials set a higher bar. So we cannot just recruit 40, 50 patients to expect randomized will get the effect. We need a much larger size to see what the placebo effect is and what is the real effect. Thank you. So the commentary will be presented by Dr. Daniel Warren from UCSF. This mouse is not working. There we go. Thank you very much. Congratulations, Sonny, on a very, very well-done and especially well-controlled experiment, which is going to be a major theme here. I'm really happy to have the chance to comment on this study. As Dr. Po just shared with us, his past work showed us that vagal enhancement via tragus stimulation can reduce the burden of atrial fibrillation. The question, of course, was, can it also suppress PVCs? Now, it made sense to make sure, to think that it might. It's been shown that PVCs can be responsive to autonomic modulation, as seen here in this IV infusion experiment from the 1970s in humans with frequent PVCs. Now, autonomics is not the only thing in action here, but it definitely has something to do with it. We took these patients with frequent PVCs who had at baseline or during placebo infusion about 25% PVCs. Then they infused the vasoconstrictor phenylephrine, which caused an increase in blood pressure and a reflex increase in vagal activity, and that causes a decrease in PVC burden, as you can see in the table. Then after washout, they gave the cholinesterase inhibitor edrophonium, which potentiated vagal activity and caused the PVC burden to decrease even further than that. But then they gave atropine, of course, which directly blocks vagal and parasympathetic action and causes an increase in PVC burden back to 30% in response. So this experiment did show that following intermittent vagal stimulation at the tragus, the PVC frequency decreased. But with these results, Dr. Po, seen here as a kid coming up with his first experiment ever, he could have stopped right there. With these results, he could have used those ears that he was born with for evil. He could have convinced us to all wear these tragus stimulators in order to improve our heart rhythms. But he didn't do that because he's a great scientist. He included a sham control, which is the most important thing here in this. That's the major lesson that we're learning. That carefully executed sham control group also showed a considerable decrease in PVC burden over time with no difference between the two groups. So why was there that decrease in PVCs? Maybe this is just a really strong placebo effect, as Sonny was proposing. But there are other possibilities as well. For example, maybe these patients tended to be enrolled in the study after a Holter monitor showed a particularly high PVC burden. And then on follow-up, the patients tended back to their lower baseline. Or maybe there was actually some effect on both treatments, including stimulating a near lobe. You know, maybe it has some other effect. So with that, I'd like to congratulate Dr. Po and his colleagues again on a very well-done and importantly, very well-controlled study. And unfortunately, we might never get to see this again, at least not for the treatment of PVCs, but maybe for the treatment of atrial fibrillation. Thank you very much. Thank you very much to both of you, and congratulations, Dr. Po again. I have a couple of questions. We have a lot of questions from the audience. We're not going to be able to get to all of them. But two quick things. The first thing is when you look at the total number of patients who were screened for the trial, you started with 207. You went all the way down to 100. Can you share with us information about what the main exclusion criteria were that led you to go there? Because that actually affects, you know, in general of trials, like in terms of generalizability for future reference. Most of the patients excluded, they didn't have over 10% of the PVC burden. Some of them didn't want to participate, but that's the main thing. No. So it's not above 10% burden. And in terms of questions from the audience here, so there are a lot of questions have to do with why did you just stimulate for one hour? Why not longer? Does it matter if you do it on the right versus the left? Can you give us more information on that? So there is, in neurology, there is a thing called a long-term potentiation. So if you stimulate the neural tissue, you don't have to do that all the time. No, it will remember that it's a plasticity. So the easiest way, if you want to induce status epilepticus in rats, what you do is implant a little lateral in the hippocampus. You do the stimulation maybe a few minutes a day. If you do this every day, about two or three weeks later, the rat will go into status epilepticus. If you count the time you stimulate, it's only maybe an hour of three weeks, but the rat becomes epileptic all the time. So we are trying to use this to use the long-term potentiation effect or long-term depression effect to treat this. So it doesn't really need to be stimulated all the time. We actually based on our AF study that was done an hour, and so we designed the study for an hour. So it may be one hour is not enough, or we have to stimulate stronger or left or right. And the right ear has more, the threshold to affect the heart is lower for the right side of the ear. Yeah. Epilepsy study, they do the vagal stimulation of the left side because they were afraid of affecting the heart. Yeah. Yeah. Okay. And just one last quick question. Do you have any plans to do another study? I'm thinking about how to do it because the problem for this is we don't know how much the placebo effect is. So I don't know how to calculate the sample size for the next one. Yeah. Yeah. Indeed. Do you have any questions? All right. Well, thank you so much. Thank you. So we are at our last presentation from Dr. Derek, University of Calgary 4D Phenomenal Guide to Left and Right Ventricular Calibration and Synchronization Therapy, Lead Placement, the MAPIT CRT Randomized Clinical Trial. Thank you. Well, on behalf of the MAPIT CRT investigators, thank you to HRS and the chair for the opportunity to speak to everyone about the results of the trial, which was looking at an MRI-guided strategy for both LV and RV lead placement during CRT implantation. So as we know, CRT reduces morbidity and mortality in select patients with heart failure. However, despite our traditional selection criteria, including a wide QRS, symptoms in OHI class 2 to 4, as well as a low ejection fraction, a substantial proportion of people don't respond to CRT. And this is regardless of how CRT response is defined. The reasons for CRT response are multifactorial, but could be broadly divided into pre-procedural factors, which include bundle branch morphology, QRS with the etiology of the cardiomyopathy ischemic versus non-ischemic, and the presence of RV dysfunction. Intra-procedural determinants, as well as post-procedural determinants, including percentage IV pacing, AV delays, and the device program itself, and offsets. Now the MAPIT CRT study was designed to address the intra-procedural characteristics and making some recommendations to target location based on the area of greatest mechanical delay, avoidance of myocardial scar, and to maximize interlead distance, the RV and LV lead. So the study objective was to determine if a web-based MRI navigation tool for both LV and RV lead placement at time of CRT implantation would improve the clinical response to CRT in individuals with heart failure. Now the inclusion criteria, adults aged greater than 18 with an injection fraction of less than 35%, QRS duration greater than 120, symptoms, NHL class 2 to 4, who are on optimal medical therapy for at least six weeks. We excluded patients with right bundle branch block, persistent atrial fibrillation, angina symptoms ranked CCS class 2 to 4, recent myocardial infarction or revascularization within three months, standard contraindications to cardiac MRI, and chronic kidney disease defined as an EGFR less than 30. And the study designs as follows. So MAPIT CRT was a multi-centered prospective randomized trial enrolling patients from seven Canadian centers. Implant allocation was blinded to all study personnel except the implanting physician, of course, who had to use the MRI model guided for CRT implantation. So patients were randomized one-to-one to the web-deployed MRI navigation tool, which was available by a web application, or they were randomized to standard of care and lead placement was left to the discretion of the implanting physician, typically targeting the lateral or posterolateral wall. Now at baseline, all participants underwent cardiac MRI to generate this 4D Phenomics model. And they also underwent 12ADCG quality of life measures to assess their generic quality of life via the EQ5D questionnaire and their disease-specific quality of life using the Minnesota Living with Heart Failure questionnaire. They also underwent six-minute walk testing and a MUGA for baseline ejection fraction measurement. Now patients were followed every three months up to a year, and a MUGA was repeated at six months to assess for the primary endpoint, which was the proportion of individuals with an ejection fraction improvement of greater than 5%. Now MUGA was chosen as a more precise measure of ejection fraction change and less prone to limitations in image acquisition for things like echo. And at 12 months, we assessed for secondary endpoints that included clinical endpoints such as all-cause death, heart failure hospitalization, and ventricular arrhythmias, as well as repeated the quality of life measures. Now enrollment occurred between September 2014 to May 2020, with follow-up occurring through December 2022. So here is the 40-phenomics model. So using routine cardiac MRI data, a dynamic 3D mesh model of both the epicardial and endocardial surfaces were generated. Now each region was assigned percentage estimates of scar burden using qualitative quantitative LGE scar analysis, and estimates of contractile delay was obtained from myocardial deformation analysis seen here. Now the LV and RV recommended targets during implantation were based on a predefined paired ranking algorithm that ensured that the RV lead was placed in a region of the least myocardial scar as possible, and then based on that, the LV lead was recommended based on the lowest LGE scar burden, or positioning in a region of lowest LGE scar burden, greatest mechanical delay, and greatest intra-lead distance between the LV and RV targets. So the model was available for those randomized to the navigation, MRI-guided navigation arm. The model was available by web-based application, which was displayed to the implanting physician at time of implantation, and used as a reference for side-by-side along with the intraprocedural fluoroscopic imaging. So we can see the LAO, RAO views, and then the intraprocedural fluoroscopic images. Now the algorithm provided a plan A, so optimal RV and LV locations, but acknowledging that we're limited by the CS anatomy, a plan B, or next best option, was offered. And if the implanting operator couldn't position the leads on either plan A or plan B, then at that point, they were allowed to place the leads based on their discretion. So in the MAPIT study, 94% of implants in the MRI-guided arm achieved an anatomic location in either plan A or plan B. So between September 2014 and May 2020, 210 participants were enrolled, with 202 of them included the modified intention-to-treat analysis who weren't lost to follow-up or had their consent withdrawn. Baseline characteristics were relatively well-balanced. Median age was 69 years, 31% female, and about half had ischemic etiology. Median injection fraction, around 30%. Most had left bundle branch morphology as per the STRAS criteria, with a median QRS duration of 160 milliseconds. And 91% of implantation students had both LV-RV leads successfully implanted. So here are the study results. So at six months, a greater proportion of participants randomized to the MRI-guided arm achieved the primary endpoint than those randomized to standard of care. So that is 66% in the MRI-guided group achieved an injection fraction increase of at least 5% compared to standard implantation. There was no difference in secondary endpoints of all-cause mortality, heart failure, hospitalization, or ventricular arrhythmias, and there were no difference in quality-of-life outcome measures. In looking at the change in injection fraction as a continuous variable, we see that the delta increase from baseline to six months was 5.2 percentage points higher in the MRI-guided model compared to standard of care. There was no difference in six-minute walk test distance. So some study limitations. Well, this is a relatively short trial follow-up of 12 months, and we were not powered for hard clinical endpoints. All the secondary endpoints were exploratory. The patient enrollment was a lot slower than expected, and over that time period, there's been changes clearly in guideline medical therapy. And the initial protocol allowed for LV encystolic volume as a measure, but because of differences in image acquisition or the mugget technique between sites, planar versus specs, we weren't able to include that in the analysis, unfortunately. So in summary, this 4D modeling approach to CRT implantation is feasible, safe, and facilitates personalized delivery of both LV and RV leads. The big advantage to this technique is that it requires no technical complexity. There's no... It's a web-based app. There's no intraprocedural fusion image overlays required. This can be done using routine cardiac MRI data, and the process has been improved where automated model preparation is now available through an AI pipeline. But in conclusion, the 4D Phenomics-guided CRT approach resulted in a significantly greater ejection fraction improvement versus standard of care. And a special thank you to all the enrolling sites and patients for really coming together to make the MAPI-CRT trial a success. The commentator is Dr. Cha Young May from the Mayo Clinic. Thank you, Sena and Dr. Natale. So first, I would like to congratulate the investigators on accomplishing this very well-designed clinical trial. So, 4D Phenomics MRI provides a novel myocardial deformation analysis to assess the mechanical activation patterns of endo and epicardium, and to facilitate the optimal LV lead placement aiming at the latest activated LV segment free from scar tissue to enhance ventricular resynchronization. So this trial is very well-designed with comparative analysis. So the patient with EF less than or equal to 35 percent assessed by MAGA, usually we call the gold standard, and the QRIS duration greater or equal to 120 milliseconds. Ninety percent of the patients had the left bundle branch block. Of note, 95 percent of the patients were on beta blocker and AC inhibitor. ARB or ARNI. Two hundred twenty-one patients, two hundred ten patients were randomized to either standard CRT or MRI-guided CRT, and the LV lead was aimed to place at the lowest LGE scar with the greatest mechanical delay. The MRI-guided CRT group had a greater responder rate, 66 percent compared to 52 percent in the standard CRT group. Further, the MRI-guided CRT group also had a greater delta increase in mean left ventricular ejection fraction by 5.2 percent. And then, however, there was no difference in the secondary endpoint, including the heart failure, the machine death, and the quality of life. So what are the clinical implications here? So the study, we can conclude that 4D-MI-guided LV lead placement is a useful technology to enhance CRT outcome with a greater LVEF improvement compared to standard CRT in patients with a severe half-ref left bundle branch block and on optimal guideline-directed medical therapy. Further analysis may provide insight on MI-guided best lead location and the actual lead location because of the limitation of a CS anatomy. And I believe the audience will look forward to the potential long-term comparative outcomes from the study. Thank you. Dr. Derek, a question. How do you explain the discrepancy between the six minutes walk and the ejection fraction change? Is that because it's a sample size issue or is the increase not that much? If you can elaborate a little bit. As you hinted, I do believe it's a sample size issue. So both groups, with the 50 percent response rate based on ejection fraction definition and the 60-ish percent response rate, both groups had an increase in six-minute walk time, but the deltas had such wide confidence intervals that we couldn't actually show a difference, unfortunately. Did you do any acute hemodynamics in these patients when you put the lead there? Just pace and look at changing, you know, dvdt of the ventricles because those have been very well shown to correlate with long-term outcomes. Unfortunately not. Within rolling sites, we just try to keep it as simple as possible, have the web interface just to show as a roadmap along with the intra-procedural fluoroscopy. Any other questions? Okay, so I guess we are done with the presentation. Thank you to the presenter, the commentator, and thanks to the audience for being here. Have a good rest of the day. Thank you very much.

cardiac conditions

CT-guided ablation

ventricular tachycardia

BRAVE trial

Brugada syndrome

TREAT-PVC

transcutaneous technology

MAP-IT-CRT trial

cardiac treatment technologies

personalized cardiac care