I'm joined by Dr. Sunit Mittal right before our late-breaking trial session three, clinical trial updates and registries. Our first trial today is going to be BioLibra, reporting outcomes of sex differences in device-treated VT and VF, and it's going to be presented by investigators from University of Rochester, and then that's followed by two studies coming out of Mother Eye. Yeah, so I'm really excited about the two studies coming out from the same investigator, Dr. Ponnasamy from Mother Eye India, and both related to conduction system pacing and both addressing some really important topics. And the first study, he's actually looking at some novel CT imaging software developed by CARA Medical to really identify where conduction system pacing is occurring within the fascicles of the conduction system to see if it actually makes a difference on clinical outcomes like ejection fraction recovery, and if there is a signal there, would pave the way for more prospective studies to inform device implantations at the time of these procedures. The second study is a very unique approach they've taken, looking at the value of MRIs to determine whether patients should get a pacemaker or defibrillator, and then using some novel criteria they've developed to determine when you put a conduction system lead in, should you also add an LV lead in. So very interesting to see what their findings have been and to see whether this informs how we change the way we approach patients with respect to this. So two really exciting trials related to conduction system pacing before we end on a nice review on catheter ablation of VT. Yep, we're going to hear about the updates on VANISH2 trial, and this will be a meta-analysis for all our CTs including VANISH2, and we saw the results of VANISH2 initially last year comparing first-line therapy of VT ablation compared to antirhythmics and other pharmacological therapies, and as more ablation technologies are coming up, ablations for VT are becoming more safe and efficacious, I think it's a great trial to look into as to whether we should be offering ablations as a first-line therapy as opposed to subsequent to having failed antirhythmics. Yeah, well it should be another great late-breaking clinical trial session. Absolutely, and now to your late-breaker starting right now. Thank you very much and welcome. I am Jody Hurwitz from Dallas, Texas, past president, and my co-chair is Dr. John Treibman from Boston, the treasurer, ex-treasurer of Heart Rhythm Society. We're really excited about this session, and we want to make sure that if you have not done so already, we'd like you to download the HRS 2020 mobile app because that's one of the ways that you can put in questions, which we hope that you will be able to do. Really, the more involved you get, the better this is going to be. This is, again, late-breaking clinical trials and science, clinical trial updates and registry. So we're going to get started, and the first talk is Contemporary Outcomes of Non-Ischemic Cardiomyopathy Patients with Implanted Devices, BioLibra, and it is going to be a joint session here with Dr. Katifa from University of Rochester and Dr. Jeannie Poole from University of Washington. Thank you so much, Jody. I'm excited to be here today to present the results of the BioLibra study together with my co-PI, Jeannie Poole. These are our disclosures, and Dr. Poole will present the background and the methods of the study, and I will subsequently present the results. Jeannie? Good morning, everyone. By way of background, patients with non-ischemic cardiomyopathy have been shown to benefit from an ICD, but most studies were conducted at least 20 years ago. Adherence to guideline-directed heart failure medical therapy and CRT are now associated with significant improved outcomes. The Danish trial challenged results of earlier trials showing no benefit of an ICD to reduce all-cause mortality, though sudden cardiac death mortality was reduced. And females have historically been underrepresented in ICD trials. The purpose of BioLibra was to prospectively evaluate arrhythmic and mortality outcomes in patients with non-ischemic cardiomyopathy implanted with an ICD or a CRTD from the United States, and to enroll a high percentage of female subjects to enable robust sex-specific analyses with a goal of at least 40% women, with a specific focus to look at sex-specific and device-specific differences. The name Libra comes from the astrological sign Libra, a balanced scale, to symbolize a balanced enrollment of men and women in this trial. This is an investigator-initiated, multicenter, prospective observational study. The study population are patients with non-ischemic cardiomyopathy implanted with an ICD, with an enrollment of 1,000 subjects at up to 50 U.S. sites, and subjects to be followed at three years post-ICD implantation. There were two pre-specified interim analyses planned when 501,000 subjects were enrolled with one year of follow-up. Those results were presented at HRS 2022 and 2023. On this slide, you can see the BioLibra study organization. The scientific coordinating center was the University of Rochester Medical Center, Rochester, New York. The study sponsor is Biotronic. Also shown are key central study team members for the core labs and adjudication committee. Forty-eight sites, representative of all U.S. regions, participated in BioLibra. It was our intent to include as many females as site PIs as possible, and we achieved that with 25 percent of all site PIs being women. The primary objective was to assess a combined risk of all-cause mortality in device-treated VT or VF events analyzed by sex and device type. Secondary objectives were VT or VF alone and all-cause mortality alone, sudden cardiac death, and cardiac mortality. Tertiary objectives were medication use, changes in echocardiographic remodeling, VT or VF requiring a shock, inappropriate ICD therapy, and complication rates. Key inclusion criteria are shown here. Had to be 18 years of age or older, non-ischemic cardiomyopathy defined as not primarily caused by coronary disease or myocardial infarction, they had to meet standard guidelines for primary prevention ICD, they had to be successfully implanted, and be willing to utilize home monitoring. Key exclusion criteria are also shown here. The management of the patient was up to the investigator, including the use of ancillary imaging such as CMR or decision for CRTD. Device implant and programming followed the 2015 expert consensus document focusing on high-rate and long-duration programming. Follow-up was six months remote visits, 12-month in-clinic visits with continuous remote monitoring. You can see the BioLibra study time on the bottom of the slide. We first enrolled our patient May 9th, 2019, and then the COVID pandemic hit, but we continued to steadily enroll throughout the pandemic, completing enrollment on October 21st, the last follow-up, December of 2024. Standard statistical methods were used, including Kaplan-Meier methods, Cox proportional hazards regression, which were adjusted for significant covariance. Valentina. And now, the results of the BioLibra study. In BioLibra, we enrolled 475 females, 48% of the study population, exceeding our enrollment goal of 40% women. With increasing the enrollment of females, we also increased overall racial representation. 30% of our patients reported to be non-white, and 10% reported to be Hispanic or Latino. These are the BioLibra selected clinical characteristics. It's important to note that females more often reported advanced heart failure symptoms, but they less often had prior atrial fibrillation. The use of baseline heart failure medication was high, with females prescribed with diuretics somewhat more often. The primary endpoint of the BioLibra study, ventricular arrhythmias, or DES, were reported in 210 subjects, 21% of the patient population. You can see here on the left side, females were shown to have a significantly lower rate of VT, VF, or DES, with a three-year rate of 17%, as compared to 28% in males. And this was linked with both a univariate and a multivariate, significantly lower risk of about 30% of VT, VF, or DES in female subjects. When we looked at device-specific differences, we found that patients with an implanted CRTD also had a lower rate and risk of VT, VF, or DES events, again, with about a 30% risk reduction. The secondary endpoint of VT, VF is shown here. We had 14% rate in the total patient population. That is almost 5% of VT or VF per year in the study. VT, VF rates were significantly lower in females, with a three-year 9% event rate, compared to twice as high, 18% in males. That was linked with a univariate and multivariate, about 50% reduction in the risk of events. When we looked at device-specific differences, we found a univariate difference in the rate and the risk of VT, VF in the CRTD patients, but this did not persist in the multivariate models. The secondary endpoint of all-cause mortality was relatively high in biolibra, with a three-year rate of 12% or 4% per year. Females had a significantly lower rate and lower univariate risk of all-cause mortality in the study, but this was not shown in the multivariate models after adjustment for relevant covariates. Patients with an implanted ICD or CRTD had similar rates and risk of all-cause mortality. In biolibra, we report 61 appropriate shock events, 6.1% during three years, and 103 inappropriate events, 10.3%. 14 patients had sudden cardiac death in the study, about 12% of all of the deaths, and about half of the deaths happened due to cardiac reasons. And an interesting finding we found that for the primary endpoint, there was a significant interaction for sex and device type, and sex and race, with women who were white and were implanted with a CRTD having the lowest risk of events. In biolibra, we report a high residual three-year rate of 21% of VTVF for death events, 14% of VTVF, and 12% of all-cause mortality, despite high compliance with heart failure medications. We found important sex-specific differences. Females were significantly less likely to have VTVF for death events, even after adjustment, and females had lower rates of mortality, but this difference did not persist following adjustment. In biolibra, we demonstrated the feasibility to improve the enrollment of female subjects in a large ICD-CRT trial. Female trial leadership, female-focused trial materials, and working closely with the enrolling site resulted in a balanced, nearly 50% female enrollment. Future device trials should be designed to target a balanced enrollment of both females and males. We would like to thank the contribution of the biolibra top enrolling sites, especially sites who enrolled a large number of females, and thank all of the enrolling sites, the adjudication committees, core laboratories, our sponsor, Biotronic, and all of our enrolled patients. Thank you, and happy to take any questions. Thank you to our presenters. I will introduce now Dr. Laurent Malfle from the Montreal Heart Institute to provide a brief commentary, and encourage you to continue submitting questions through your app. Thank you for the opportunity. It's a pleasure for me to comment on this trial. I'm approaching this comment on what have we learned and what do we still have to learn from this field of interest. So the most recent guideline recommendation for primary prevention of sudden cardiac death did not distinguish between indication between men and women with non-ischemic cardiomyopathy. And this is an important point because the benefit of ICD in women has been questioned over the past years. And unfortunately, none of the RCT of primary prevention ICD in that population involved enough women to address this issue. As illustrated on the graph on the left, you can see that the number of women in the landmark trial that were used to do the recommendation, to make recommendations in the guidelines actually involved a limited number of women with non-ischemic cardiomyopathy. So I would like to congratulate the BioLibra team, and Dr. Poole, and Dr. Kukifa, because they enrolled more women than in any of these landmark trials that were used to make those guidelines. And they were able to show that they were in the lower risk of VTVF in women. So significant arrhythmia were about half in women than in men. However, it remained a 3% annual risk of this significant arrhythmia, well above the threshold justifying a defibrillator in that population. Now the second question is that the landmark trials as well that were used to draw those guidelines were before the era of optimized medical therapy with ARNI and SGLT2 inhibitors. And we know from the PARDIGM-HF and DAPA-HF trial that these drugs are associated with significant reduction in sudden cardiac death. But on the right panel, one should remember that there's a residual risk of sudden cardiac death in these patients, even in the context of randomized clinical trials, once again, well above the threshold for which we would recommend ICDs in that population. What we've learned, in addition from the BioLibra, is real-world experience is very different than randomized clinical trial. As you can see, the suboptimal use of ARNI was used in that trial, and that's the experience of the real-world application of these agents with less than 50% of the patient at two years receiving ARNI, for example. So what do we still have to learn? Well, most patients, about 85% of the patients in BioLibra did not receive a therapy from their device. So the question is, can we better select men and women with non-ischemic cardiomyopathy that are receiving optimal heart failure therapy for primary prevention ICD? The question of ICD versus no ICD in that population remain, and the question of CRTD versus CRTP also remain. Of course, this will need to come from randomized clinical trials, like the CONTEMPT-ICD, in which Dr. Khatifa is involved, or the other ongoing trial. Hopefully, we'll be able to address these questions. I would like to thank you for the opportunity again, and congratulations again to the BioLibra team. Thank you very much. I think we have time for one or two questions. There is one that says, did you look at improvement in ejection fraction in different device types, CRTD versus ICD only? Yes, this is an excellent question. We have some data on echocardiographic remodeling as a tertiary endpoint, and I think this is specifically important to look at in the CRT population. Some of our preliminary data show significant improvement. We just did not have the chance to show that today. And then one of the other questions was, what were the number needed to treat to save one life in men versus women? And that may be something that you're looking at, too. Stay tuned. I said, stay tuned. Oh, OK. And I just also want to stress that BioLibra is not a randomized trial. It's a prospective registry, primarily looking at event rates. But what we found that I think this is a quite high event rate in a non-ischemic population with a three-year rate of 15% of VTVF and 12% of mortality. So an annual mortality rate of 3% on high, really more optimized medical therapy. So potentially, ICD benefit remains in this population, although that was not directly studied in BioLibra. Can I just add to that real briefly, this whole concept of guideline-directed medical therapy? BioLibra is similar to the Danish trial in the fact that the Danish was mostly triple therapy, and there wasn't a huge use yet of ARNIs. So it can be, in that sense, thought about as the same error. But it also points out the need for continued education for appropriate use of heart-filling medications, especially the newest medications. Undoubtedly, if we have populations that are well-treated, maybe these numbers will change and, in fact, decrease. Yeah, that was one of the questions I was actually thinking, even though it says these folks were on guideline-directed medical therapy, what does that really mean, especially with men versus women? So I think it may be very different. Thank you very much. We'll move on to our next study. And in fact, the next two studies will be presented by Dr. Shumuga Sundaram Poonasamy from the Vellamal Medical College Hospital and Research Institute. The title of the first presentation that he will give this morning is Hierarchical Physiological Pacing to Enhance Clinical Outcomes in Conduction System Pacing. Dr. Poonasamy? Thank you. So I'm going to present the results of hierarchical physiological pacing to enhance the clinical outcomes in conduction system pacing. These are my disclosures. Lumbar branch area pacing terminology was introduced not only to simplify the procedure, but also the inability to define what exactly is lumbar branch pacing and what exactly is LV septal pacing. We know that his bundle and left bundle branch pacing are physiological, whereas LV septal pacing, where there is no activation of conduction system fiber, is going to be non-physiological. Precise location of the lead position to the conduction system and its impact on clinical outcomes has not been elucidated so far. So main aim of our study is to classify the lead placement with a specialized software with the help of computer tomographic angiography into lumbar branch pacing and LV septal pacing, and to assess the effect of pacing lead location relative to the conduction tree hierarchy and the LV endocardium on clinical outcomes in patients who had undergone successful lumbar branch area pacing. These are the two study centers. It was a non-randomized observational study. The enrollment period was between 2022 to 2024. And those patients who were aged more than 18 years who had undergone successful LBB-AP or either symptomatic bradyarrhythmia or CRT indications were included. And those patients who were allergic to iodinated contrast agent with an estimated EGFR of less than 60 ml or who were not willing to undergo a computer tomographic angiography were excluded. We have previously demonstrated that with the help of a specially designed software, the CTA could predict the location of the lead within the endocardium and it gives us an idea of the stability of the lead. We did a CT at zero months and six months. We could show that the lead remains stable. So with the knowledge gained from that study, we have used the CT angiography to reconstruct the anatomy of conduction system fibers based on fixed anatomical landmarks. We have measured two important dimensions, the LH, distance between the pacing lead to the tip of the his bundle, and LE, distance between the lead tip to the LV endocardium. And we could reconstruct the anatomy based on the fixed anatomical landmarks and we have classified the lead position into truncal, which was seen in 27.5% of patient, septal fascicle in 61.5% of the patient, and in LV septum in 11% of the patient. These are the clinical parameters, baseline parameters. Those patients who had a baseline EF of less than 50% had a poor NHF functional class and prolonged QRS duration. So as expected, those patients with labrador branch truncal pacing and labrador branch fascicular pacing had their leads closer to the his bundle and closer to the LV subendocardium as compared to those patients who had a pure LV septal pacing. After adjusting the baseline LV function, we could show that both LH distance and LV distance predicted the follow-up LV ejection fraction, but only the LE distance predicted the change in LV end-diastolic volume and end-diastolic diameter. So we have classified the patients into three different subgroups, less than 35%, 35 to 50%, and more than 50%. We have plotted the change in LV function and the change in LH and LE measurement. What we could show was as the lead moves away from the his bundle, as the lead moves away from the LV subendocardium, the change in LV function deteriorated, indicating that if the lead is placed closer to the his bundle and if the lead is placed closer to the LV endocardium, better will be the clinical outcomes. This can be better described with this graph. As you can see, nearly 14 patients had their leads deployed more than 35 millimeter from the his bundle, and they had a lesser change in LV function. So for each one millimeter of LH, ejection fraction reduced by 0.175%. Similarly, as the lead moves away from the LV endocardium towards the right ventricle, there was a decline in LV function as compared to the leads which were either on the subendocardium or just piercing the LV subendocardium into the LV cavity. For each one millimeter of LE, EF increased by 0.3%. Interestingly, we have noticed pacing-induced cardiomyopathy in four patients. The fall in EF was more than 10%, and we could show that these patients, there was a larger value of LH, meaning that these leads were away from the his bundle, and they had more negative values of LE, meaning that these leads were predominantly in the mid-septum. Clinical outcomes, all-cause mortality was seen in 3%, heart failure hospitalization in 4.7%, composite of heart failure and mortality was seen in 7%. And as expected, both LE distance and LH distance predicted the occurrence of the composite outcomes with an odds ratio of 0.85 for LE and 1.06 for LH. So we could introduce the concept of hierarchical physiological pacing where we need to deploy the lead not at the distal fascicular or in the LV septum, but in the proximal main trunk of the left bundle. Also, the lead should go all the way into the interventricular septum to reach the LV endocardium to have enhanced clinical outcomes. This is based on the concept that the complexity of anatomy and complexity of conduction system disease, that we have demonstrated a segmental fascicular block within the conduction system fibers. So when you activate the proximal end of the conduction system, be it the HISS bundle or the left bundle, you have a global synchronized activation of the left ventricle, resulting in superior electrical resynchronization. Limitation, it's a prospective study of retrospective data, a non-randomized one, without having RV pacing or a biventricular pacing control group. We included only two centers with a rich experience on conduction system pacing. The median follow-up was only two years, and the classification of lumbar branch pacing versus LV septal pacing was based on operator's decision. So we are going to take it forward. Since we have shown that the retrospective reconstruction of conduction system anatomy is feasible, we're going to take it prospectively. If you could do a pre-procedural CT angiography and create the conduction system anatomy, merge it with the fluoro, you'll be able to deploy the lead in a position wherever you want to deploy the lead. So the first picture showing a very dilated atrium, but with the help of the reconstructed anatomy, the leads could be clearly deployed in the septal cycle. Not only left bundle branch pacing, even we are going to take it for a backbend bundle pacing where this is going to give a continuous visualization of the aortic shadow. All we have to do is go just behind the aortic shadow at the SVC-RA junction to deploy the lead in the backbend bundle. To conclude, we are going to introduce a terminology called HPP approach, which is a CTA-based methodology to visualize the conduction system and to guide the lead placement high up in the left bundle trunk, closer to the LV subendocardium. Closer the lead to this bundle, closer the lead to the LV endocardium, better the clinical outcomes. Distal fascicular pacing and LV septal pacing may result in lesser degrees or even worsening of LV function, so it should be better avoided. Thank you very much for your patience. Thank you very much. The commentary will be offered by Dr. Martin Stiles from Wakato Hospital and University of Auckland. Thanks very much for the opportunity to give a commentary on this paper. My name is Martin Stiles from New Zealand. So physiological pacing, what do we mean by this? I think what we mean is that nature is best and that millennia of evolution have occurred to develop a rapid and synchronous heart contraction, and the best way to achieve optimal cardiac function is, in fact, to mimic nature as closely as possible. But this term is not new. There are two papers here from 1978 and 1980 describing physiologic pacing. And there's been various iterations of physiologic pacing over the years. Initially it was taken to mean atrial ventricular synchrony, first VDD and then DDD, then atrial based pacing, later with a minimization of ventricular pacing. Then physiological pacing was meant to mean rate response, initially accelerometers, ventilation, and impedance-based measures of contractility. Physiological pacing has been taken to mean biventricular pacing, or CRT. And there was a brief fad for right ventricular outflow, or septal pacing, and now his bundle pacing and left bundle branch pacing as iterations of physiological pacing. And what about the future? If the attendance at the Bachman's bundle pacing session that I just attended, which was standing room only, is anything to go by, this will be a future iteration of physiologic pacing. And I've been involved in some respiratory sinus arrhythmia pacing, where we slow the heart rate as you breathe out and increase the heart rate as you breathe in in heart failure patients. And the animal models have been excellent. We've started human clinical trials. But hierarchical physiological pacing, as described today, conceptually means that pacing the proximal conducting system is better than the distal conducting system. And pacing the conduction system directly is better than pacing nearby myocardium. And he's introduced these two new parameters to me, the lead to HIST distance and the lead to endocardial distance. So the implication of these results is that pacing closer to the HIST bundle maximizes the left ventricular ejection fraction. And pacing closer to the left ventricular endocardium, that is, i.e., the left bundle itself, also maximizes the LV ejection fraction. So in fact, to mimic nature, one needs to place the pacing lead tip as proximally as possible in the conduction system and as endocardially as possible. There are, of course, limitations with this trial. It's a retrospective, non-randomized, two-year follow-up. And the left bundle was determined by the operator. So just looking to the future, how might we achieve this? I think we need better tools. We need better leads. We need better delivery systems. And we need education on what ECG characteristics signify optimal placement. I think that this paper shows that image guide leads placement may be the future, either pre-procedural or intra-procedural imaging to predict the left bundle branch site and appreciation of what anatomical landmarks might guide us. But if we are to continue to strive to mimic nature, should we be surprised that six decades of pacing has yet to emulate millennia of evolution? Thank you. Thank you. Dr. Ponasamy, we've received a number of different questions. I'll summarize several in a two-part question. Can you speak a little bit to the risk of perforation as you follow the natural evolution of this procedure? And you've discussed some procedural innovations that are used to enhance the performance of this lead placement technique. Can you speak to the identification of the variable anatomy of the left bundle and how it relates to procedural success? Yeah. Thank you. So as far as the septal perforation is concerned, so it is a fearsome complication if you are not going to address it on table. So if you can identify the septal perforation on table by means of current of injury, unipolar pacing impedance, and the amplitude of the R wave, then probably you can correct it on table so that the patient will not have any future complications. The risk of lead perforation is very, very rare. You can see some case reports here and there. Otherwise, if you could deploy the lead right into the LV subbendocardium in the future, unless there is an on-table perforation, there will be any risk of late-onset perforation. This we have shown in our previous locate LBBB study, where the leads get deployed at a mean distance of 0 millimeter from the blood pool, remain there at a mean distance of 0 millimeter at the end of six months. So it's reassuring that the late-onset perforations are very, very rare. And as far as the second question is concerned, yeah, so the reconstruction is based on the fixed anatomical landmarks. So the location of AV node, the location of penetrating portion of Isbundle, and the origin of left bundle fibers can be better predicted with the help of anatomical landmarks. The AV node will be in the floor of the Cox triangle, and the penetrating portion of Isbundle just comes out of the non-coronary cusp, right coronary cusp commissure, where the left bundle fibers will originate. And from there, we'll have the fibers coursing towards the anterolateral papillary muscle, where we call it as anterior fascicle, and post-traumatic papillary muscle, what we call it as a post-traumatic fascicle, posterior fascicle. So in between, we'll have the septal fibers, which innervates the interventricular septum. Thank you very much. I guess the lead's being moved upward a little bit, and your follow-up is two years. I'm assuming that you didn't see significant changes in voltage requirements. But you'll be watching for that, I'm sure. Yeah, exactly. Okay. Thank you. I'm going to invite you back to the podium now, and you're going to ask you to talk about cardiac resynchronization therapy, risk stratified by CMR imaging and optimized by left bundle branch pacing results from the long-term follow-up of Midori left bundle branch pacing study. Thank you. So I'm going to present my second study on CRT, risk stratified by cardiac MRI, optimized by left bundle branch pacing, long-term follow-up results from Madurai LBBB study. These are my disclosures. Role of ICD for primary prevention in non-ischemic cardiomyopathy is a matter of debate. LBBB-associated non-ischemic cardiomyopathy can be considered as a potentially reversible form of cardiomyopathy. As the trials have shown, normalization of LB function in as high as 75% to 80% of patients at the end of one year. We previously reported the safety and feasibility of cardiac MRI to risk stratify LBBB-NICM patients undergoing cardiac resynchronization therapy. The aim of the current study is to assess the long-term outcomes of CRT, risk stratified by cardiac MRI, and optimized by left bundle branch pacing in patients with LBBB-associated non-ischemic cardiomyopathy. It's a single center, non-randomized prospective observational study. The enrollment started in 2019. Patients with more than 18 years of age, LBBB-associated cardiomyopathy, with an EF of less than 35%, in major functional class between 2 to 4, and who had the ability to undergo cardiac MR were included in the study. On the other hand, patients with ischemic heart disease, documented ventricular tachycardia or ventricular fibrillation, those who had a prior ICD, or those with renal dysfunction were excluded from the study. All these patients received three months of guideline-directed medical therapy before considering device therapy. We defined LBBB-associated non-ischemic cardiomyopathy as the presence of typical LBBB, along with EF less than 35% at the time of diagnosis, in major functional class between 2 to 4, no documented history of STEMI or coronary artery disease, absence of other identifiable causes for cardiomyopathy, and unknown duration of LBBB and LB dysfunction. So this is a Madurai LBBB approach. We classified the patient based on the scar burden, as assessed from cardiac MR, into two groups, less than 10% and more than 10%. The low-scar burden group received only left bundle branch pacing, and the high-scar burden patients received both LBBB and ICD. If there is a complete correction, we'll stop without putting a CS lead in both the groups. Outcomes. We defined primary outcomes as a composite of time to death, heart failure hospitalization, or sustained VTVF. Echocardiographic response as an absolute change in LVEF by more than 15% at six months. Secondary endpoints, echocardiographic hyper-response, defined as EF more than 50% at six months and more than one year. And indications for ICD upgrade, where the persistent LV dysfunction less than 35% or a sustained VTVF at the end of one year. Adverse clinical events are defined as composite of persistent LV dysfunction, death, heart failure hospitalization, or sustained VTVF at the end of one year. So we have rescategorized the patient into two groups based on scar burden, out of 225 patients included, 202 patients received only LBBB and 23 patients received LBBB plus ICD. Those who had a complete correction received a lot DDD in the lowest group, and those who had an incomplete correction received lot CRTP. Similarly, those with a complete correction received only lot ICD in the highest group, whereas incomplete correction required lot CRTD. These are the baseline characteristics. You could see the female sex was less in group two, and the LV ejection fraction was less in group two, and the baseline NYJ functional class was little worse in group two. 93% of the patient with the lowest scar burden, we could get away with a dual chamber pacemaker. Only in 7% a CS lead was implanted. Pace QRS duration was better in group one, RY peak time was better in group one, and we could demonstrate non-selective-to-selective transition in nearly 86% of patients with group one as compared to only 39% in group two. The pacing parameters were comparable between both group one and group two. So group one patient, low scar burden, complete correction of lumbar branch block where it can demonstrate non-selective-to-selective in high percentage of the patient, they received only a dual chamber pacer. High scar burden, you can see the cardiac MR showing a dense scar completely occupying the septum, apex, and the lateral wall, where the correction was incomplete. You can see this QS to QR, which we often see in patients with a dense scar. These patients more often receive a CS lead as compared to those patients with a high scar burden. Primary endpoints, time to death heart failure hospitalization of sustained VTVF occurred more frequently in group two as compared to group one, and the curve separated as early as three months with a hazards ratio of 16.52. Increase in LVEF by more than 15% at the end of six months, we could demonstrate in 78% of patients in group one as compared to only 16% in group two. Secondary endpoint, normalization of the LV function was seen in 75% of patients in group one at the end of six months, and 82% of patients at the end of one year. Similarly, in group two, nearly 25% of patients had normalization at the end of one year, and 25% had normalization at the end of two years. Post-sustained LV dysfunction, this is what we are interested, was seen in 4.4% of patients in group one as compared to 31% of patients with group two. A subgroup analysis was done in group one patient where we could predict the normalization of the LVEF and to predict the occurrence of adverse clinical events with the help of SCAR. Absence of SCAR predicted the normalization of the LV function with an odds ratio of 5.2. Presence of SCAR predicted the occurrence of adverse clinical events with an odds ratio of 5.2. Limitations, there's a single center, a non-randomized study without a by-week group comparison. Only those patients who had a non-schemic cardiomyopathy with a typical LVV were included. The SCAR burden cutoff need to be reconsidered, as in the subgroup analysis we could demonstrate that even if the SCAR is between 1% to 10%, there is a higher incidence of adverse clinical events. The rhythmic events were monitored purely based on clinical symptoms and device-detected algorithms, so we might have missed some non-fatal arrhythmias, as fatal arrhythmias we could follow them closely. To conclude, CRT may be safely performed by moderate LBBB approach of restatifying the patient with the help of cardiac MRI. A lot of DDD could be considered as a safe device therapy for a non-schemic cardiomyopathy with LBBB without scar, as these patients did not have any adverse clinical events despite the absence of defibrillator therapy. Future large-scale multicenter studies comparing the traditional bimentricular ICD versus moderate LBBB approach are warranted. Thank you. Thank you, Dr. Ponasamy. Providing a commentary on this study is Dr. Wataru Shimizu of Nippon Medical College. Thank you very much for the nice presentation on the long-term outcomes of moderate LBBB left bundle branch pacing trial. As stated in the background of the study in non-schemic cardiomyopathy patients with left bundle branch block and minimal myocardial scarring, the benefit of CRT can be expected to be substantial. Therefore, the necessity of a primary prevention ICD implantation in such cases may be questionable. In the Danish trial in 2026, the benefit of ICD for primary prevention in non-schemic cardiomyopathy patients did not reach statistical significance between those with and without ICD. In this Danish trial, 58% of the patients had CRT implantation in both groups, and it has been suggested that the lack of the observed ICD efficacy might be attributed to the heart failure improvement conferred by CRT itself. This moderate LBBB trial provides an excellent opportunity to further discuss the role of a primary prevention of ICD implantation in non-schemic cardiomyopathy patients with left bundle branch block. Recent data suggests that left bundle branch pacing can achieve effects comparable to or even superior to conventional CRT. Based on the scar evaluation with MRI, this moderate study anticipated a lower risk of arrhythmic events in group 1 with scar burden of less than 10%. With strong confidence in their study design, this moderate study selected only LBBP, but deliberately chose not to implant ICD in group 1. In group 2 with scar burden of greater than or equal to 10%, both LBBP and ICD was performed. Now the long-term results have been presented, and as hypothesized, group 1 demonstrated a lower incidence of events. Based on these remarkable findings, given the widespread use of LBBP pacing today, I hope that this study will further advance the discussion on the necessity of primary prevention of ICD implantation in non-schemic cardiomyopathy patients with left bundle branch block. Thank you very much. So there are some interesting questions. One of them was, did location of scar matter, septal versus non-septal? And along those same lines, there was a question about infiltrative diseases such as sarcoid among those with scar. Yeah. So definitely the location of scar matters. We have previously demonstrated that any scar and any transmural scar in the septum is going to have a negative prediction of successful left bundle branch pacing. So if you have a transmural scar in the septum where the leads are going to get deployed, the lead will not go. Even if you are going to push the lead, the stylet-driven lead, you may not be having a surviving Purkinje fibers to provide adequate resynchronization. So scar really matters. A non-septal scar, this is going to be beautiful. If it is a complete transmural septal scar, it's better to go with a conventional biventricular pacing strategy rather than a left bundle branch pacing strategy. As far as the infiltrative cardiomyopathy groups are concerned, so we have not specifically looked for the diagnosis of infiltrative cardiomyopathy. As you can see in the picture which I have shown, the dense scar completely occupying the septum, lateral wall, everywhere. These patients can very well, might have had an infiltrative cardiomyopathy. We didn't do any biopsy or PET CT to specifically look for it. But yeah, these group of patients still can have a typical LBBV and a dense scar. So you need to really look for the underlying diagnosis with the help of additional modalities. There's a lovely question here about are there any sex differences within the Midori CRT. And I know that one of the groups had more women than the others, but I'm sure you're looking at this too. Yeah, so we could find a non-significant trend towards a better response in female sex. But multivariate analysis didn't show that the female sex were better responders. And of course, in the group two, the scar burden, definitely the females were a winner because the burden of scar was very much less in females as compared to males. And I guess the last comment I'm going to make is, and you commented that it's time to look at the group of less than 10% much lower. But I thought it was very interesting that it looked like 25% of people who had scar burden greater than 10% did respond. So those are the people to also look for. Yeah, I have probably, yeah. Thank you. Our last presentation this morning will be by Dr. Girish Nayyar of the University of Ottawa Heart Institute. The title of Dr. Nayyar's presentation this morning is, Efficacy of Catheter Ablation for Management of Ventricular Arrhythmia in Subjects with Ischemic Cardiomyopathy, Analysis of Randomized Controlled Trials Updated with the VANISH-2 Trial. Dr. Nayyar. Sorry, I'm trying to get the pointer activated, the laser pointer, the mouse. All right. So I'd like to thank the Scientific Committee of Heart Rhythm Society for giving us this opportunity to present our research. I would also like to thank my colleagues who made this possible and gave me the opportunity. A special mention to John Sapp, who has been doing excellent clinical trials in the field of catheter ablation, and to all the unnamed ablators who spend hours taking care of some of the sickest patients that we have. So ventricular arrhythmias are often associated with an adverse outcome of death, ICD shocks, which are quite disturbing to patients with a spectrum of post-traumatic stress disorder and even severe depression in some of them. And for many years, we only had anti-epidemic medications as a treatment option until the pioneers of catheter ablation started the process of developing tools, techniques for ablating the scars and the substrate for VT. The goals of ablation include reducing ICD shocks, but overall arrhythmia burden, VT storm reduction, and ultimately, like for any therapy, other clinical outcomes such as heart failure, hospital admissions, and mortality. Despite the first randomized trial being published in 2008, over the last 15 to 20 years, we've had only a limited number of catheter ablation trials attesting to the fact that these are very difficult to recruit to and conduct well. And that brought us to VANISH2, which was recently published. And since it was a substantial contribution to the pool of patients enrolled in randomized trials, we sought to examine how it influenced the strength of evidence for catheter ablation. Because it's very important, there are many questions raised about catheter ablation, including whether it is harmful in terms of serious side effects, and whether it may actually reduce ventricular arrhythmias but enhance mortality, and so on and so forth. So we performed a systematic review with all the rigors required to conduct a good one, and we subjected our analysis to catheter ablation in patients with ischemic heart disease. In perspective, there were about 1,000 patients enrolled in RCTs prior to VANISH2, and VANISH contributed about 416 more patients. And now it contributed about one third of subjects enrolled in randomized trials. Now this is very important, because when you have a small group of patients, a large input of subjects can actually change the strength of recommendations and give you newer assessments of efficacy, harm, et cetera. Because as you know, when the sample size is small, you may tend to overestimate benefit in some cases, or underestimate benefit both ways. So this is a busy slide, and I apologize, but this is required to tell you the intricacies of the trials which may affect the interpretation. So first off, I would like to divide this into two groups. The first group of trials, other than Dr. Al-Khatib's trial, which is a pilot trial, really looked at ablation versus guideline-deducted medical therapy without any anti-atomic medication. And we know that there are good anti-atomic medications that can reduce ICD shocks and ventricular arrhythmias. Therefore they may have a more exaggerated response to catheter ablation. The next group actually are a cluster of trials where we looked at composite clinical outcomes in addition to composite ventricular outcomes, and therefore they are more comparable. I deliberately did not put catheter ablation strategies because they were pretty uniform, the principles being all mappable sustained tachycardia that were hemodynamically tolerated were ablated. And when you couldn't do that because of hemodynamic compromise or non-inducibility, a combined approach of substrate ablation using voltage mapping and pace mapping was performed. So with that background, we can go into the first systematic review forest plot. And before I go ahead, I'd like to highlight that we used risk ratio as a point estimate because odds ratios generally tend to overestimate the benefit, especially when there are a lot of events. And I would also like to say that we should not concentrate too much on the relative risk number, rather the confidence interval and the strength of the P value, which is telling us whether the observation is really believable or not. So this includes composite primary outcomes from BT ablation trials prior to VANISH-2. And as you can see, the confidence interval is quite wide. The P value is not significant. When we introduced the VANISH sample set, you notice that the confidence interval has tightened and actually the P value is not significant. While it's not very strongly significant, it's made a positive direction. And then this is important because, you know, it's not like we can replicate VANISH-2 the next year. It's very difficult to do another one. So it makes it important to see that what we are observing in VANISH-2 is strengthened by our analysis. So if you had the ability to do 10 more trials like this, then this would be not really required. Now when it comes to ICD shocks, what you notice is prior to VANISH and post-VANISH, you know, there's not much difference. And part of it is, why is this important? It's important because we've introduced a large number of patients, and therefore it tells us that we are not probably overestimating the benefit when we had fewer patients. So it's important, even though it's not dramatically different, because we have multiple examples where when you increase the sample size, you do not see the benefit that you see when you have a fewer number of subjects. So it reinforces our prior observations. VT storms were significantly reduced. And here, we noticed that the pre-ablation sample set was so small that you really couldn't have a confidence interval for the point estimate, and now we have one, which is significant. Recurrent VT, and this is where the results were slightly different or surprising to us, is that recurrent VT, the risk ratio was definitely lower. However, with the addition of VANISH, too, the response or the effect was less. And the reason for that is VANISH compared subjects on good doses of effective anti-arrhythmics, whereas a lot of the previous trials had no anti-arrhythmic effects. So it's not surprising, but it still tells us that it does reduce recurrent VT. Also we have to remember that ICD trials, almost all the subjects have an ICD, and you're continuously monitoring outcomes. Therefore you will pick up even two minutes of ATP, or two minutes or one minute of sustained ventricular tachycardia that can be ATP terminated and may not be clinically relevant, akin to 30 seconds of AF recurrence in patients after ablation, which may not be clinically meaningful. In hospital admissions, yes, we did see that it was reduced and that it was statistically significant. It's a subgroup. It's a secondary outcome, so it's not really part to demonstrate it, but we are sort of taking this to show that the act of going into the ventricle and doing a six-hour procedure is not associated with hospital admissions for the next one month. Ultimately, the goal of any therapy is to reduce mortality. When it comes to mortality, unfortunately none of these trials have power to detect mortality, and this is a subgroup of patients with multiple comorbid conditions and competing death risks. So even though you may reduce ventricular arrhythmias and ICD shots, they may have strokes, you know, renal dysfunction, advancing progressive heart failure, et cetera. So though the point we can see is that the point estimate of mortality is not going over the line of unity and telling us that there is a signal towards increased mortality in these patients. So what are the limitations? Handful of trials, differences in trial methodology with variations in interventional strategies, and competing cardiovascular risk factors for outcome due to different inclusion-exclusion criteria and follow-up duration. So in conclusion, VANISH reinforces that catheter ablation is superior to medical management, looking at the outcomes I've listed below, and that it has refined the estimation of catheter ablation for management of ventricular arrhythmias, and due to the difficulty of replicating the trial, it probably strengthens our conviction that catheter ablation does work in this situation. Thank you. Thank you very much. The commentary will be given by Dr. Christine Albert, Cedars-Sinai Medical Center. Great. Thank you. First, I want to congratulate on a great presentation and study. And so what I'm going to do is just kind of put it in perspective. What can we learn? So what are our guidelines right now for VT ablation? And this one graph from the ESC guidelines sort of summarizes that if there is sustained VT in an ICD and someone's on amiodarone, and this is from the first VANISH trial and others that were presented, that we really do have a class 1 indication for VT ablation already. If they were not on amiodarone, like say they were on Sotolol or Betablocker, it's a class 2A, and that's based upon these trials. But these are patients that has already had a shock sort of treated. And then for first presentation, we've got an indication of a class 2B, perhaps in the setting of also adding an ICD. So this is really where VANISH adds to that literature. And just to go over what VANISH showed, this was a highly positive trial, a positive primary endpoint, and it was also the longest trial, 4.3 years compared to the other trials that were shown before. And this is its first line therapy of VT ablation versus antiarrhythmic drug therapy. So how does this add in the setting of this meta-analysis? Well, one of the issues with these VT ablation trials is they were all very heterogeneous, and we heard that already. The problem is when you try to combine a meta-analysis, heterogeneous trial, sometimes it doesn't work very well. And we didn't hear about whether there was a test for heterogeneity, but we know that they're heterogeneous. They had different trial designs. Some were for recurrent VT on antiarrhythmic drugs. Some were first line for VT in the setting of an ICD primarily, and some were even prophylactic. Some of those ones that did not have an antiarrhythmic drug were prophylactic VT trials. The ablation protocols did differ. Control treatments differed, as we heard about. And the composite endpoint was different for many of the trials. And they actually differed in the way that they defined hospitalizations, what they collected hospitalizations for. So when you're looking at an endpoint that's defined differently across trials, it can be different. I mentioned the follow-up time, and two of the trials actually had non-ischemic patients, so likely these were excluded from the meta-analysis. So combining studies with different populations, interventions, and outcomes really can sometimes even obscure real treatment effects or can lead to misleading results. But what can we take away? Despite this heterogeneity, if you look at the graphs for recurrent VT, for ICD shock, they all look to be on the side of benefit. So I think that this is, again, just reinforcing, compared to antiarrhythmic drugs or maybe control in patients who haven't had a shock, that VT ablation works and reduces VT. The reduction hospitalization, I think, is much more iffy. It's based upon one trial that really had a strange high rate of complications in the antiarrhythmic trial. So again, that happened in one trial. And there was no mortality reduction. So future directions, you could do subgroup analyses to estimate the heterogeneity, but these trials are small to start with. The investigators could do an individual patient-level meta-analysis where you combine the actual patient data to see who might selectively benefit and to do those subgroup analyses. But basically, VANISH-2 is going to impact guidelines based upon its individual results. And this meta-analysis, unfortunately, can't replace such a well-designed, large-control, randomized trial. Thank you for your attention. Thank you very much. I'm afraid we're out of time. But I think that, as Dr. Albert said, the hope is that this is going to change guidelines. So look forward to seeing the future. So thank you all very much. This was great. Have a good meeting.

ventricular arrhythmias

heart failure

implantable devices

BioLibra study

sex differences

ventricular tachycardia

ventricular fibrillation

conduction system pacing

VT ablation

clinical trials