It's 8.01, and apparently the last day is not a good day for doing this kind of a presentation. So anyway, we welcome you to this session, and we're going to have the ability to ask questions at the mic, or it's possible also for those that are looking online to do those using the QR code on the web app. So okay. First speaker, Weiji Yaman from Geisinger, he's a famous EP for conduction system pacing, and he's a recipient for fund lectureship last year. And today he will introduce the fund award, please. Thank you. Thank you, Dr. Wang. So just to confirm, we both are recipients of the Founders Lecture, so Dr. Wang has done a lot of work on conduction system pacing. It's my great honor and privilege, and it gives me immense pleasure to welcome Professor Pierre Gies to give us the Founders Lectureship today. And he is someone everyone in EP clearly knows for a long time, more than three decades he has trained and taught us how to do various aspects of ablation. It's hard to mention all the contributions that he had given, but one thing for sure is the field of electrophysiology, as we know, in terms of atrial fibrillation ablation, and the innovation that he and his group, along with Michelle Hasegara, had done has completely changed our practice and management of atrial fibrillation. And apart from that, he leads new research into ventricular fibrillation. He's the CEO of the Innovation Research Center called LYRIC in Bordeaux, France. And the most important work that Pierre has done is to train thousands of young electrophysiologists and welcome many of them, whether it's a few days, a few weeks, months, years, spending time in their lab. And I was one of them almost 16 years ago, had an opportunity to spend three weeks in his lab and learned so much from him. Pierre, welcome. Thank you so much. Thank you very much, Mr. Chairman, for this very kind introduction. I'm particularly honored for being here, and I want to thank you also in the audience for being here at 8 a.m. on a Sunday morning. I'm very touched. So yeah, a few words on the past, present, and future of catheter ablation for atrial fibrillation. I also wanted to speak about ventricular arrhythmias, but I ended up having 100 slides in 20 minutes. That makes no sense. So I had to make choices, unfortunately. So I'd like to take you back to 1978, where we've got this vision that atrial fibrillation was due to fast-moving wavelets, and with different types that have been described, representing different level of chaos, in a way. And at that time, all we had for mapping was pretty simple catheters, and you can tell that things have changed. But based on this concept that those wave fronts were propagating until they hit a boundary or a zone of refractoriness, the surgeons led by James Koch published as early as 1991 a surgical strategy that was having very good results on AF treatment. It was pretty aggressive, and patients were swelling because of ANP disorders, et cetera. So it wasn't that convenient for patients, but it was working, and it was the first proof that AF was, in fact, amenable to non-pharmacological treatment. And at the same time, there has been very few new drugs, and we don't see much coming in the pipeline, unfortunately. And then John Schwartz, in 1994, had this incredible effort that was reported during the AHA meeting, where he, in fact, has been using point-by-point RF to replicate the maze. And these were eight-hours procedures. It was really difficult in arduous, and associated with complications like stroke, et cetera. But it was, again, a proof that AF was amenable to some non-pharmacological treatments. And this time, even if it was very aggressive, it was less aggressive than surgery. And we did, and Michel, in fact, Michel A. Seguer in Bordeaux did that. First patients were using a 14-electrode catheter from BARD, with 14-electrode energized sequentially with RF. It could demonstrate AF termination in that single patient. It was very lucky, because then you know that the success rate ablating from the right atrium, I mean, this is something we tried after that, and it was very limited. But it was lucky that the first patient terminated, and then we followed his inspiration, which was, look, instead of trying to understand why fibrillation perpetuates, let's try to understand how it gets initiated. And we spent hours and hours in the lab for two years before we finally end up. So this is not the first patient. The first patient, I remember very well, had a PFO, and by chance, we ended up in the right superior vein. And the catheter was outside the cardiac silhouette, was not tamponade. So we thought this could be a pulmonary vein. This is how much knowledge and habit we had at that time of what the left atrium was. And again, a second miracle was that the fibrillation started from that vein at that moment. And what we saw was a very sharp activity that was so early versus the surface P wave. And I said, oh, this is interesting. This may be the spot where it starts. And then we had, you see here, a series of patients. Fifty percent of them had initiations from the veins. That was the first understanding of the role of the veins. And after the third patient, I was convinced that there was something there. And we, you know, pursued the effort, and this is this paper that you have seen and read, I'm sure, in the New England in 98, where we had this clustering of initiation from pulmonary veins for those paroxysmal AF. Now those patients were not standard AF. They were having very frequent initiations, otherwise it's impossible to map. This is why it took us so much time. And then out of this observation, we did the ablation, which was focal on the spot triggering AF in each vein. Problem was that in the same vein, you could have, and this is thanks to the lasso that Michel A. Seger designed, we could have different type of initiations, meaning different focus in the same vein. And so typically what was happening was that on Monday, we were having the first ablation of a given patient, and then Tuesday was a recurrence, and Wednesday was a second ablation in another vein or in another site of the vein. And we had that for a couple of years until we understood that, in fact, we could perform an anatomical ablation of the vein by going around with RF that hopefully was contiguous and that was resulting in this disappearance of the venous activity. And that was the beginning of what we still do at present time. So it took us about 10 years to get access to the recommendations. In fact, there were a previous recommendation the year before in 2006, but this one was really the one that was establishing a potential role for catheter ablation for atrial fibrillation. So 10 years, that's long, but that's what it takes to be acknowledged for not being completely crazy. And one of the major statements in these guidelines was the 30 seconds duration of arrhythmia for defining recurrences, which I voted against with Sonny Jackman. It was only the two of us, and I still think that this was a mistake. It was due to the fact that TTM were allowing for 30 seconds only, but it's not a good reason. And as a consequence, 20 years after, we still have this 30-second definition, which has been so harmful, I think, to the field, because we have patients with one-minute recurrence after persistent atrial fibrillation that are considered failures, even if they have one episode every year or just a single episode. So this is wrong and should be changed. It will change, I'm sure, but it will take time. And then another 10 years after, we've got some incremental improvement of the technology to perform the isolation of the veins. The cryo-balloon was there. It was simple and effective, but it was producing similar results as RF encirclement of the veins. But this was consistent with shortening of the procedures that became way easier and faster, and also associated with much better results, which was great, of course, for patients. And then I think the most accomplished approach when using RF was developed by our friends from Bruges in Belgium, was the CLOS protocol, because it was not only taking into account the depth of the lesions, but also the contiguity of the deliveries. And that was a very good point, very important point, in my opinion. And very good results. And we are still struggling understanding what atrial fibrillation, we're not even sure that it is a mappable reason. And there has been plenty of efforts to identify drivers in those areas of chaos and fractionation. Now I'm absolutely convinced that most of this fractionation comes from an artifact, which is far-field accumulation of signal. And so I don't believe it's the way to go. Even if the tailored AEF trial was surprisingly successful, with the caveat that if you look at the results based on any arrhythmia recurrence, meaning that you include those organized rhythm, then there is no superiority as compared to PVI only. So it's still an interesting demonstration that using artificial intelligence, you can see through the chaos. But I suspect that the future of mapping atrial fibrillation will come from dedicated mapping catheters with the effort that CoreMap is doing, and Bison's web series is doing similar efforts to produce improved mapping catheters with really small electrodes that are very shortly coupled. We are talking about submillimetric electrodes here. And the very smart idea by Peter Spector was to superimpose the electrodes and to have some insulation in between the two so that when you subtract the signal, in theory, what is left is only what is in contact with the first electrode that touches the tissue. I think that's very smart. And you can see here, this is an AEF model we have at Lyric. You can see how organized it is and how simple it is for a mapping system to annotate each activation as compared to what we have here with the HD grid, which is a fairly decent catheter for mapping, as we consider. So I think this is the future. I do believe that if we have a chance to map AEF, it lies in these dedicated super small electrodes. And again, the difference between the two things is the massive reduction of the far field components that we have with those electrodes. The other revolution that you all know of is electroporation. Now I had a chance to be involved with the idea of Stephen Michelson from the beginning and Alan Zingler has been instrumental to the success of Iowa which then was becoming Far Pulse and finally got acquired by Boston Scientific. At the beginning it was somehow crazy because it consisted in using that linear electrode catheter with some pretty complex approach. It was some xiphoid, a picardial, with some dedicated device that have been prototyped to cross the pericardial reflection with some magnet to align things and it was really complicated. Every physician involved in their advisory board said, look, we should consider some endocardial solution. But this is in fact super nice for surgery. I don't know why they didn't pursue this avenue, probably that the market is too limited as compared to endocardial, but it was working amazingly well. I was shocked to see those patients from Paraguay where they have plenty of very severe mitral disease which results in really ectasic left atrium. This one was 65 millimeters diameter in transthoracic echo with the prasternal view and from the first attempt you get the anterior posterior wall and veins isolated with some, you see here, isolated activity from the posterior wall. And we did some in Bordeaux with the collaboration of our surgeons. It was working remarkably well, again, these dissociated potentials from the posterior wall. But what was instrumental to success, I think, were the first animals that we did where we could isolate the veins so easily. Now, I don't know if all of you have been into pulmonary vein isolation in swine, pigs. It's super difficult. Even with point-by-point RF, it's a challenge because the anatomy is very different. We're not used to it. It's very small left atrium unless you take pigs of 300 kilograms. And so, you know, for me to see that it was doing it like that was the guarantee that it would work very nicely with patients' anatomy that is way more favorable. So I'd like to review now some of the premises by PFA. Superior efficacy. Well, we have the champion trial now that is positive for superior efficacy over cryoblation. And I think that we're going to see more of these superiority trials. The end point, again, as discussed earlier, was the 30-second definition is, I think, wrong. Champion was smart enough to, Tobias Riesling, by the way, was smart enough to use ILR. It is largely why the trial is showing superiority, in my opinion, because you have a very fine detection of everything that is happening. Tissue safety. Well, the major point, in my opinion, is that there has been no esophageal fistula. It's over 250,000 cases performed so far, not a single fistula. It is very meaningful to me. No PV stenosis. And frank nerve, there is one case which I'm not entirely sure that it's due to the technique because it's just one out of these 200,000 plus. Esophageal selectivity, not entirely. It is there, but partially only, in my opinion, Vivek Reddy demonstrated that there are some esophageal lesions that are mild, very modest, in fact, and that are never bad enough to turn into fistulas. Non-thermal, not really, but it's no thermal lesion. So there is an increase in temperature that is modest again, and that doesn't result with any lesion. Faster and easier, absolutely. This resulted in way more patients treated. You just have to look at the numbers in the U.S. It's amazing. Cost for healthcare system, that's a problem. The cost of those devices will have to come down, otherwise the system will crash and I suspect the reimbursement will have to decrease. This is probably not sustainable. Sustainability in itself, absolutely no. There has been no improvement, and this is super important because I remind you that healthcare in itself is responsible for 5% of carbon emissions, meaning that when we treat patients, we kill patients, or persons that are not even patients. So that's a big problem, and I hope the industry will face that at some point of time. Unexpected complications, well, yes, hemolysis was to be expected, in fact. It has been known forever, and it has to be acknowledged. Coronary arteries, it was there in the earlier publications as well, but it came under the radar, not sure why. It's not a major deal when it comes to coronary arteries, in my opinion. This is the champion trial, and very interestingly, if you look at what happens during the blanking period, the difference is there immediately. I think this is also interesting and should question us on what the blanking period duration should be. I'm not even sure we have to have one for PFA, which produces less inflammation than RF, for example. These are wonderful things we observed with Hubert Cochet, our radiologist. You see how the veins after PFA are hyper-intense with late-gan enhancement. Interestingly enough, the cryo is producing some enhancement of the anterior wall of the oesophagus, not PFA. We've never seen that with PFA. The way it appears on late-gan enhancement is very different. It is super bright at the beginning, acutely, and then chronically, even though the lesion is still there, it appears very different. The reason for that is that it respects microvascularization and tissue architecture, unlike cryo or RF. In the arteries, I mentioned that. This observation with OCT, where there is a mild impact with intima or media hyperplasia. We should all keep in mind that RF is not safe either. It's not as frequent, it's not spasm, but it's potentially occlusion acutely. I had a case no more than 10 days ago. There is a protocol with nitroglycerin that we should all know and use to prevent those spasms from happening. What's next? Well, I think better understanding of lesion formation. We still don't know if there are ways to predict recurrences, PV reconnection. Maybe unipolar mapping can see through stunning. Revisit ablation strategy, I think this is needed, particularly with persistent AF. Line blanking period, develop next systems, generation for AF. This is the first generation for PFA. We have to see further improvements in the future. Dedicated VT systems, I think this is super important. And there is room for improved workflow. This is showing you some apoptotic death after PFA from a Chinese study using Chinese prototypes. If China is super active with PFA, it will show up. Marshall Plan, we recently finished the Marshall Plan trial, which showed superiority of PVI plus versus PVI only for persistent AF. This has been also acknowledged with the PROMPT-AF study from China again, which was recently published against superiority of PVI plus. And we are also at the end of the BETA-AF study, which compares PFA versus RF for paroxysmal PVI and for persistent AF ablation. There are two groups, two studies, plenty of sub-studies that are going to be super interesting. And again, I think that we have to revisit all of this, because everything I said before with persistent AF is with RF. We have to revisit that with the best tools that are using PFA. And namely for mitral isthmus, it's the AFERAR system that is, I think, performing best. And in the near future, redefine endpoints for ablation. I think we should consider burden, at least for persistent AF, more than this 30 seconds definition. Revisit recommendations for persistent AF. I think we are wrong in focusing on symptoms and on paroxysmal AF. Patients who benefit most from AF ablation are those with persistent AF, irrespective of symptoms, in my opinion. Identify patients in whom more than PVI is needed. This is super difficult, in fact. We don't have clear algorithms for that. Aim for non-destructive therapies. And these are my last two slides. I was very impressed with the work by Kevin Donahue with some connexin gene transfer in his canine AF model, which resulted in non-inducibility of AF. It would be nice to restore function versus what we are doing at present time, which is delivering destruction over destruction. Thank you so much for your attention. We have time for a few questions. Thank you, Pierre, for that impressive lecture. Regarding persistent AF ablation, you mentioned that beyond PVI, it's still a challenge, and we don't have a strategy. You showed us so many different strategies in the past with persistent AF and RF ablations. Now that you have a more powerful tool and your new mapping ideas, what do you foresee in the future in terms of some stepwise approach or a new Marshall Plan, or what do you think might win? Yeah, absolutely. You are absolutely right. I think that persistent AF is going to change tremendously in the next few years because of us revisiting previous strategies with PFA, which is producing way more durable lesions as compared to RF. Also PFA has an intrinsic superiority in case of fibrosis, which happens in AF, and in case of trabeculation and for some, let's say, rotors or focal activities that would be located in trabeculated areas, PFA is going to be way superior. So there are different strategies. We like linear lesions in Bordeaux. It's not the only one, and I think there will be a role for mapping during AF and for targeting two, three, I don't know, four regions. The difficulty will be that if you don't connect those areas to a boundary, then you get macro re-entries or localized re-entries. So it will have to be taken into account, but I think PFA will help with respect to that as well. Thank you. Thanks. Quick question, please. Pierre, congratulations. Just to draw you out a little bit on your somewhat heretical statement that we should ignore symptoms and treat everyone with high burden atrial fibrillation, I'm convinced as well, but I just sort of want to draw you out a little bit on your thoughts. Why do you say that, and what evidence do we need, maybe, to convince our colleagues? That's a difficult point. It has always been. I think we have enough evidence that, in fact, AF burden is what partly, at least, determines the risk of complications for patients, like stroke, for example. It is somehow related to AF burden, but the risk for dementia, for example, is also linked to that in a way, because it's higher with persistent as compared to paroxysmal, and it goes down if you are successful with ablation. So all of this points toward a new approach where we would have, I think, probably multi-parametric tools to combine AF burden plus the existence of structural heart disease plus maybe diabetes or renal failure, and all of this should be doing a much better job in the indication for AF ablation. But I can't see any situation where AF, particularly persistent AF, would be superior to sinus risen. So this is why I think we will end up with large ablations. Largely indicated ablation. Okay, thanks. Thank you. Okay, it's my pleasure to introduce the Ralph Lazara Lectureship. So, this lectureship seeks to recognize a basic or clinical scientist who has made significant contributions to our understanding of EP by clarifying the mechanisms, localization, or elimination of arrhythmia sources. And this award is in honor of Ralph Lazara, who co-founded and served as medical director of the Heart Rhythm Institute in Oklahoma and was a very active, not a founder, but a very active member of NASPI and the Heart Rhythm Society. His research sought to clarify the mechanisms of arrhythmias including Wolff-Parkinson-White, AVNRT, the LQT syndromes, and ventricular tachyarrhythmias. He was a skilled laboratory scientist with expertise in microelectrode recordings and set the stage for some of the advances in catheter ablation that have been obviously extended significantly by Dr. Jais and colleagues. This year's award recipient is Igor Efimov, and he is a professor of biomedical engineering at Northwestern University. He's made significant contributions to our understandings of the mechanisms underlying fibrillation and defibrillation. And speaking personally, I know that Igor is a highly collaborative and an outstanding mentor. He's got a broad interest in arrhythmia mechanisms, and he's going to present some new ideas. Igor. Thank you, David. Thank you, Vikamitra. Thank you, the committee, for selecting me as a recipient of Ralph Lazaro Lectureship Award. I've been fortunate to have met him, and we had wonderful discussions about the mechanisms of AVNRT, which was part of my research for many, many years, and also defibrillation pacing. So I really appreciate this award. So I was debating whether to present historical studies we've done for many years or rather to talk about the future. And that's what I would like to talk today about. So we just published two weeks ago this novel pacemaker, as you can see here. We call it Millipacemaker. As you can see, it's the size of half of a grain of rice. And jokingly, we say in the lab, so now you can take a pill, and this pill is actually a pacemaker. Of course, it's not entirely accurate, but nevertheless, this is the analogy. Well, I already had my disclosures. I don't need to repeat it. But I would like just to say that it's also my honor to speak after Dr. Jais because I also consider myself to be an alum of Bordeaux, of Lyric, so I've been there, what, visiting for over 10 years every summer. So we've done a lot of interesting work, and we continue to work with the group in Bordeaux. So let me start with real history. So the pacing electrical stimulation started really with Swammerdam. But also what we actually keep forgetting, not only electrical stimulation, but actually physics of electricity started from that, as well as electrophysiology in general. What Swammerdam did in 1664, he took frog leg attached to a nerf, and then he pinched the nerf between silver wire and copper wire, as you can see here. So nerf was held in the silver wire loop, and then the holder was here, copper. Of course, at that time, he didn't know that these two metals formed what we now call galvanic element, even though galvanic was not born yet. But these two metals produce approximately one volt of electricity, and this was sufficient to stimulate nerf. So he documented it. Unfortunately, for him, he published it in Dutch, and nobody read this book, and nobody gives him any credits. Therefore, we all know it as a galvanic effect. Galvani published it in 1781, more than a century later. It was a really similar experiment, except he used two different metals. He used zinc and copper. Zinc and copper actually form also galvanic element, as we call it now, which has more voltage, and he was able to reproduce this with more accuracy. What was also important, this work led to Volta, Alessandro Volta, who actually recognized this as a source of electricity and created what we now call voltaic pile. He was also inspired by dissections of Dr. Hunter in England of an organ of electric fish. So the actual structure of his galvanic element, of galvanic pile, was actually exactly reproducing the electrical organ of electric fish. So in our early work, I was really fortunate to focus on mechanisms, how stimulation works, and these are some early papers from over 20 years ago with Vladimir Nikolsky. When you apply cathodic or anodic unipolar stimulation, so this is theoretical prediction. Under the cathode, you will see what Vicks-Wahoo described theoretically first, a dog bone-shaped virtual cathode is formed, which is shown here in red, which means tissue was slightly depolarized and reaching the threshold at lunch excitation wave front. But what was also interesting, on both sides along the fiber orientation, you will see virtual anodes, because current has to return from the cathode. And this was a universal phenomenon. If you flip the polarity, it will be exactly the opposite. So on the anode, you will see negative polarization, and two cathodes will be on both sides. For bipolar stimulation, as shown here, depends how you orient your bipole with respect to fiber orientation. Patterns take very interesting shape, but ultimately, depolarized regions in this case, for example, for this bipolar stimulation, excitation will start in these three depolarized regions. So the same mechanism applies to defibrillation, and actually to ablation as well, for electrical ablation. So the history of pacemakers, and I will be talking about pacemakers today, was very interesting, and now we went through several generations of pacemakers, so of course, we still have domination of this traditional pacemaker with leads, either dual-chamber or single-chamber leads. So we seem to transition to leadless pacemakers, which show more and more promise, but still, one remaining challenge for this technology is that 70% of the body of the pacemaker consists of a battery, and still, battery has a limited lifetime of about, correct me if I'm wrong, about six years or so. And then, explanting this pacemaker will be challenging, because it's all embedded and encapsulated in fibrous tissue. So we've been working on a different technology, how you transfer data, how you program it remotely, but also for applications where you can actually make device transient. So the whole notion of transient electronics emerged several years ago through work of material scientists who developed many materials which have finite lifetime, and after that, they dissolve safely in the body. So we developed two different types of such bioresorbable transient electronic pacemakers. So this one I will show you was published two years ago. It doesn't have a source of energy on board. It only has antenna, which basically allows you to transmit energy wirelessly, the same way you transmit energy when you charge your cell phone. And this new one, a milli-pacemaker I will show you today, actually does have a battery, the same way battery was shown by Galvani, so we're using almost the same metals for producing electricity. And yesterday, we had a wonderful session on history of electrophysiology, which was called a never-ending conversation, where people who witnessed, actually, the origin of pacemaker technology brought the first pacemaker developed by Earl Bakken in response to a request by his boss, Walt Lillehei, at the University of Minnesota, because patients after open-heart surgery required a pacemaker. And he developed it. This is the box. Actually, yesterday, you could see the original, one of the five original boxes. And over 60 years, Medtronic developed a number of these devices. But the technology for temporary patient is still the same. You have to attach surgically a wire to the patient, and you have to externalize it and attach to external box. And the problem, basically, is that even though rare, but there are complications with that. For example, some of you probably know that Neil Armstrong, famous astronaut, died from this complication after surgery, because when wire was removed, his heart was lacerated, and he died because of blood loss. So initially, we thought about making a very small pacemaker, which can be implanted and doesn't have to be explanted because of its small size, and ultimately can be replaced with bioresorbable technology. So in order to miniaturize this pacemaker, we got rid of any electronics on board and any battery. So this basically consisted of, as you can see here, an antenna shown here. There are a couple of diodes. Initially, it was actually microchip, but later we replaced it with bioresorbable components. And then it was attached to this zigzagging serpentine electrode, because it was very soft, compliant with the heart, and did not obstruct motion of the heart. For experimental work, we equipped it with two platinum electrodes for electrical pacing or a light-emitting diode for optogenetics, so we can use it also for optical pacing. So this was initially developed for animals, of course. So this is an experiment on rats. So you can surgically attach it, externalize it outside the rib cage, but subcutaneously because it didn't fit in the chest of the animal. And then the experiment can be basically done in a way that you transmit power to that antenna from outside circuit, which is outside the animal. So now the question was, can we make it bioresorbable? The same idea, but make of materials, as I mentioned, which are all bioresorbable. So fortunately, like I said, material scientists developed these materials. Some of these materials actually are well known to you. You don't even think that they're bioresorbable, but they are. For example, magnesium. Now we make from magnesium some devices. For example, stents could be made from magnesium. In small quantities, it's not toxic, and it's bioresorbable. If you make it a few micron in thickness, it will dissolve within a month approximately. Silicon, from which transistors, semiconductors are made, is also bioresorbable. If you make it several micron in thickness, it will resorb also about a month or two. So we have also different materials for interconnects, for insulation. Some materials are transparent, some are very well conductive. There are also organic materials now which can be used. So the device was produced exactly the same idea as I showed you before. Now from bioresorbable materials, if you place it in the saline at 37 degrees Celsius, so you can see it about 40 days, there will be no trace left. It will completely resorb. So idea again, the same. You place device on the heart of a patient. After surgery, you close the patient, there are nothing externalized, so the patient is untethered. And then the circuit can be placed outside the chest. It will transmit power to the device, and you can pace essentially the device. In animals, it would be instrumented very easily. You can put a coil around plastic cage, basically animal inside the cage will always be under control of that electromagnetic field. Of course, it's not the case in patients. I'll show you how we solve this problem. So we did a lot of validation work. So first of all, we established safety. So if such device is implanted, so we see minor fibrosis at the site of implantation with suture, but then later we developed bioadhesive, which replaced surgical suture. You can basically glue this device to the surface of the heart, and fibrosis was dramatically reduced. There was no evidence of any kind of damage to the muscle. Only a picardial layer had a little bit of fibrosis. Animal had no impact on body weight. Ejection fraction was normal over three weeks of dissolution of the device. And also we looked at various markers of inflammation in the animal, and you can see here there was no evidence of inflammation up to eight weeks post-surgically, and basically after the device was completely dissolved. So we developed a number of variants of this device. So here is shown one of them. For humans, we believe we don't need this long electrode, because obviously you can place a dime-sized device directly on the heart of the patient, even pediatric patient. So instead, most likely we will develop a dart-like electrode, very similar to what is currently used, for example, for ultrasonically actuated device just FDA approved a couple weeks ago. And then it will have antenna for controlling it from outside. But how do we control it from outside? So it's controlled by a wearable device shown here. It's a small device size of a postal stamp, which you place on the chest of the patient directly above the implanted pacemaker, and it has everything you need to program the device. It has a microprocessor. It has coil for charging the device, because it does have a battery, of course, the external device. It has a coil for powering the implantable component, implantable pacemaker. It also has various sensors. For example, it has ECG sensor, so you can see comparison with a clinical LID-1 ECG. It's very high-quality ECG recording, so we can provide essential information for the microprocessor to do on-demand pacing only when you need it. We can follow heart rate, as you can see quite accurately on treadmill, respiratory rate, oxygenation. We have PPG there. And there are also various other sensors, such as, for example, XYZ accelerometers to look at behavior of the patient and physical activity. However, again, we wanted to move beyond that, make it even smaller. And then idea was going back to the original experiments of Galvani and Svammerdam. And when you look at it, it's very, very simple. But it was not simple to come up with this idea initially. So the idea is the following. So the device consists of only three components. So there are two components similar like Galvani and Svammerdam. These are metals, essentially, which form galvanic elements and form a little battery. In this case, it's magnesium and molybdenum trioxide. These two metals form a battery, same way you find your lithium ion beta battery. And it produces about 1.3 volt. Then they are coupled to one another with a phototransistor. Normally, this transistor is open, so there is no circuit, essentially, no current flow. But if you shine light on it, it will close, connect the two, and it forms the battery. And then all of that is encapsulated in a non-conductive but optically transparent material, which does not allow it to penetrate biofluids inside the elements. But of course, then on the other side, this device will be in contact with tissue, and blood will form, essentially, connection with tissue. So it will form galvanic element connection to the heart. So therefore, the way it works, essentially, is you shine light on it, you connect the device to the heart, and you can stimulate the heart by optical pulses. So we developed a number of approaches how it can be deployed. So first of all, you can deploy it, of course, surgically directly during open-heart surgery, for example, in pediatric patients after septal defect repair. You can also inject it, presume we're still working on it. We didn't show it yet in large animals, but we showed it in acute experiments. You can inject it with an injection through the chest, place it directly in pericardial space, in, for example, cases of emergency. And then, basically, like I said already, device will be controlled by external module. It will connect the two elements, anode and cathode, and form, essentially, stimulation circuitry. If you place this device, all these materials are bioresorbable. Here, you can see we did accelerated aging, but essentially, one month is sufficient to fully dissolve this device without a trace. And all these materials, all chemistry is shown here. It's published in Nature two weeks ago. We also conducted optical calculations whether or not you can actually reach this device with a pulse of light from the chest of the patient. And we showed that you can safely reach within approximately 7 centimeters and beyond using the infrared light. So this is how it works. If you apply pulses, square pulses, 1 millisecond, 2 millisecond square pulses of light, infrared light, it produces current, as shown here. And then, light intensity is linearly dependent. It depends, essentially, producing current. And there is a plateau phase, so it safely stimulates the heart. If you need to increase the amount of current or voltage, you can basically, like Galvani's voltaic pile, you can basically connect several elements in series. You can double, triple voltage if you need for different applications, including, for example, for bioresorbable defibrillator, which we are working now for post-operative atrial fibrillation patients. So it has a decent strength-duration curve, as you can see here. So you can safely pace with a 2 millisecond, 1 millisecond pulse. And we showed, initially, proof of concept in the explanted in vitro pig heart and explanted, also, donor human heart, which was not taken for transplantation for reasons of age. So you can safely pace these two hearts outside the body. Then, to prove that it actually works in a real-life situation, we constructed a very similar system, like I showed you before. So heart was attached to the pacemaker here. This is a rat heart. We also did a mouse heart, rodents, essentially. And a wearable device was attached to the back of the animal after hair was shaved. Again, the same idea. There are electrodes to sense ECG. There is a light-emitting diode, which controls pacemaker. And there is a circuitry, which does, essentially, machine-learning-based recognition of heart rate. And we programmed this device for 220 beats per minute, which was considered below that will be bradycardia. So when bradycardia is detected, it will commence pacing at 240 beats per minute. Normal heart rate of rat is 400 beats per minute. So just you know. We also tested it in an animal with Rishi Arora in his lab. So the pacemaker was first directly implanted with a line-of-sight surgically. And then we also used this injection catheter. So you can place it directly on the surface of the heart, as shown here. It's very small compared to the heart of rat. And again, the same way we showed that you can basically program this device. And we paced also dog at 240 beats per minute. So how do you basically do it in humans? So as in animals, so we'll have implantable component and external component. External component, our heart module, will have several systems. First of all, it's powering the system. But in this case, by pulses of light or in case of inductive power transfer, it will be inductive, producing electromagnetic field. Fully controlling one-to-one, bit-to-bit, the implantable component. Then it has a number of sensors, which will provide vital information to a microprocessor, which will produce on-demand pacing for this patient. There is also a system for haptic actuators, but also potentially can make it voice feedback. Basically, it will inform patient if patient doesn't need pacing anymore. And of course, this system will be fully integrated with online system. Physician will have full access to data 24-7. Data will be streaming to the cloud computing and to physician's desk. So overall, we believe this will be the pipeline for various indications. So if patient needs emergency pacing or post-operative pacing, temporary pacing, so pacemaker will be implanted or surgically or injected. So then patient will not be tethered to external box like it is done now. It can be discharged earlier, can recover using a physical exercise. We develop procedure how external device can be safely charged without interruption of pacing. And physician, like I said, will have full control of the information. And physician will inform patient that you don't need pacing anymore. You can basically remove the module, and the internal device will be absorbed within approximately a month. What are applications in addition to what I already showed? First of all, resynchronization therapy. Of course, you can directly implant it on the left bundle branch. We're already working on that through aortic access. So it plays very nicely on the left bundle. You can also do biventricular or multi-site pacing. So we showed here, for example, that you can use different wavelengths to control several pacemakers at different pacing paradigms. So you can, for example, modulate phase of pacing so they are not synchronous, not at the same time. And shown here, we can do basically multi-chamber pacing of the explanted human heart. We also think that interesting application would be TAVR-TAVI patients. As you know, depending on the manufacturer, from 15% to 30% of patients after TAVR implantation have a AV block, develop AV block, some transient, some permanent. So what we can do, essentially, we already did proof of concept. You can integrate a number of such pacemakers on TAVR device because they are so tiny. And you can provide this option to the patient if patient discharged after TAVR procedure and finds in bradycardia. So basically, placing external device on the chest can take control of the TAVR pacing. And you can see here, of course, depending how TAVR device is oriented with respect to conduction system, you have to hit the conduction system you can pace. So in this six pacemakers integrated here, two of them were not properly oriented. They did not capture, but four of them did capture. So we also did a safety study. As you can see here, again, as before, this device is safe. We don't have any evidence of inflammation. And just to tell you that lifetime of these devices can be modulated depends on materials and manufacturing process. As I already said, magnesium molybdenum device lasts about one week, so safely six days. After that, it stops working, and then it will be dissolving after that. However, if you go with the materials used by Galvani and replace with zinc molybdenum, in this case, lifetime of the device prolonged to be on two weeks. And we can modulate it to one month or three months or six months, depending on the application. So it's really safe and can be easily modulated for applications of different duration. I hope I convinced you that the future of temporary pacing is really bright, very interesting, totally new approach. But also, we can make these devices actually permanent, if necessary, including inductive power transfer integrated on the tower device, for example, if you need permanent pacing. So I'd like to give credit to big team, especially Yamin Zhang, who was in Eric Ritkin, who first offers on our big paper. Yamin is now a professor in Singapore. And Eric just received honor of 40 under 40 by Cardiovascular Business Magazine. And also, we have a number of interesting pieces in mass media. This is an interesting explanation of our technology by The Times of London. And I recommend to send it to your children. So hopefully, they will be inspired to go to cardiac electrophysiology. Thank you. This presentation is open for questions. Outstanding lecture. Thank you so much. One question for you, particularly this temporary when you think about having an external modulator, is it reliability if the patient is not putting it right? Will that be an issue? Will that be a good thing to have some sort of subcutaneous implant there, just as a control? Yeah, for some applications, definitely we'll use subcutaneous implantation. But again, I don't expect patient will be placing device him or herself. It will be done by physician, of course. And the good news is that diffusion of light in the chest is actually quite large, so a large area will be covered. There is quite large safety margins where you place it. But again, I do think that physician will be in charge, not the patient, for placing it. Thank you. Congratulations. It was amazing. I would love testing it, though. Did I understand correctly? Can they connect to each other? Because you mentioned AV synchronization, this kind of thing. So is that already the case? And I guess the second is you mentioned endocardial passing. Is it compatible right now, or this is in the future development? Answer for both questions is yes. So yes, you can do atrial ventricular dual chamber, multi-chamber, and also endocardial. So we're working on several types of implantation. For example, one type of implantation, of course, is intravenous through coronary sinus. So you can navigate inside the branches of venous system of the left ventricle. Not only that, we're actually working on a micro-robot, which will allow you to basically inject pacemaker in the venous system. It will actuate and deliver pacemaker to appropriate site. And you can even adjust remotely without any catheter, just relying on the locomotion of this micro-robot. You will select the appropriate, the best spot for stimulation for resynchronization of the left ventricle from multiple sites. Thank you. Igor, fantastic. Your contribution to the field is just spectacular. You mentioned defibrillation. How are you going to have enough power for that? Because it usually use a condensators, et cetera. Yeah, it's a great question. And as you know, we've worked on low energy defibrillation for a number of years. And currently, it's lower than normal defibrillation, but it requires about 50 volt. But again, current version of this low energy defibrillation, it relies on a relatively low resolution delivery system. We only have two or three coils. So it's still from just a few spots. So we're working on a system where you will have more than that. So if you have, for example, 20 or 30 sites from which you deliver energy, and each site will tie to a local dynamics of atrial fibrillation, for example. So it will be tied to frequency at that particular site. So essentially, you will be stimulating an excitable gap at that site, of course, which will be distributed non-uniformly across the heart. So our initial work suggests that we can get away with probably about 5 to 7 volt. And 5 to 7 volt is already feasible with this approach. As I said, even one element only produces 1.5 volt. But basically, there are new materials which can increase that. And then you can connect them in series. So we can bump it up to 10 volt easily. I don't expect to bump it up to 50 volt, but 10 volt will be sufficient. So I think we are already on track. And hopefully, now we'll get funded. As you know, we have some issues with our university on funding front. But my grant received 2% percentile on that subject. So hopefully, it will be translated in Bordeaux with you. You're welcome. Thank you. Thank you very much. That's the end of this session. Thank you all for your attention and for coming in early on a Sunday morning.

electrophysiology

atrial fibrillation

catheter ablation

electroporation

pacemaker technology

bioresorbable pacemaker

temporary pacing

resynchronization therapy

TAVR-TAVI

cardiological interventions