Hello everyone. Good afternoon. I'm Patti Larkin. I'm the Registry Product Manager for the EP Device Implant Registry and I thank you for coming. I'd like to introduce our speaker. Dr. Omer Youssef is a board certified interventional electrophysiologist and cardiologist. He completed medical school at University of Missouri, Kansas City and his internal medicine residency there. Cardiac, I'm sorry, in his internal medicine residency, cardiology fellowship and cardiac electrophysiology fellowship at Johns Hopkins Hospital in Baltimore. He was inducted into the prestigious Alpha Omega Alpha Medical Honor Society and Gold Humanism Honor Society. He is a Castle Conley top doctor and he practices at Carrient Health and Vascular, Inova Heart and Vascular Institute and University of Virginia Health Systems in Northern Virginia. Prior to Northern Virginia, he was at the Mid-America Heart Institute in Kansas City, Missouri. He is an assistant professor of medicine at University of Missouri, Kansas City, and he has previously spent time as a clinical research scholar at the National Institutes of Health and at the FDA. Dr. Youssef specializes in management of heart rhythm disorders and has experienced expertise in performing complex catheter ablation for atrial and ventricular arrhythmias. He is a nationally recognized leader in cardiac electrophysiology, serving on several national committees for American College of Cardiology and the Heart Rhythm Society. He's delivered many talks at both local and national meetings, authored numerous papers in leading cardiovascular journals, and actively participates in research studies and has been co-investigator in several leading clinical trials. Thank you, Dr. Youssef. Thank you, Patty. All right. It's the last session, so try to be succinct and we'll get through this. So my topic is pacing down Hollywood Boulevard. So we'll get to discuss some novel pacing techniques and see how the field of pacing therapy has evolved over the last several years. So the goals of the presentation are what is wrong with right ventricular pacing? What is the role and limitations of cardiac resynchronization therapy? Review the anatomy of the AV conduction system. How can conduction system pacing overcome under branch block? And is there evidence of benefit with conduction system pacing over RV pacing? And is there benefit of conduction system pacing versus biventricular pacing for cardiac resynchronization therapy? So RV pacing actually was identified as being deleterious in the early 1900s by Carl Wiggers. Shown on the right here is a simulator where he placed two hooks in the LV apex and LV base. And then shown on the left is a hand crank, which was used to actually pace the heart faster than, in this case, there were dogs. And what he looked at was what was the effect, hemodynamic effects of pacing therapy. And what we see is on the left is normal conduction. And on the top is the aortic pressures that's generated. And in figure B and D are pacing both from the base and apex. And we can see that the hemodynamic effects are suppressed with RV pacing, both basally and apically. So this was identified as something that was potentially an issue way back in the early 1900s. And there's been numerous studies that have looked at RV pacing and how it compares to normal conduction. One of the most prominent ones was the David study, which showed that there was over a 30% greater risk of death and heart failure when the RV pacing burden was over 40%. And there's been several other studies that have shown similar findings. And when we think of RV pacing-induced cardiomyopathy, there's no real definition, but it can include any of the following, which can be a drop in ejection fraction below 50% or in a drop in EF anywhere from 5 to 10%, but still having a relatively preserved EF of over 50% or developing symptoms, or it can be simply elevation of natriotic peptides. And the term is more correctly appreciated as dyssynchrony-associated cardiomyopathy, which can be a function of the burden of RV pacing, and it's directly proportional to that. So the higher the burden of RV pacing, the higher the dyssynchrony, and if there's sort of a dose-response relationship, the worse the outcomes are. And similarly, left bundle branch block can induce a similar type of dyssynchrony. And the way we treat these is currently with cardiac resynchronization therapy, and I want to discuss with you a little bit more about the different ways that we can achieve cardiac resynchronization. So this is the BLOCK-HF study. This was published now over a decade ago, and this looked at patients with systolic dysfunction who had AB block, and they compared outcomes with RV pacing and biventricular pacing. And you can see that the outcomes were worse with RV pacing, and this was largely driven by left ventricular and systolic volumes, which were worse in RV pacing versus biventricular pacing. And after this study, namely, as well as some of the other ones, we now routinely consider cardiac resynchronization therapy in patients who we anticipate higher burden of RV pacing. And so what's the limitation of cardiac resynchronization therapy? Well, we know that it works. It's a proven therapy. There's been 65% to 70% response rate, and people live longer. People have less heart failure hospitalization. And the way CRT works, just to kind of briefly highlight, is shown on the left here, is someone who has left bundle branch block or dyssynchrony. We can see the yellow is the interventricular septum. The blue is the area of the lateral free wall, and we can see that the lateral free wall is activated much later than the interventricular septum. And after CRT, we can see that the activation has changed significantly, and the activation is much earlier as shown with the red activation pattern with CS pacing. But the issue is that nearly 40% of patients still don't respond to CRT, and this can be measured through a variety of ways, including different echocardiographic parameters or functional parameters as well as symptoms. But this is a major issue. And the reason for non-response is quite variable. It can be due to patient selection factors such as scar or akinesis in the segment of the area where the coronary sinus or LV lead is implanted. If there are arrhythmias that are competing with biventricular pacing, as well as comorbidities and lead positions and programming factors can also play a role. And so, you know, can conduction system pacing be an alternative? And before we can really address that, it's important to know what the anatomy is and what the lay of the land is. And so this is what's shown over here is the interventricular septum and the outline of the conduction system. And what we can see here is that the penetrating his bundle, that's where conduction system initiates. And then it branches out into the right bundle branch block and left bundle branch block. And shown on the lower fluoroscopic slides is on the bottom right hand image is the top lead is placed in the area of the penetrating his bundle. And we can see the lower lead, which is placed a little bit more distally into the septum, into the left bundle branch conduction system. And you can see that the left bundle region is actually quite a large area. It's an arborization of Purkinje fibers. And there is a huge target that can be achieved with left bundle pacing. And it's actually become much more of interest than his bundle pacing. And so how can pacing the his bundle or the conduction system circumvent bundle branch block? And so shown here is a schematic of the conduction system. And there is a concept that's been described as called longitudinal disassociation. And essentially what it means is that the conduction system is encased in a membranous sheath. And the thought is that these fibers are predestined to either the left bundle or the right bundle. And the block is often in the proximal his bundle region. And so if you can pace just distally past the area of block, you can engage the conduction system and achieve resynchronization just as we would with native conduction. And so these are electrograms, intracardiac electrograms in someone with normal conduction. And you can see, let's see if I have a pointer. I don't have a pointer here. But the sharp electrograms show that the electrical activation extends in a normally conducted heart all the way. H is the his and then LB is the left bundle all the way down to the ventricle. The large electrograms are the ventricular activation. This is what normally occurs. This is someone with a left bundle branch block. But we can see that the conduction system is actually pretty intact here. There is no level of block. And so sometimes the levels of blocks are not in the conduction system. And that's not evident unless you put these catheters, which are not routinely done. But the block can be much more distally in the conduction system or in the intramicardial delay, which can result in what is perceived as a bundle branch block. And shown here on the right is someone, again, with a left bundle branch block. But here the block is much more proximally in the his bundle or just past the his bundle. And this study was out of UChicago where they looked at this. And what they noticed is that in all patients with left bundle branch block, nearly half of them had block in the proximal his bundle. And this could be overcome by pacing just distally in nearly 94% of people where we can narrow the QRS duration and engage the conduction system. And about 20% of patients had a block a little bit more distally but still relatively proximal in the conduction system, which also could be corrected with pacing. And a third of patients had block much more distally in the Purkinje system or intramicardial block, which could not be corrected with conduction system pacing. And you can see here, shown on the top is the his bundle. You can see that's a very narrow target. So it can be difficult to sometimes engage the his bundle area. This is generally about a 20 millimeter long area. It's four millimeters wide. It's like landing a plane in a very narrow zone. Whereas the left bundle region is a much larger area and there are larger areas to engage and you have a much larger target. And that's one of the fundamental principles behind why it has become a more favorable approach because the outcomes are more reproducible and the lead stability is much greater. This is a micro CT scan from piglets and you can see on the green is representative of the his bundle and the purple is the left bundle. You can see it's a much larger arborization of network that can be engaged. And so when we think about engaging the left bundle, certainly the goal ideally is to engage directly into the left bundle. But there's an area of tissue, myocardial tissue, just adjacent to that shown in that purple area represented by site three. And so that's if we engage that area, it's called left septal pacing as opposed to directly engaging the conduction system, which would be the left bundle branch pacing. And these nomenclatures do become important when we're trying to distinguish where we have achieved our final position for the lead. And a lot of the QRS morphologies can determine where the lead was placed. This is a schematic of such. Shown here is where the lead has been deployed into the interventricular septum, but it has not quite yet engaged the left bundle. And we know that because if we look at lead V6, there is a measurement from the stimulus to the peak of the R wave, which is considered the left ventricular activation time. And that's representative of bringing in that left ventricular activation early. And so if we're just in the myocardial tissue and have not engaged the conduction system, this time is generally longer, generally over 85 milliseconds. Shown in the next schematic here is screwing in the lead a little bit further and engaging the conduction system. And we can see that that V6 lead, the peak LV activation time has shortened generally below 70 milliseconds. And that is a suggestion that we are engaging the conduction system. This is an example of a patient I recently had, a 78-year-old man who had an aortic valve replacement about a week ago and presented with syncope as an ejection fraction of 45%. This is a baseline electrocardiogram, which shows a right bundle branch block. And while he was actually in the emergency department, he exhibited this, which is heart block, and was referred for pacemaker implant. And we attempted to implant a conduction system lead here. You can see here in lead V1, if you look at the morphology of that, and here we were pacing at 5 volts and the LV activation time was close to 100 milliseconds. As we paced at lower outputs, we actually engaged much more of the conduction system. And that's exhibited by a dominant R wave in the terminal part of that QRS in V1. And so the morphology changed because we're not capturing as much of the myocardial tissue when we lowered the output. But yet the LV activation time is still relatively long, suggesting that we're still capturing a significant amount of local myocardial tissue. However, as we deployed the lead further into the interventricular septum, getting a little bit deeper, we can see that the terminal R wave shown in the purple here, the big bunny ears, has quite much more positive. And this is very reflective of a very classic for a right bundle branch block morphology or conduction via the left bundle. And the peak LV activation time from the stimulus to the peak of the R wave in V5 or V6 is very short. It's 54 milliseconds, and the QRS duration was quite narrow at about 120 milliseconds. And this is what it looks like on imaging. And so you can see that the left bundle lead is placed directly into the interventricular septum, and shown there are the echocardiographic views of such. So is there evidence that conduction system pacing is beneficial beyond traditional RV pacing? And so I want to share some of this data over the last couple of years, and it's been quite profound. This is a study where they looked at death, heart failure, hospitalizations, and upgrade to by the pacing in patients with preserved ejection fraction largely who are undergoing RV pacing. And they were randomized to his bundle pacing or RV pacing. And we can see that there was a significant reduction in outcomes in those who underwent his bundle pacing over traditional RV pacing. And specifically, when they looked at patients who were pacing quite a bit, over 20%, the curves separate even further. In fact, there isn't much of a difference in the outcomes when there's minimal right ventricular pacing. And similarly, this was another study that's recently been published just this year looking at outcomes of left bundle branch pacing as compared to right ventricular pacing. So they included about 300 patients in each arm. And again, shown here is a pretty significant reduction in heart failure, hospitalizations, mortality, and upgrade to by ventricular pacing in those who achieved left bundle branch pacing as opposed to traditional RV pacing. And this was all driven by those who paced quite substantially. There was a relative reduction of 60% in outcomes in those that were pacing above 20%. So historically, we've thought of 40% as the cutoff where there may be an improvement in outcomes with resynchronization therapy, but this study actually showed that as little as 20% ventricular pacing can result in significantly worse outcomes with RV-only pacing. And so as such, the guidelines now actually have a recommendation for CRT or conduction system pacing for anyone who's going to pace a substantial amount of time. And so what about conduction system pacing in those with left bundle branch block and cardiomyopathy? This was one of the first randomized studies looking at that. And so they had a very small number of patients, about 40 patients that were randomized to receive either traditional CRT, Bi-V CRT, or His bundle CRT. And this study had significant crossover. So several patients from each arm crossed over to the other arm because they could not achieve adequate amount of QRS duration reduction. And they attributed largely that to having intramentricular conduction disease, and so distal Purkinje system disease or intramyocardial disease. And so the initial results, the intention to treat analysis actually showed that between Bi-V CRT shown in the blue and His CRT shown on the right, that there was a significant reduction in QRS duration narrowing in both arms, greater so with His CRT. However, the change in ejection fraction, although both groups achieved a reduction or improvement in LVEF, there wasn't any significant difference. And when they actually looked at on treatment analysis of the patients that actually received the therapy, the findings were similar that His CRT resulted in significant QRS duration reduction. It went from 170 milliseconds, as you see here, down to 125 milliseconds. Bi-V CRT did not achieve that level of electrical resynchronization. And the rate of response with respect to improvement in EF both achieved some improvement, but there wasn't any significant difference with respect to superiority for His CRT over traditional Bi-V CRT. This was another study, interesting study, where they took patients who were candidates for CRT, so patients who had a QRS duration of over 130 milliseconds and cardiomyopathy, and they put this Y adapter, and so they implanted both a traditional CS lead as well as a His lead, and it was a crossover study. So patients for six months, they were blinded to it. So for six months, they had one lead on, and then six months later, they crossed over to the other lead, and they looked at outcomes, and the findings were essentially similar in that His bundle pacing had equivalent CRT response as bi-ventricular pacing. It wasn't necessarily better. There was electrical resynchronization, but the outcomes were similar. A more recent study, which is called the His Alternative Study, again, tried to answer this question, took about 50 patients, low EF, left bundle branch block, and randomized them to, again, His CRT versus Bi-V CRT, and similar sort of findings, that there is electrical resynchronization, and there is improvement in EF in both arms, but His CRT may not be necessarily better than Bi-V CRT. And so all clinical parameters improved in both arms with no significant difference, but the electrical resynchronization is better. What's important to note is that the thresholds in the His bundle leads are generally higher, and that's one of the reasons why they've gone a little bit out of favor, and left bundle pacing has become more attractive. This is a study looking at left bundle pacing, so switching gears from His bundle pacing to left bundle pacing in non-ischemic cardiomyopathy, and patients who have a left bundle branch block, you can see that the intrinsic QRS duration was quite prolonged at 168 milliseconds, and most patients had an EF of 33%, and the paced QRS duration with left bundle pacing reduced very nicely to under 120 milliseconds, and the pacing thresholds over the course of six to 12 months was very stable, all under a bolt, and this is one of the biggest attractions for left bundle pacing, the lead stability is much better. And when we look at baseline to six-month and 12-month follow-up of ejection fraction, these patients who improved their EF from 32% to 52%, and in fact, the super responders, so people who achieved an EF of greater than 50%, there were nearly three-quarter of patients who achieved that with left bundle pacing, so these are candidates who have, patients who are class one and two way indications for CRT therapy, but achieved really robust responses to echocardiographic parameters with left bundle pacing. So the group out of Chicago and Geisinger have a collaborative registry, and they've looked at left bundle pacing specifically for CRT, in a total of 300 patients, in patients with left bundle branch block, they were able to successfully implant left bundle pacing leads in over 90% of patients, and when they looked at electrical resynchronization as measured by QRS duration, there was a significant reduction in QRS duration with left bundle pacing, not as low in those with non-left bundle branch block, given that some of them may have had IBCD or right bundle branch block, and similarly, there was improvement in EFs from the low 30% to the mid 40 percentile range. And so IBCD, as I noted earlier, is a different beast, the electrical delay is not necessarily in the proximal conduction system, it can be much more distally, although they can also have concomitant electrical delay in the conduction system, and it's not quite apparent on the electrocardiogram, and so it's difficult to know how best to treat this, and so there's been some recent interest in not only implanting a traditional CS lead, because if there is intramyocardial delay, that CS lead would potentially be helpful to bring in the lateral wall, but also if there's concomitant conduction system disease, perhaps conduction system pacing can also help with that. And so in this study, they took a small number of patients where they implanted a conduction system lead, a left bundle lead, as well as a traditional CS lead. And it's quite interesting. So if we look at the QRS duration with IBCRT, it's shown over here in slide B, and it's reflected in the blue column on the left, which has a QRS duration, median QRS of about 170 milliseconds. If we combine that with left bundle pacing, we can see that the QRS duration is markedly narrower at 140 milliseconds, even narrower than just left bundle pacing alone as shown in the third graph there. And so perhaps this is one potential solution for those with IBCDs. It's another recent patient I had who's a 74-year-old woman who has a non-ischemic cardiomyopathy with an EF of 25% who presented with significant fatigue and class III heart failure in two to one heart block here with a left bundle branch block with a low EF. And shown here on the left is pacing at 5 volts. And you can see the output-dependent changes that can happen with left bundle lead. So the peak LV activation time there was 65 milliseconds. But as we lowered the output, the activation time actually increased, suggesting that we're actually not capturing much of the conduction system, but capturing more of the local ventricular myocardium, and we lose engagement in the conduction system. So we engaged the lead with a few more turns, and we can see that the QRS duration actually narrowed to 97 milliseconds. So again, suggesting in this case that the level of block was much more proximally, and we can overcome the left bundle branch block with a left bundle lead. And this is the paced morphology, which looks like a very nice, narrow QRS duration. And so when we think about alternative strategies in those who are considered potentially non-responders, nearly 35 to 40% of patients with CRT won't respond, certainly conduction system pacing is a no-brainer in those patients. And if they have a left bundle branch block, we can think about either doing a HISS bundle lead or a left bundle lead, or consideration for both CS lead as well as a conduction system lead, depending on what the outcomes are. And so I think the take-home points are, we want to avoid dyssynchrony. We've sort of underappreciated, you know, a lot of these patients are older, and they come in with heart block, they have preserved EFs, they get an RV apical lead, and their EFs may not reduce, but they develop subtle signs of heart failure, and we, you know, underappreciate what dyssynchrony does, as shown by some of the data that I showed you. And so it's important to avoid RV pre-excitation. And the preference is to have endocardial to epicardial activation. When we place a coronary sinus lead, that's placed in the venous branch, and so the activation is not physiologic, the myocardial is being activated from the epicardium to the endocardial. For CRT, narrower is likely better. Conduction system pacing is preferred over RV pacing, and conduction system pacing may be a good alternative to CRT if QRS duration narrowing can occur. The recent trend has been more towards left bundle pacing over HISS bundle pacing due to more lead stability and performance over time, and in some cases where we can't achieve electrical resynchronization by narrowing of the QRS duration, there may be benefit to implanting both the conduction system lead and a coronary sinus pacing lead to achieve adequate CRT. There's a lot of future clinical trials that are upcoming where we hope to learn a lot more about this. Most importantly, I think, is understanding that there's great biological variability and we have to be humble as we go through this. Thanks for your attention. I'm happy to take any questions. Thank you very much, Dr. Youssef, for taking us on that pacing journey. That was fabulous. We do have a few questions. The first question says that you mentioned the difference between septal and left bundle branch pacing. Is a permanent pacemaker with deep septal pacing lead captured as a HISS conduction system pacemaker, like a HISS or left bundle branch? It depends. It depends on where the lead is implanted. I don't know if you're getting at this in terms of coding, like from an NCDR standpoint, but the lead can be placed in the interventricular septum to pace the HISS bundle region, or it can be placed more distally to pace the left bundle region. When we allude to left bundle area pacing, that's a terminology that includes both left ventricular septal pacing and also left bundle branch pacing. To distinguish these are largely, you have to use QRS morphology and some of the characteristics I shared. The terminology is still a little bit confusing, but I think at least from the standpoint of coding, you have to really look at the operative report and see where the lead was exactly placed. Thank you. You also talked about in your presentation that sometimes you might anticipate increased RV pacing and then consider CRT. Can you describe a little bit what those patient indicators might be that would lead you to anticipate increased RV pacing? Yeah. Certainly anyone who has heart block, so if they come in with two to one block or complete heart block, those patients are likely to pace almost all the time unless their conduction system improves. In those patients, we strongly suggest conduction system pacing. Even beyond that, some patients just have winky back and bradycardia, or those patients may benefit as well. Certainly I think if you have a patient who already has a pacemaker, these are patients who are often missed and underappreciated and they're constantly just getting admitted for heart failure and their EF may still be preserved. Most people don't think about these patients, but it very well could be that it is related to RV dyssynchrony and we should consider either upgrading them or consider changing them to a conduction system lead. Thank you. And then we do have one more question. Do you feel perhaps in your facility what you see or do you think there is a trend towards left bundle branch pacing instead of pacing via the CSLV when you're implanting CRT? Yeah. So I think that's the ultimate question. And a lot of the studies I've shown you, they're smaller studies, but it's promising. In my own practice, I have evolved a bit in that I will try to, in someone who has a very typical appearing left bundle branch block, I will first just try to place a left bundle pacing lead to see if I can electrically resynchronize them by narrowing their QRS duration. And if that can be achieved, then I'm done and we actually don't implant CRT in those patients. But if I'm not getting adequate electrical resynchronization, then we implant a coronary sinus lead. This is a ripe area for investigation. There's several randomized studies, larger trials that are being conducted that will hopefully answer this question a little bit better. The other piece of this is where it can be tricky is someone who needs a defibrillator, for instance. So they have a low EF, they have a left bundle branch block, and they're referred for a CRTD. The ICD lead cannot be placed in the conduction system, ideally, because the defibrillation vector of the way the lead is would not be optimal, because part of the coil, the defibrillation coil may extend into the atrium. And so in those cases, we often place an RV lead in the traditional sort of distal septum or apical location and then implant a conduction system lead for LV pacing or cardiac resynchronization therapy. But this is where the device manufacturers haven't caught up with all of this and how do we do all this. But it is also an area of investigation and they are working on a defibrillator lead that can also be placed in the conduction system. Very interesting. Well, those are all the questions we have. So thank you again very much, Dr. Youssef, for being here with us. Right. And there's one more thing I forgot to mention, but the updated EP device registry for NCDR now actually includes some of these pacing strategies that traditionally used to be just for ICDs, but now actually includes CRT pacemakers, leadless pacemakers, as well as conduction system pacemakers. So I encourage all of you guys who participate in the EP device registry to think about those patients and try to develop a protocol whereby you're capturing those patients as well for the registry because traditionally it's been an ICD registry and so it's a very different way of thinking and we have traditionally not reported those patients in the NCDR registry. But this will really allow us to get a better understanding from a real world experience and outcomes related to these novel pacing therapies. Yes. Thank you very much. Thank you. Thank you. And I'll just say a quick thank you to all the attendees who are still left and stuck it out for the final session. It was wonderful to be in person and just I wish you all safe travels home and we look forward to seeing you in 2023 in Orlando, Florida, October 11th through 13th. Yay! Thank you. It was wonderful to see everyone in person.

pacing techniques

cardiac resynchronization therapy

conduction system pacing

bundle branch block

biventricular pacing

electrical resynchronization

heart failure hospitalizations