Now, this is a really amazing and exciting topic today. I have the pleasure now of introducing Dr. Maggie Infeld, who is really an expert in this field in talking about the future of conduction system pacing and pacing in general for the heart failure population. Maggie? Thank you so much. It's my pleasure to introduce Dr. Marcus Meyer, who is from the University of Minnesota and is truly one of the pioneers in using cardiac physiologic pacing as a therapeutic target in patients with heart failure with preserved ejection fraction. Thank you, Maggie, for this nice introduction. Thanks for sticking around. It's already later in the afternoon. Time is out, so there are other places where it would be nice to be. I was tasked to talk about HFPAF, the pathology, and why pacing could be an approach towards treatment of heart failure with preserved ejection fraction. These are my disclosures. Most importantly, I have IP in this space. So by background, I'm a HFPAF guy, but what really drives HFPAF and also atrial fibrillation is actually the rise in filling pressures that occurs actually in all of us as we age. At about mid-age, our LVEs, on average, decrease by about 1% volume per year. In essence, this goes along with a rise in filling pressures. Obviously, the left atrium sees these pressures and, as a result, gets larger as we age, also at about a rate of 1% per year. This is a major driver of the age-related association between AF and HFPAF. This, however, is largely accelerated by the presence of hypertension. These days, hypertension is driven mostly by obesity. Obviously, renal disease is another factor. Increasing atrial stiffness will also accelerate this process and is basically the main reason why we see so much atrial fibrillation in HFPAF these days. Besides the regressive remodeling that I just talked about, there are other factors. We had, about 10 years ago, we collected LV biopsies from patients undergoing open-heart surgery and had an opportunity to look at the myocardial changes. What is really striking is an increase in fibrosis driven by accumulation of collagen. Another factor at the myocardial level is titin. Titin is a sarcomeric protein which tends to be hypo-phosphorylated in HFPAF. When it's not phosphorylated, it gets basically stiffer. The major factor besides the remodeling is basically the increase in fibrosis. This by itself does not explain why relaxation slows in HFPAF. This is really driven by calcium. First, in 2011, using the same biopsies that we had from patients, we saw that there is an augmentation of intracellular calcium in HFPAF. The augmentation is at the level of the sarcoplasmic reticulum, which is this organelle that handles about 50% of the calcium that is taking part in contraction and relaxation. What we found is that when we challenged these, these are strip preparations which are isometrically contracting, again from patients. When we challenged them with increasing rates, there was a buildup of cellular calcium levels with a rise in diastolic calcium that you can see here. This was accompanied by a rising force. However, when you look at patients, there's no isometric contraction, obviously. Isometric would be when you clamp the order, which never happens. It took me a couple of years to understand how this would translate into patients. When you look at pressure-volume loops and you compare resting heart rates versus accelerated pacing loops, you will see that in patients with HFPAF, there is an increased left and downward move of the pressure-volume loop, mostly affecting the anti-diastolic pressure-volume relationship. If you focus on the right-hand side, you will see that, and you all have seen this in training, that the pressure-volume relationship in HFPAF is disproportionately steep. When you expose these hearts to increased heart rates, you will augment the calcium and make, basically, the diastolic pressure slide down that really steep relationship. In normal patients, this would be only a very small shift in the pressure-volume loop with really minor changes in left ventricular and diastolic pressure. When we developed this idea, I had my colleague at the time, Dan Luskarton, who we'll talk shortly, who said, well, if you want to do this, you better do it safe. He already, 10 years ago, told me, to do this really safe, you have to combine his bundle pacing with Bachmann's bundle pacing, because they are the most physiological ways to excite the chambers. In an intermediate study that we did in the EP lab, we did pressure recordings in the left atrium. And lo and behold, we saw that with accelerated rates, that there was a reduction in filling pressures. This was more pronounced in patients with HFPAF, as expected. And so it provided us with a means to, basically, lower filling pressures, which, again, is the driver of both AFIP and HFPAF. In other case series, up to 60 patients, they basically saw the same thing on the left ventricular and diastolic pressure. And in fact, you could normalize left ventricular and diastolic pressure in the majority of patients with accelerated pacing. And of course, as shown here, with the reduction in left ventricular and diastolic pressure, you will effectively decongest the left atrium. However, if you expose mammalian hearts to above normal heart rates, you will induce some degree of eccentric remodeling. And so we had a micro-pig model of hypertension, which is basically HFPAF stage B with a pacemaker, and with a baseline resting heart rate of 90 beats per minute. If you about double the heart rate within a few weeks, you will be able to more than double the left ventricular and diastolic volume while the wall thickness actually decreases. So this remodeling process is mass neutral. It's physiologic. It happens to all of us throughout life. When we exercise more, there will be some of this remodeling play a role. It's not really well understood why this happens. So it's an innate plasticity mechanism that has certain features of athletic remodeling where accelerated pacing can be used to increase the LV volume, reduce LV thickness. This, however, will go along with a small reduction in ejection fraction, as you would see in endurance athletes. And heart rate itself becomes the dose. So if you feel that you overdid it, the only thing you have to do is just go a little bit lower on the rate, and there will be regression of the changes in geometry. So what heart rate would you pick? And so it's worth to discuss the association between body size and heart rate, also called allometric scaling, that's well-preserved in mammals. You know, mice, they go at rates of 600 beats per minute, blue whales at 10, and we're living somewhere in between. In fact, as we are born and grow up, our heart rates drop. And the relationship is really well-preserved to about midlife. And after midlife, we're obviously not growing much anymore, at least in height. But our heart rates continue to drop, so there isn't a dissociation of this relationship. And this is another way to plot this, and it just shows you how well-preserved the ratio is, so between ages 5, 10, and adulthood, this is basically the ratio is preserved. If you happen to end up to be a Witherspoon, your heart rate would be expected in the range of 80 beats per minute, whereas if you end up to be a Jordan, your heart rate would be expected to be 60 beats per minute. And it's really important to understand that these populations live about 20 beats per minute apart. So we really have to move away of using population data to say any heart rate between 60 and 100 is normal. That is really not true, especially when you go on the low side to an elderly female, small frame, and you basically have their pacemaker set at 60 beats per minute. That's far away from a normal heart rate. What the population data basically means is that only 2.5% of the adult population have a natural heart rate, resting heart rate of 60 or less. We try to combine all the knowledge we had about heart rate on the HFREF side from obviously beta block outcomes trials into a formula that would give a patient something better than the population data heart rates or the 60 beats per minute that we previously used. And this became the MyPace algorithm, which is a height-based EF modified personalized heart rate. So a patient with an EF of 50 would be expected to be a normal heart rate for their height. Anybody with ejection infection above 50 would get an incremental increase in heart rate in a range where the feeling was that this could be a safe heart rate, that we would not do harm to patients. So what are heart rates in HFREF outcomes trials? They are in fact not normal heart rates. So the medium heart rate in the adult population is 80 beats per minute. In the healthy adult population, it's 72 beats per minute. In the HFREF outcomes trials, it's actually below the 72 beats per minute. And that's not a benefit to these patients because that will lead to effectively a rise in feeling pressures. So in other words, most HFREF patients have below normal heart rates. Taking away the beta blocker or reducing beta blockers is the right step in the direction of helping patients to breathe a little bit better and maybe improve outcomes. We don't know that because that has never been really tested in randomized control trials. So as a next step, we engaged in a randomized controlled trial and both Maggie and Dan were very involved in this too. This was at the University of Vermont where Dan had convinced everybody to put in physiological pacemaker systems so we could do this safely. And we had about 100 patients with pre-existing pacemakers who had mild to moderate HFREF. And we compared the usual care rate of 60 beats per minute versus the MyPace heart rate, which was on average between 70 to 80 beats per minute. And lo and behold, we found marked improvements in the health status scores. They are like certain risk scores out there. We used the Minnesota score and quality of life that continued to improve over the course of the study, which was one year, whereas patients left at 60 beats per minute had a deterioration in how they felt. This was accompanied by corresponding changes in antipopein P levels. To my surprise, at least, we found marked improvement in physically activity hours as recorded by the pacemaker with an increase of daily activity levels of above 30%. There was a 28% reduction in the burden of atrial fibrillation also detected by the pacemaker. On the patients who continued on their treatment arm, we now have four years' data. This is obviously observational, where indeed we see a small reduction in LV septal thickness, where we see the expected small reduction in ejection fraction of 3% and trends towards a slightly larger LV. We also, when we look at clinical outcomes, there's a marked reduction in cardiovascular outcomes, most importantly heart failure, but trending behind that atrial fibrillation events too, with about a 50% reduction in clinical events. A paper is submitted and hopefully should come out over the next couple of months. What are other populations that may benefit from this? An important population is the hypertrophs, because most of their mutations have actually calcium sensitizing effects. You could, by increasing using the same protocols, you could actually lower the filling pressures probably the most in these patients. Another group is patients with cardiac amyloidosis. We just had our first implant at the University of Minnesota, where we basically used a dual regimen where we toggled the heart rates during the day to induce a little remodeling stimulus that may help us to unload the amyloid burden over time. So far, the patient is like one year out and he's doing very well. The biggest group, however, will be patients with atrial fibrillation, because remember, there will be atrial decongestion. You will induce an elevated rate floor, which helps you to treat the irregulopathy. The irregulopathy is basically based in the sarcoplasmic reticulum, which as an intracellular organelle can never adjust to these varying cycle lengths all the time. So by giving the patients a rate floor, you will induce or at least alleviate the irregulopathy. So this will, in all likelihood, will find some use in the primary and secondary prevention of atrial fibrillation as well. So in conclusion, it's important to not forget that AFib and FFib have a shared myocardial substrate. If you see a patient with AF, you can basically say there's also some HF-PF in play, even if they don't carry a diagnosis. Personalized accelerated physiologic pacing is a way to decongest the hearts and induce some beneficial remodeling, and this may play a role in HF-PF and atrial fibrillation prevention and treatment. We are proud to announce that we will start enrolling into a large global randomized controlled trial that is sponsored by Medtronic by the end of the year with about 500 patients. Thank you very much for your attention. Thank you so much, Markus. We will actually have time for questions once all of the three speakers have finished. So please keep those questions, put them into the Q&A. Now it's my pleasure to introduce Dr. Randy Nagarkanti. He's joining us from Northern Arizona Health, and his talk will really nicely expand upon some of the ideas that were just brought up by Dr. Meyer. He'll be talking to us about prolonged PR, diastology, or RV dysfunction, which patients are most likely to benefit from pacing for HF-PF. Dr. Nagarkanti. Thank you, chairs, for the kind introduction. I would like to thank the organizers and the HRS for this invitation. I am Randy Nagarkanti from Northern Arizona Health Care, and I'm going to discuss which patients are most likely to benefit from pacing for heart failure with preserved EF or HF-PF. Is it prolonged PR, diastolic dysfunction, or RV dysfunction? So there will be some duplication of data that Dr. Markus presented, so bear with me. I have nothing to disclose. As you all know, HF-PF and heart failure, as well as atrial fibrillation, are very prevalent cardiac condition, and HF-PF accounts for more than 50% of the heart failure patients. And as Dr. Markus already mentioned, EF and HF-PF are deeply intertwined, and it is estimated that 6 million of the U.S. population will experience a combination syndrome of EF-HF-PF by 2030, so it's a true epidemic. HF-PF is defined as a clinical syndrome of heart failure with the left ventricular ejection fraction greater than 45%. Generally, these patients are older, with a greater proportion being female. There is high prevalence of comorbidities such as diabetes, obesity, hypertension, chronic kidney disease, and atrial fibrillation. Prolonged PR interval is commonly due to inter- and intra-atrial conduction delay, which increases the P wave duration. It is also caused by conduction delays in the AV node, as well as the His-Purkinje system when we will see a widened QRS. And epidemiologic studies have told us that prolonged PR interval is associated with adverse outcomes, with two times the risk of developing AFib, three times the risk of needing a pacemaker, and one and a half times of early mortality. And in patients with heart failure who have prolonged PR interval, there is a greater risk of adverse clinical outcomes. Prolonged PR is associated with impairment of ventricular filling. And we also see diastolic mitral valve regurgitation due to incomplete or ineffective closure of the mitral valve. And these symptoms could be similar to pacemaker syndrome. So we call it pseudopacemaker syndrome due to alteration in the AV synchrony. Patients experience fatigue, shortness of breath, and dizziness. Pacing is currently indicated in prolonged PR only in patients who have significant symptoms or risk of high-grade AV block. And as Dr. Marcus discussed, accelerated atrial pacing has been evaluated in patients with HF-PEF and AFib and prolonged PR. A moderate increase in resting heart rate to 100 beats per minute has shown improvement in left atrial pressure, going down from 12.8 to 10.4. However, even further increase in heart rate, about 130 beats per minute, that actually worsened the left atrial pressure, where the left atrial pressure increased to 14.7 millimeters of mercury. I don't want to bore you with this. Dr. Marcus already discussed the mechanisms of diastolic dysfunction. However, it results in impaired relaxation and decreased compliance of the left ventricle due to systemic inflammation from the comorbidities such as aging, obesity, hypertension, diabetes, and renal dysfunction, eventually resulting in mechanical, it will result in the microvascular dysfunction, hypertrophy, fibrosis, which are also seen in atrial fibrillation patients. With diastolic dysfunction, there is increase in left atrial pressure. There is also structural remodeling that is assessed by left atrial volume index as well as increased LV mass. It also causes myocardial wall stress, which causes increase in natriuretic peptide levels. There are other, there are many markers of, echo markers that can be used to diagnose diastolic dysfunction as described here. However, in atrial fibrillation, there is loss of atrial contraction, hence we won't see any A-wave on the transmitral flow on the echocardiogram. So we use other parameters, such as mitral E-wave, mitral filling E-wave, which will be increased. The tissue annular mitral valve, E-prime, will be decreased. So there is an increased ratio of E to E-prime. And studies have shown that E to E-prime ratio greater than 15 correlates very well with increased filling pressure and the pulmonary capillary wedge pressure. With diastolic dysfunction, there is an increase in left atrial size, which will result in intra-atrial as well as inter-atrial conduction delay, increases the P-wave duration as well as atrial dyssynchrony. Currently, there is no pacing guideline recommendations for inter-atrial conduction defect with diastolic dysfunction or HEF-PEF. However, with the emergence of dual-chamber pacemaker, biatrial pacing was shown to improve the hemodynamics with the increase in atrial wave amplitude as well as the atrial synchrony on the tissue Doppler image that's shown here. Dr. Lemery et al., they have evaluated the activation of biatrial activation in sinus rhythm and atrial pacing. They noted the electrical coupling of the right atrium and left atrium happens predominantly at the level of the Bachman's bundle as well as the coronary sinus ostium. The low lateral right atrial and distal CS pacing greatly delayed the septal activation. However, the CS, proximal CS pacing has resulted in a shortening of the left atrial septal activation. Doe et al. evaluated different pacing sites in the atrium, HRA, distal CS, and biatrial pacing. With biatrial pacing, they've shown a significant reduction in the P wave duration with the most improvement in cardiac output and pulmonary capillary wedge pressure. And these benefits are predominantly seen in patients with a delayed intraatrial conduction delay greater than 33 milliseconds. Our group has reported, Dr. Saxena is sitting here, the dual-site right atrial pacing, where the first electrode is placed at the posterior rim of the coronary sinus. The second electrode is placed at the usual place of the right atrial appendage. With dual-site atrial pacing, there is inverted P waves in the inferior leads, and there is a shortening of the PR interval, mostly due to the reduction in the interatrial conduction delay. This is the biatrial, this is the 3D mapping of the dual-site atrial pacing. You have two waveforms in the right atrial appendage area and the CS os, there is high to low septal activation, and the CS wave propagates the left atrium preferentially along the CS, and there is collision at the left atrial septum. Biatrial pacing and dual-site atrial pacing resulted in the most reduction in the P wave duration. This slide shows the hemodynamic effects of the atrial synchronization using dual-site atrial pacing. As you can see here, there is an increase in the left atrial A wave amplitude without affecting the left ventricular structure or the left ventricular systolic function, where the LVEF is preserved. We also performed a subgroup analysis of patients who underwent the atrial re-synchronization with dual-site atrial pacing for a longer-term follow-up. All these patients had a baseline echo as well as a follow-up echo performed. Here is an example of a patient with a baseline left atrial diameter of 5.2 centimeters, and it has improved to 4.1 centimeters after 12 years. This slide shows the long-term follow-up data, echo data, and as you can see here, there is a left atrial diameter that has declined from 4.45 at baseline to 4.2 centimeters. And again, there is a preservation of the LV systolic function with no significant drop in LVEF. And usually in the dual-site, dual DDD pacemakers with predominantly RV pacing, we do see a drop in the LVEF, whereas here it is preserved. We also compared the HEF-PEF versus HEF-REF in patients with AFib-4 refractory antiarrhythmic drugs that are implanted with the atrial re-synchronization with dual-site atrial pacing. And there is improved survival. The survival is better in HEF-PEF group compared to HEF-REF, both at five years as well as 10-year follow-up. And with the added dual-site atrial pacing, the AF rhythm control was similar in both HEF-PEF and HEF-REF patients. Here is a paper that was done by Dr. Madan. She's also here today. And there is a significant preservation of sinus rhythm or rhythm control in AF patient involved varieties of atrial fibrillation. Again, as Dr. Marcus discussed, a variety of atrial pacing programming have been studied in diastolic dysfunction. In the rapid AF study, in patients with chronotropic incompetence, they compared rate-responsive pacing versus no pacing. With rate-responsive pacing, where there is a significant increase in heart rate, there is no improvement in exercise capacity or peak oxygen consumption or patient-reported health status or BNP levels. And there is increased adverse events. However, with moderate accelerated pacing, like he showed in the MyPace study at 75 beats per minute compared to 60 beats per minute, there's improvement in quality of life, physical activity, and reduced AF burden. Accelerated atrial pacing reduced even the septal LV, septal wall thickness, and the lower LV mass to systolic volume ratio. The Backman bundle area pacing was evaluated in a small niche group of non-obstructive hypertrophic cardiomyopathy patient with heart failure-preserved EF, but not in the majority of HF-PF patient who usually do not have structural heart disease or vascular or valvular heart disease. And Dr. Narasimhan is here, I think. They submitted this abstract. So they showed a reduction in P wave duration. They have shown a significant improvement in diastolic function, functional capacity, as well as a reduction in the natriuretic peptide levels. Diastolic dysfunction alters the pulmonary vasculature first with a decreased pulmonary vascular reserve and increased pulmonary vascular hypertension, and eventually results in right ventricular hemodynamic changes with right ventricular right heart congestion, decreased RV systolic reserve, and causes RV systolic volume reduction, RV stroke volume, or RV dysfunction. Currently, there is no evidence for pacing therapies in RV dysfunction and HF-PF. However, we do think avoidance of right ventricular apical pacing can be beneficial from the HF-REF data. And as you have seen previously, the RV dysfunction is usually associated with HF-PF. So the pacing therapies that may be beneficial in HF-PF could also be beneficial in RV dysfunction. There's a recent AHRQ AF study that was published that showed that AF recurrences were prevalent after index ablation, and additional rhythm control strategies were frequently used. One in six patients who underwent ablation also needed a repeat AF ablation, with the majority being on concomitant antiarrhythmic drug therapy. Long-standing persistent AFA, prior ablation, post-index ablation, antiarrhythmic drug use were strongly associated with increased risk of repeat ablation. However, this data is with prior ablation technologies. This data suggests that a combined strategy using catheter ablation and antiarrhythmic drug therapies is being currently used for rhythm control in clinical practice. We do propose that there is a role for atrial pacing with novel pacing therapies in AF today, as an adjunctive therapy for drug-refractory AFib, sick sinus syndrome, documented interatrial conduction delay, drug-induced pedicardia, failed ablation therapy, as hybrid therapy and for prevention of heart failure. So I would like to conclude that HF-PF is a growing epidemic in cardiology with associated electrophysiologic, hemodynamic, and clinical consequences. The evolving pacing therapies and pacemaker programming options may have a role. Dual-site right atrial pacing has a potential for benefits in patients with HF-PF and interatrial conduction delay. Larger clinical trials are warranted to evaluate this therapeutic option and other evolving pacing therapies. Thank you for your attention. It's a privilege for me to introduce our next speaker, Dr. Daniel S. Garten, who's a professor of medicine at the University of Vermont and has been a world leader and pioneer in ventricular conduction system pacing as well as atrial physiologic pacing. And I've had the honor of working closely with Dan and Marcus on a number of studies. Thank you, Maggie. And thank you, Gaurav, for putting together this awesome session. So I'm delighted to have been invited. And full disclosure, much of what I'm about to talk about is not going to be found in any pacing guidelines and is largely predicated on a lot of the work that you just heard beautifully presented both by Marcus and Randy. And they spoke largely on why you want to pace these patients, and I'm going to be focusing a little bit more on how we should be pacing in the setting of HF-PF. The key objective in these patients, as you're already picking up on, is that for, but for decompensated HF-PF patients who are going to be tachycardic, in the setting of symptomatic compensated heart failure HF-PF patients, you want the pacing to be every beat and accelerated. And you want to be able to provide dynamic pacemaker responses without creating dyssynchrony. And of course, when we talk about dyssynchrony in EP these days, everybody thinks about the equally important in this context is going to be atrial synchronization as well as AV synchronization, as Randy was just focusing on a bit. So the ideal setup in this patient population, I would argue for every single patient you put a pacemaker in, is what I refer to as comprehensive conduction system pacing, referring to active fixation of the atrial lead in the Bachman bundle, which is the critical or acritical part of the atrial conduction system. And the V-lead should be as proximal in the hysperkinesis system as you can possibly manage to get it, particularly in this patient population who have small, stiff hearts and will tolerate ventricular dyssynchrony poorly. I'm going to focus mostly on atrial pacing, as this audience is likely to be very aware of the importance of ventricular conduction system pacing from the perspective of avoiding iatrogenic ventricular dyssynchrony as well as allowing the possibility of treating underlying ventricular conducting disease, but perhaps not as well acquainted with Bachman bundle pacing. So as Mark has mentioned, accelerated rate pacing has been found in a MyPace study to benefit patients with HFPEP. This group of biomedical engineers in Maastricht developed a computer simulation model called CircAdapt, which is actually available. You can play with it for free at circadapt.org. Tim Van Loon and colleagues in Maastricht recently demonstrated that where you pace the atrium matters, at least in the computer model, specifically that Bachman bundle pacing was predicted to dramatically lower left atrial pressures and strain relative to either right atrial appendage or lower right atrial septal pacing and over a wider range of heart rates. The computer simulation results may explain one of our chair's, Dr. Infeld's findings, that Bachman bundle pacing is associated with a lower incidence of AF compared to either right atrial appendage or right atrial septal pacing, comparing patients with standard pacing indications who had a minimum of 20% atrial pacing as well as stored electrogram data that allowed us to be able to accurately diagnose AF episodes. And what you can see is that there's a real separation here over time. This is a retrospective analysis, of course, given all its limitations, but critically, if you look at the P wave duration in each of the three groups, the three cohorts, they were essentially identical. In fact, the right atrial appendage cohort had a slightly shorter P wave, which should favor less AFib, but in fact they had the most AFib. So why would Bachman bundle pacing potentially be so important? The majority of HFPF patients being older, hypertensive, demonstrate evidence of interatrial conduction abnormalities apparent in these four examples of patients with HFPF and varying degrees of P wave duration increase or P wave morphology abnormalities. Focus, for example, on this patient who has this bimodal peak P wave in the inferior leads, which is what we define as interatrial conduction delay. This is Bachman bundle pacing in that patient. Note the inferior P wave now looks completely normalized and it's narrower and it's taller. So because you're correcting abnormalities of native sinus propagation, you want to be able to program these patients to pace. So you're actually wanting to pace every atrial beat with this kind of form of correction. In other words, think about the way the sinus node gets to the Bachman bundle. It's going to be either an anterior crista pathway or a posterior. So there's two routes potentially around the SVC. The histology of the SVC junction shown here in this beautiful slide provided by Damien Sanchez-Quintana demonstrates that the Bachman bundle inserts into the infrared septal aspect of the SVC. And it's activated serially either by one or both of these pathways from the sinus node. The RA inputs to the Bachman bundle approach the Bachman bundle obliquely. And this tissue, if you look at the histology carefully, has a relative paucity of sarcomeric tissue. The safety factor of activation here is probably quite low. So very small changes in tissue behavior start to uncouple the crista and Bachman, which is probably why, as all of us age, our P wave duration increases. This is showing that patient with the bimodal peak P wave. So what happens when you pace Bachman bundle? You're simultaneously now activating Bachman bundle. So you're pre-exciting the Bachman bundle. And for the initial portion of what would normally be activated antigrade, you go retrograde to where the sinus node activates the RA. Then the remainder of the RA is going to be activated normally. The consequence of pacing a site like this in a patient like that is normalization like that. So there have been numerous previous studies demonstrating that interatrial conduction delay and block associate proportionally with AF. Keeping things au courant, this paper just published online last week in Heart Rhythm shows that abnormalities in P wave duration and morphology predict the subsequent development of AFib. Again, Bachman bundle pacing normalizes often to dramatic degrees both the duration and P wave morphology by re-synchronization atrial activation over the normal conducting pathways of the atrial chambers. So how is it defined? Well, it's defined ultimately by the paced P wave morphology, the final arbiter of successful Bachman bundle pacing. And what you should see is normalization essentially in all 12 leads of the P wave axes and critically importantly shortening of the P wave relative to the sinus P wave. It's important to keep in mind, we just demonstrated in a paper that should be coming out any day in Heart Rhythm, that there are atrial myocardial extensions that go up into the SVC that connect directly to Bachman bundle. So if you map high in the SVC and pace there, what you can wind up with is a beautiful looking P wave, but a really dramatic isoelectric time between the stimulus and the onset of the P wave. That's the time it takes to get through the tissue to Bachman and to the crista. This would be undesirable because you're adding unnecessary time to the PR interval. Bad. There can be enough disease locally where you want the lead to be sitting, which is right at the SVC RA junction. And you'll note the electrograms when there's a lot of disease present in this area will be very split. They start after the P wave, they're high frequency and multi-component and they can be separated in time. And what can happen is at a given output, the P wave looks great. As you start to decrement the output, you can actually elicit this appearance of an isoelectric segment from stimulus to P wave. Again, undesirable. And you need to be aware of where in your threshold testing this is occurring. It should make you think twice about using auto capture management algorithms in this setting. So I'm going to take this moment to plug the paper I just mentioned a little bit more. That should be out in HeartRhythm maybe tomorrow. We visualized the right atrial Bachman bundle pacing target by electro-anatomically mapping the right atrium while pacing the left atrial Bachman bundle. When you do that, well now you can see exactly where Bachman bundle is in the RA endocardium. All of this red is the Bachman bundle. And we did this in a series of patients and what we demonstrated is that very consistently in terms of the vertical superior-inferior relationship, every patient has Bachman bundle, at least the superior portion of it, plugging into the SVC at the root. Where there's variation is in the anteroposterior plane. So in the setting of implanting a device, you're limited to fluoroscopy and electrograms that you see on your lead. And that's plenty of information to get at what you want to get at. So what I'm showing here is an RAO view of a lead delivery, a sheath delivering a lead that's high up in the SVC, injecting a tiny bit of contrast so you see the SVC length here and then the RA starting to fan away over there. The Bachman bundle target is going to be in your mind's eye right around there. So that's where you're going to be wanting to direct your sheath. In the LAO view, you can confirm septal placement of the sheath and lead. Now foreshortened, Bachman bundle on its length going from the RA to the LA. And then if you tip the camera, the intensifier so that it's now caudal, you're looking straight up at the SVC like a clock face and where you're going to want to be mapping is in the anterior-posterior direction, which you achieve simply by slight, very slight clockwise or counterclockwise torque of the sheath delivery system. The electrograms we seek in the setting are typically preceded by a low amplitude farfield signal coincident with the onset of the P-wave, this tiny little thing here, which probably is crista activation, followed typically by a multi-component fractionated electrogram signal that usually the duration of which will fit within usually the first two-thirds of the P-wave. The filtered unipolar electrogram in the exploded view shows all that. Just by pushing the sheath delivery system up against that tissue using an unfiltered signal, you can start to see injury current in the latter portion of that fractionated signal. And screwing into that tissue, you see this really marked impressive injury current. This first of all shows you that you're in the latter component of those electrograms, which is where you'd expect the Bachmann bundle to be timing. And when you see this degree of injury current, you're going to see a very rapid decrease in voltage and capture threshold. And again, finally, you want to prove that the proof of the pudding is the P-wave morphology, which in this case is normalized in all the 12 lead axes and narrow compared to the baseline. So as we start to think about the overall device setup and programming, the observation seen here in the computer simulation model raises a potentially important point. Dynamically shortening the AV delay in the computer model broadens the heart rate range over which you can elicit a decrease in left atrial pressure. In real patients, when you just pace the atrium faster and faster, the AV delay gets longer and longer, and you start to lose that effect of decreasing left atrial pressure in response to rate. Think about the rapid HF trial results in that context. The other point of this is that you want to be able to control the AV interval, therefore you need to be able to pace the V, and you don't want to be pacing the RV. You want to be pacing as close to the hiss, ideally in the hiss, as you possibly can. And the other thing is you want to avoid using algorithms that are designed to minimize ventricular pacing in this context. What about rate response? The prevalence of chronotropic incompetence is high in the HF-PEF population. It varies depending on what study you look at. In the RELAX trial, the incidence of chronotropic incompetence, RELAX being a HF-PEF trial, looking at some drug to treat it, the incidence of chronotropic incompetence was nearly 80%, so providing rate response pacing is probably important in these patients. And again, the rapid HF trial that Randy just mentioned, that was not a comprehensive conduction system pacing setup, and I suspect that a large reason why that study was negative was because there was a lot of dyssynchrony being caused by the pacing, offsetting or undermining the increased rate. So to conclude, the objective in this patient population is to accelerate the rate and mandate atrial pacing. The lead targets are the Bachman bundle and the hiss bundle, and programming on both AV hysteresis and rate response is probably prudent and helpful. And finally, just to also chime in about elevate HF-PEF, which we're going to be starting hopefully this fall or early winter. In this study, we're going to be encouraging Bachman bundle pacing. Not everybody's going to be doing it. We're hoping that we have a large enough signal that we can use this as a means to prospectively compare these two forms of pacing in a large multicenter trial format. And with that, I shall conclude. We have some time for questions. I have one question while we're waiting for people to come up to the microphone online. And this question, I'll start with Dr. Nagarakanti. In patients who require RV pacing, how do you optimize your AV delays to maximize the E to E prime ratio? Do you perform echo to confirm? Yeah. Yeah, I mean, in the study, we did perform baseline and the follow-up echo, but I think it will be a good way to evaluate that, to look at the AV amplitude. Usually it gets increased. Okay. Dr. Saxena, you want to comment on that, about decreasing the AV delay with the kind of pacing we set up? Is there a role for echocardiogram to evaluate that? I'm sorry, I didn't get that question about DAPA, but it sort of had bearing on two comments I'll make on the presentation. Extensive histopathologic studies that have been done in search of preferential atrial conduction have never shown anatomic evidence or physiologic evidence. In fact, most of these spike potentials that are seen are related to anisotropic conduction occurring and Lino Rossi's study showed a long time ago that the interatrial septum is made up from both the right and left atrial septal fibers, rather than a tract. There have been no, I'm intrigued by the plan for these pacing studies. No pacing studies have ever shown good control of atrial fibrillation by themselves with any pacing mechanism. In fact, the only way it has worked has been when we have added antiarrhythmic drugs, when we did the DAPA study. So as you can see on the graph that were showed, 75% of patients in Backman's bundle pacing were in AF at two years. Since the vast majority of HFPEF patients will get AF, you really have to find a way to control AF if you're going to treat HFPEF. The absence, they don't stay in sinus rhythm very long, and therefore, we went through this in DAPA when there was this belief that you could treat atrial fibrillation with pacing in the absence of any adjunctive therapy. All of those efforts, even the Balin studies failed for any long-term, and certainly there's no hemodynamic long-term evidence with Backman's bundle pacing. So I'd hate to see 25 years later, we walk down the same path and think of it as standalone therapy. Thank you. Those are excellent comments, Dr. Saxena. If it's possible, could I ask Dr. Luskartan to respond briefly about what he has noticed when he's doing these implant procedures, and does he find a difference between modern approaches to Backman bundle pacing versus what's been done historically? Well, I have a lot to say about what you just said. So in terms of, first of all, whether or not there's a conduction system of the atrium, if we apply the definition of conduction system as his Purkinje system, this is absent from the atrium. And the reason it's absent from the atrium is because that's not what the atrium needs to be synchronous. What the atrium needs to be synchronous is what evolved, which is probably largely anisotropically dependent pathways of activation. But that's a form of specialization in itself. So these pathways are not random, and they're consistent between individuals. And with all due respect, nobody in the prior literature did anything to try to map, at the time of implant, the Backman bundle. So none of the studies that were done in the past looked at the electrograms, associated them with respect to the onset of timing of the P wave, and looked at what happens when you pace those electrograms. And indeed, the one paper that almost did that is Steve Valen's paper, which showed a dramatic reduction in relative risk of AFib in a 100 by 100 comparison of Backman bundle versus right atrial appendage. So the single prospective paper that was done, focusing specifically on Backman bundle granted fluoroscopically defined placement, came up with a positive signal. There are no other studies from that era that did that or tried to do that, that I'm aware of. There's a very nice meta-analysis of all the multi-site atrial pacing studies that had been done over the last two decades that concluded that alternate site pacing in the atrium was pointless, because when you add all of those in a meta-analysis, then there's no signal. But only a tiny proportion of that was actually Backman bundle. So the way I would frame this is that we really haven't studied this in detail yet, as I've defined it. And I think that it's just very compelling. You look at the anatomy, you look at the P wave response, and you think about it, I think the probability that we're not going to see a clinical signal here is incredibly low. And I would encourage more people to come up to the mic. Let's make this a real discussion here in the room. I have a question here for Dr. Meyer. HFPEF is one of the most global terms that we have to describe a population of patients. And I'm worried, at least a little bit here, that we're having a conversation where we're just saying all HFPEF patients are going to benefit from a strategy, potentially a strategy of increasing heart rate. How would you further parse out this population? Are there echo characteristics? Are there ECG characteristics that you think you could use to better define a phenotype of patient who will benefit from this approach? That's a very good question. And I agree that not everybody will benefit, I do believe. And we looked a little bit into what the features are in the MyPace trial that drive the benefit. It's clearly the patients with the most symptoms. So that would be a clinical driver of applying this. At the structural, on the structural side, so echo findings, it seems likely that patients with small LVs, thick walls, higher filling pressures as a result would benefit more. But I do believe it could have also, because remember, like an average pacemaker patient is like 75 years old or close to that, they all have some level of diastolic dysfunction at the time of implant that it could be like for prevention still useful in these patients because you just don't know how the clinical course is going to be. You know, I'm heart failure by background, but I do believe that everybody would apply the principles of conduction system pacing, that we could probably do this safely, hopefully with the outcomes that we have seen so far. But right now, you cannot be certain, you know, who is going to benefit the most. We just need more data. And could you tell just the group here for Elevate, which is going to study this question in a systematic way, in the enrollment criteria, how are symptoms being assessed? Are there other either biomarker measurements or E to A prime ratios, anything else that can be used? Yeah, there will be an associated echo study with that. And to get into the trial, you need to have structural evidence of hypertensive heart disease. We used similar criteria to the medication trials, but added that there should be structural benefit of, like, adverse remodeling, because that's probably one of the benefits of the accelerated pacing. Again, we cannot be certain who is going to benefit the most. My pace would suggest it's the patients with the most symptoms that benefit the most. And typically, most symptoms goes along with more concentric remodeling, more LVH, bigger left atrium, thicker septum, these sort of things. I do believe may be, like, the drivers of, you know, driving the disease, and therefore the benefit with the pacing. Kind of going along with that, it was interesting to learn that a lot of HFH patients have lower than normal heart rates. And also, kind of the evidence about the deleterious effects, perhaps, of low heart rates. But people with HFPF have heterogeneous reasons to have HFPF, and lots of inflammatory comorbidities. And I'm just wondering, it's probably not practical to do a CPET test in everyone to see how much this low heart rate is contributing to the symptoms, but what would be, like, the gold standard test to determine how much this low heart rate is contributing to the symptoms? Is it a CPET? I mean, you know, we all, as we age, we have some level of chronotropic incompetence. Our peak heart rates go down, and it's probably some, it's sinus node dysfunction. And when we correlated chronotropic incompetence to resting sinus rates, there is actually a correlation. So we all develop some level of sinus node dysfunction as we age. And it's actually reflected in the population data that after midlife, our heart rate continues to slightly drop. But you know, we are not, our body does not, the body size does not change. I do believe that patients with low heart rates benefit the most. And maybe for now, at least that's how we are going to structure this in the ELEVIT trial. So we basically get a halter to make sure that the differential between their true 24-hour heart rate and the paced heart rate is going to be large enough to really provide them with the heart rate effect or the benefit of the hemodynamic benefit of heart rate. Question from the audience. Well, thank you all for the great presentations. My questions are about Backman bundle pacing. While synchronization, achieving synchronization and reducing arrhythmia sounds like great and promising, I find the procedure can be quite challenging both anatomically and technically. Some of the issues that we encounter is like low P waves and high threshold. So is there different parameter cutoffs that you would say acceptable in terms of P waves and thresholds with Backman bundle pacing? And my second question is, the only way, at least I learned to do it from Maggie, is using an S4 sheath and a 3A therapy. We had great outcomes, absolutely. But do you use other leads or other sheaths that you can find acceptable? I work in Saudi Arabia, and getting an S4 sheath was quite tough in the beginning. So is there any other tools or leads that you would recommend? And thank you. Thank you for the questions. So the injury current on the unfiltered signal, I think, is extremely helpful. When you see that, the likelihood that you're going to have a threshold that's around one volt or less at 0.8 millisecond pulse width is extremely high the next day. So basically, when we see that, and the output, the capture threshold starts at 3.3, and within 10 minutes of doing whatever we're doing, it goes down to 2.1. That lead is going to be durable and excellent, in our experience. And to that point, we have been implanting leads along these lines since 2006. The incidence of threshold rise over time in these people is extremely remote, certainly not higher than the horrible appendage. That's a terrible place to put a lead. In terms of sensing, what's critical about this is the amplitude of the signal is pretty low at the tip. The ring is where you sense. So you need a lead that you can drape down into the right atrium from the inferior SVC. So you need a floppy lead that can do that. And you also want to make sure that you don't leave torque behind on that lead. But when you do that, the sensing is absolutely fantastic. I would say in terms of difficulty, absolutely fantastic, I'm like Donald Trump. I can't believe I just said that. In terms of the sensing, I'm talking like two, three millivolts, characteristically. So you should get totally adequate sensing in that approach, generally speaking. Diseased atrial myocardium is diseased atrial myocardium. So generally speaking, you get great sensing relative or compared with conduction system pacing on the ventricular side, this is much, much, much easier than that, whether you're talking about HISS or left bundle branch area pacing. To learn this is much, much easier. And it is very, very easy to perforate the right atrial appendage. It is impossible to perforate the infrared septal SVC. So from a safety standpoint, it makes a great deal of sense to be doing this, even if all this clinically ends up being completely neutral, which it's not. Sorry to interrupt, Masab, we'll chat after too, but Dr. Karsten Israel, I know implants his Bachman leads using a stylet driven method. So there's other methods, but I know at Tufts, we would do the S4 sheath. And like Dr. Lesgarden said, it's really important to like counter clock the sheath a little. So it's like a candy cane and you have the tip and the ring both lying on the septal tissue for better sensing. Hey, Dan, thank you very much for an absolutely fantastic session. One thing that I'd be interested in is any tips or tricks from the panel in terms of approaching an AF ablation after implantation of a Bachman's bundle lead. Are you modifying your lesion sets or ensuring to map the LA with Bachman's bundle pacing to avoid ablating the insertion site, but, you know, please share. These patients won't need AF ablations. Maybe I should have asked Maggie. Maggie. I guess mine do. You know, I hear her Bachman's leads aren't quite as effective. No, I think like Bachman, I think is a good adjunctive potential therapy. We still need more evidence. But I think just like appendage leads, you just, I do my transseptals under fluoro and so I'm just watching and making sure that it's going up over the limbus and not, you know, tangling the lead and I haven't had problems. And in terms of once you're in the left atrium, any modification of the lesion sets or any newer challenges with PFA, which sometimes you have the, oops, I went a little more anterior than I. No, I think the Bachman's bundle is so thick. We had talked about this, I think, at another session Grav and I were at and it's so thick, it's going to be hard to get transmural ablation across the left atrial insertion site of the Bachman bundle. Yeah. I'm not sure I agree with that. Oh, okay. I defer to Dr. Lester. It's easy enough when you're doing your right pulmonary vein encircling to keep the circle anterior, that's anterior to the right superior pulmonary vein, proximal to the vein so that you're not disrupting the initial breakout of Bachman bundle, which, and by the way, that's a beautiful site for complex fractionated electrograms because that's what Bachman bundle looks like on the left atrial site too. So I think a lot of like the not a Monday era cafe targeting was actually targeting Bachman bundle, which is a very bad thing to do because what you wind up with is a really long P wave, which is profibrillatory. Thank you. Do you think we really get transmural ablation? Well, remember the, well, now that you have PFA, I mean, there are endocardial insertions that distribute anterior to the right superior pulmonary vein and across the roof towards the left atrial appendage. And a lot of that tissue is killable. In terms of the epicardial nature of the Bachman bundle, the vast majority of the Bachman bundle is epicardial, but it's not inside the atria, right? Spanning the atria. But the endocardial breakouts I think are imminently ablatable. So we have time for one more question. I have a few questions actually, but thank you for the wonderful talk. Regarding the trial that you are guys starting, having the right and left being more synchronous, being better. Do you think there is a role of the patients benefiting more from lot CRT or hot CRT rather than just physiologic pacing with a cure restoration that may not be as narrow even with attempt was one of the questions I had. And the other question was, with the biatrial pacing, where are you putting the leads in in the header? So Dr. Nagarkanti, could you comment on dual atrial pacing? For the dual site atrial pacing, the anode is the CS electrode, the cathode will be the right atrial appendage electrode. It's connected to a Y connector that is put in an atrial port of the dual chamber pacemaker. I would encourage everyone to stay. We can spend another hour here. Our session is technically over. Please I'd encourage anyone else with questions to come to the front and speak with our discussants. I hope we'll stay with us. Thank you so much. I hope this is a wonderful first day for you at Heart Rhythm Society 2025.

conduction system pacing

heart failure

preserved ejection fraction

HFPEF

pacing therapies

atrial fibrillation

hypertension

Bachman bundle pacing

diastolic dysfunction

personalized medicine