Dr. Stuart B. Prenner discusses how to diagnose HFpEF, reviews the epidemiology of HFpEF, treatment for individual patients, and outlines the importance of having an HFpEf program in this CME.
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Final grand round for this will also be our final grand rounds for this academic year. Uh Hopefully everyone will have a great summer and will reconvene in September. All right. Well, um it's my pleasure to introduce uh Doctor Stewart Renner who uh was kind enough to join us for cardiology. Grand rounds today, Stewart is originally from Miami Florida, did his uh undergrad training at Yale and then got his MD from Mount Sinai School of Medicine in New York. He then came to the University of Pennsylvania where he did his internal medicine residency, went to Northwestern um in Chicago for his cardiology training and then returned here again for his advanced heart failure transplantt training where he then stayed on faculty. He's been on faculty for several years now, specializing in heart failure and transplant and has really developed a, a nice interest in niche in heart failure with preserved ejection fraction. Um Stewart in a in a group of uh heart failure docs uh a few months ago, put on a very nice symposium um on HE F P F. There's been a lot of recent advancements while most of the the studies and, and headlines have all been in. He um there's really been some interesting developments in HE P F as well. Uh Stewart's talk was, was uh was fantastic at the symposium. And um following that, I thought it would be a nice idea to invite him to educate all of us on how it felt with preserved ejection fraction. Um as it's something that we see quite a bit of. So with that Stewart, I'm gonna stop sharing. I'm gonna let you take over here and um great, uh can you see my slides? Yep, they're perfect. Fantastic. Um Well, thank you so much. Uh Samir for that um uh warm introduction. It's great to be here. It's great to see some uh familiar, familiar uh names and some new as well on the uh on the zoom today. So, thanks for having me. I'm delighted to talk about uh something that's near and dear to me, which is uh he and as Samir said, you know, we really after a very long time of not having a ton to say about this condition, I think are really on the cusp of uh a very exciting time and I'm excited to share um you know, really where we are with this condition um in 2023 in terms of diagnostics and therapeutics. And I'm also excited to leave some time to engage with everybody about how folks are managing this and kind of how we can uh work together to take care of this uh growing group of patients. Um I have no disclosures and so the outline of the talk is here. Um We'll talk a little bit about the epidemiology of half path and spend a good amount of time talking about diagnosis of this condition, which I think uh is something that uh um we all struggle with and now we've got some medical therapies to talk about uh uh with some new trial data. And then I'll spend a good amount of time talking about what? Besides medical, the therapy we can offer these patients. Where is this field going? How do we individualize the approach for these patients? And then I'll spend the end talking a little bit about the program we've built and the importance I think of uh doing so uh to take care of, of these patients. And so I'll start off with a case that will come back to a couple of times. Uh as I think it's fairly illustrative of the types of patients we see and the case evolves a little bit. And so um this is uh a 75 year old gentleman who has a history of a fib, he's had an ablation. Um He's obese, he's got a hypertensive history and um he's coming in with disme on exertion. His B N P level, which was measured is, is 98 which is uh in the acceptable range. We calculate uh his half pe risk scores. Which we'll talk a little bit about. And uh his H two F P F score is eight. His H FA P F score is four. And on his echo, his E F is 65% with indeterminant diastolic function A L A that's moderately dilated and the P A systolic pressure of 41. So pretty typical data coming back uh for a dys patient uh uh with the above comorbidities. And so we actually send him to the calf lab. And what I'm gonna show you initially is his resting right heart calf where his wedge pressure is clearly under 15. So his peak wedge and end expiration would at best, I think be 14 and probably a little bit less. And so we'll come back to this case. So half path fits into the classification scheme of various types of heart failure uh uh defined in part by an ejection fraction that's greater than or equal to 50%. And we'll talk a little bit about some additional requirements uh based on the recent heart failure guidelines. So the question is why are we talking about this? And the reason we're talking about this is because he both in terms of the incidence and prevalence is on the rise. So this is a condition that is increasing significantly. And importantly, the incidence and prevalence are rising relative to reduced ejection fraction, heart failure. Part of this I think is that we've gotten better at treating the risk factors for half raf. Um and additionally, half path is a uh age related phenomenon. And the US population, as we all know is aging. And one of the key takeaways from this talk is that among new heart failure in the community, half half is is now the most common flavor of heart failure. So this is really here to stay and it's increasing. Another important point is that, you know, we don't really talk about stage B half path, which is sort of the patient with asymptomatic diastolic dysfunction. But it's been shown in large community cohorts that even patients with mild or moderate diastolic dysfunction will progress to incident and symptomatic half pa at nontrivial rates over just five years. So this is from data uh from Jama um showing that in patients with mild or moderate diastolic dysfunction, they progress to incident half path at rates over 10% over five years. And so there's a huge group of patients I think that are on the cusp of potentially developing symptoms of heart failure um by virtue of their comorbidities and some echo abnormalities that are already present. And so I think there's a very, very large group of patients. And when we think about stage a meaning risk factors for this, the group grows even larger, you know, with hundreds of millions of patients with hypertension and diabetes and obesity. It's not surprising, you know, when we talk about half pep that we have to recognize that these patients have a lot of comorbidities. And so, in comparison to patients with reduced or mildly reduced, uh E F heart failure at any uh degree of comorbidity. Patients with half peth have that comorbidity more frequently. And we'll talk a little bit about how those comorbidities play into the diagnosis. The other challenge is that these patients have severe functional ability. And so, um the figure on the left compares the K C C Q scores of patients with half path in the Paragon study, which was A versus A R B compared to those with the reduced D F. In the paradigm study with the same, you know, um uh um uh drug and basically, they have mirror images in their case C C Q distribution. So even though their E S may be preserved, these patients have significant and similar um K C C Q um uh abnormalities compared to reduced patients. And on the right, what you can see is that the peak V 02 in patients with half path in the studies where it's assessed, puts them sort of at a functional disability that's basically in between walking three miles an hour and functional independence. And so many patients in half P F studies operate at a level where they're functionally not uh independent. And lastly why do we care about this? We care about this because when patients with he pep have a heart failure hospitalization, their five year mortality mirrors that of all other forms of heart failure. And so again, even though the E F may be preserved, these patients had a poor five-year prognosis that is identical to those with reduced E F heart failure once they're hospitalized. So growing population up until recently, lack of medical therapy as shown here. And so um this I think is, is a huge challenge in this field. I think there up until recently was a ton of therapeutic nihilism. In part because iterative clinical trials that applied blanket hera therapies to half pef did not meet their clinical trial end points. And so we saw this over and over and over again. And there was this interest in sort of doing subgroup analysis and trying to kind of find something positive. But the reality is most of these trials were negative and we'll talk a little bit about why. And so I think with that background, recognizing the fact that this is a growing patient population and that the incidence and prevalence is increasing relative to half ref will pivot a little bit to talking about how to diagnose this condition. Um sort of nowadays. And so I'll show the figure again that reminds us that half path is a distinct heart failure classification, distinguished from other forms of heart failure, like half raf or mildly reduced E F and also distinguished from heart failure improved because these patients have never had a low ejection fraction. One of the changes though in the heart failure guidelines is that in patients with mildly reduced and preserved E F heart failure, in addition to signs and symptoms of heart failure, the guidelines suggest that we should demonstrate cardiac congestion as the cause of their symptoms by one of two ways, either by elevating B N P level or quote unquote objective evidence of cardiogenic pulmonary or systemic congestion. So it isn't just enough to have signs of symptoms and have an E F that's preserved or mildly reduced. The guidelines are telling us that we should have some corroboration of congestion sort of as the source of their symptoms, either by B N P or some other measure. And that's consistent with, you know, a definition that I, you know, walk around with when I'm, you know, thinking about this condition, which is what I've shown here, which is, you know, you're thinking the patient has half path. So it's a clinical diagnosis. They should have signs and symptoms of heart failure. The E F should be greater than 50 with no aniseed and LV dysfunction. We have to rule out severe valve disease like uh M R or aortic stenosis. And then ultimately, you need some evidence of a cardiac pathology, either with elevated B N P level or some type of typically provocative test, either in the echo lab or in the cat that demonstrates congestion, either with elevated filling pressures on echo or a resting wedge pressure of over 15 or an exercise wedge pressure of over 25. And so we'll come back to how to utilize um the scoring systems and caf to kind of cinch the diagnosis. One of the challenges with B N P is I'm sure everyone here is aware of is that particularly in half path, it can be misleading. These patients are often obese. And um when we think about the night for um wall stress, unlike the heart on the left, which is dilated and thin walled, the typical he pe heart is normal size and or thick and so the the impetus for wall stress is much less and so accordingly, um the B N P level will be normal in at least 30% of patients where we've already calfed them and know their wedge pressure is elevated at rest. So these are patients with manifest congestion and yet the B MP is normal. And so while it's helpful if it's high and it's very helpful if it's very high, particularly for thinking about half pep mimickers like amyloid, it will be normal in many patients and may not help you. And so when we think about half pa and kind of its garden variety flavor, we are reminded that these patients have a typical comorbidity profile that's, you know, echoed in the data on this slide from the Paragon study, which was the R E versus A R B at half pa. And so these are patients who are typically in their seventies B M I, you know, 30 plus invariably hypertensive, 96% of patients had a history of hypertension, almost half have diabetes and at least a third have a fib. So that's who gets garden variety half death. And conversely, if somebody is carrying around this diagnosis and they're much younger, you know, in their forties or fifties and they lack these comorbidities. That's a scenario where I'm definitely wondering if there's some other diagnosis or half, half mimic or going on. And the reason this is important is because these comorbidities are incorporated into some of the scoring systems that are suggested to be used to work up unexplained dym on exertion. And so let's talk about them. So the H two F P F score, which has been around now for, I think five years was published by the Mayo group from their cohort and has been subsequently validated in many other patient groups and it computes like the H two F P P score. So if you have a patient with unexplained dym on exertion, meaning, you know, they're not on oxygen for C O P D, their P F T s are reasonable. Um This is a score that's worth calculating and points are given for some of the comorbidities that we just mentioned. So they get points for B M I over 30 they get a lot of points for a fib which makes a lot of sense because we think about a fib as being kind of the consummate left atrial, uh you know, uh abnormality. And so if patients have had long standing, left sided uh stiffness, their left atrium will dilate, they get points for age and then they get a couple of points for um elevated P A pressure and, or elevated E ovary prime. And so the s the score computes up to nine and scores of six or higher are thought to be highly predictive of half path. Whereas scores of one or two or less are low and many patients will fall into an intermediate score. The European group has a similar sort of scoring system called the H FA P F score that relies much more heavily on structural and functional abnormalities from the echo and also on biomarkers. And so their score computes um by two points if you're in the major area and one if you're in the minor for each of the functional and morphological parameters shown there. So there are things that make sense, right? It's low tissue Doppler high E ovary prime dilated L A, increased L V mass, things like that. And then you also get two points for your body marker score depending on whether you're in sinus or a fib. There are in different cut points and you get one if you're in the minor. And so their maximum score is six uh and scores of over five are thought to be high uh versus scores under 11 or zero or are low. And then, you know, many patients again will fall into the intermediate. And so why calculate these scores? Well, again, it's helpful because um uh again, pretest probability can skew your subsequent work up. But the other reason to calculate these scores is that these scores are also predictive of subsequent heart failure uh uh risk. And so this is data from one of our former fellow Central Salvage who looked at what these scores tell you in a large um patient cohort in the ERIC study, which is a large several 1000 patient uh community cohort uh patient that's been followed longitudinally. And what he showed is that some uh compared to patients in this cohort with known half path in patients with unexplained dysnea on exertion, serial elevation in both of these scores, meaning stepwise elevation is associated with a subsequent heart failure risk or death risk that is increasingly elevated and approaches that of manifest half path. And so again, calculating these scores is helpful, not only to guide your work up, but it's also prognostic particularly if both of these scores are elevated. The scores don't entirely agree with one another, which is not surprising because the H FA P F score gives a lot of points for biomarkers. And the H two F P F score gives a lot of points for um a fib and uh comorbidities. And so they don't entirely agree with one another, but they are correlated. And I think confer additive information. And so how should we use these? Well, if we have a patient with unexplained dysthymia, we should calculate these risk scores. And if one or both are high, the patient has a very high pretest probability of half path. And you may not, for example, need to go to the Cath lab just to rule in the diagnosis. There may be other reasons to go there. And conversely, if both scores are low half path is probably not the main driver of their dyspnea. Again, with some exceptions, many patients however, will fall into the intermediate probability and for those patients, some provocative test is often needed and will help you to rule in or out half that. And how should we do that again? The gold standard I think would be exercise calf and demonstrating either a wedge of 15 at rest or a wedge of over 25 with exercise. There are other reasons to exercise patients either on the treadmill or in the calf lab. One being what is their chronotropic response actually documenting their functional capacity, which is somewhat prognostic and data from the mayo group shows us that if you simply just do a resting Cath, you will miss a lot of half path, right? Because 50% of patients particularly early on will not have an elevated wedge pressure at rest. And most of them, you know, if they're gonna demonstrate pathology will have it with exercise, right? Because it's an exertional um condition and you're better off, at least in their study doing a exercise echo or a diastolic echo and looking for elevated E over E prime and T R velocities than you are doing a static, right? Hard path. I will say that. Um practically my experience has been that it's very, very tough even though we know that technically, you know, diastolic abnormalities persist in echocardiography beyond systolic abnormalities. Often, in my opinion, the signals are contaminated. I'll show a, an a an example of a diastolic stress echo. But practically, I think it's very tough. But the point is if you're going to take the patient to the calf lab, you need to do a provocative test of some sort and not just exonerate half pet because the resting wedge pressure is normal. And in fact, Barry Blog's group shows that just doing a passive leg race alone may adjudicate a lot of these patients if the lab cannot do a full on exercise cap. And so what he showed was that basically, if you give the patient, you know, a little bit of a fluid bolus by raising their legs. If the patient's wedge pressure went over 19, every single one of those patients in this small cohort of 42 up ruling in with full on exercise. And conversely if you did a leg raise and their wedge did not go above 11, every single one of those patients ruled out by exercise. And so again, not all labs can do a full exercise protocol, they don't have the bike et cetera. Um So this is, this is provocative and interesting to me in terms of, again, underscoring the importance of some sort of provocative maneuver, whether it's a sailing bolus et cetera to rule in or out. Half. The other thing that was interesting from his study is that in the group that actually manifested resting congestion with a wedge of over 15, only a third of them had a high H two F P P score of six. And so the take take away from that is that yes, high scores are helpful. But many patients, even those with a wedge that's elevated at rest will fall into that intermediate um risk elevation. And these are patients that should move on to provocative invasive test testing if you want to rule in the diagnosis. And so I think again, this is further um evidence uh supporting the fact that high scores are helpful, but intermediate scores should not um take the diagnosis off the table. And so let's go back to my patient. So the resting wedge was 14, we put his legs in the pedals. And with that, we don't quite get a wedge pressure that's over 25 yet. But we see kind of a very obvious in my opinion, development of a V wave and just, you know, the overall contour of this, of this tracing changes. He doesn't, you know, by the way, have M R so his L A is very, very stiff. He's had an ablation and we're starting to see that elicited with just his, um, you know, leg raise and then he goes on to exercise here. And what we can see is at peak exercise. You know, I think I could convince you that, you know, his a wave at peak exercise is, you know, probably close to or greater than 25. It's not 40 but it's not normal and he develops these V waves to 50. And this is a, you know, a wedge tracing that was confirmed with a SAT and, you know, again, no M R and so very clearly stiff left atrium and his lungs are obviously seeing a lot of this. And so we're eliciting some of his hemodynamic abnormality by exercising him. Importantly, we also see that his peak heart rate despite nine minutes and I think 60 watts on the bike is only 78. And so there's also a chronotropic abnormality here that may also be fruitful in terms of addressing. And he was also on moderate doses of beta blockers and and subsequently, we, you know, thought about changes there. And so again, there's a ton of information you gain from exercising these patients and also um looking at their heart rate response and other abnormalities like the blood pressure, you know, going at 2 50 with very little exercise. And so, you know, just to kind of tie it all together in terms of making the diagnosis. There is a clear spectrum of disease. Here, patients very early on will have minimal echocardiographic abnormalities. Maybe the L A is a whiff dilated, maybe the tissue Doppler is a little bit low, but the B N P levels will be normal. These people will probably not have a wedge pressure that's elevated at rest and will require provocative testing as the disease progresses. And patients end up accruing heart failure, hospitalizations. We end up seeing kind of more striking pathology that ultimately leads to right heart failure and high B N P levels, diuretic refractoriness. These patients that are frequently hospitalized and some of these patients may, you know, be relatively refractory to most of our interventions. And this I think is underscored a little bit by um some data from the M G H group that I wanna just uh briefly mention they did a very interesting study where they took 400 some odd patients who were referred for a level three C pet. So C pet and right heart calf for unexplained dym on exertion and basically had a calf diagnosis of half path with the same parameters we mentioned. So wedge of over 15 or um wedge of over 25 with exercise and basically what they said is OK, you know about half of the patients ruled in for half peth. How many of them met contemporary society guideline definitions for half path and how many of them would have met inclusion criteria for contemporary half peth clinical studies. And what you can see on the right is that among the group of patients that ruled it in for he he in the calf lab minority of these patients like 20% actually met criteria for clinical studies like top cat spro lactone or Paragon Arnie, which is fascinating to me, right? These are patients that clinically have this disease and yet would not have been considered clinical trial candidates. You know, only 60% of these patients met European society guideline definitions at the time for half largely because their B N P levels were too low. And so if you look at this group of patients that M G H ruled in for HE F P F, if you look at what their B N P levels were as stratified by what threshold of criteria they met, you see serial elevations in their B N P as they meet criteria for more rigid um society definitions or clinical trial inclusions. And you see a serial reduction in their V 02. And uh you know, during the C PC. And why do I say this? Well, this is important because frustratingly many of our patients with earlier disease are not candidates for clinical studies. And importantly, there are signals from clinical studies like top cat that some of the sicker patients don't respond to therapy. And so when you look at the B N P levels in top cat patients with the highest tt ti of B N P elevations did not respond to spirono lactone, whereas patients with lower B N P S did. And so again, there's a disconnect to some degree between rigid clinical trial deficit and this more pure hemodynamic definition that I think helps us identify earlier um disease pathology. And so in summary, and again, I think the latter couple slides could be a subject of their own for an entire talk. Restrictive historical society definitions of half path. Absolutely miss early disease. There's no question about it, particularly if like the E S C criteria, they require elevated B N P levels, ambulatory half peth patients who have not been hospitalized are not well represented in half peth clinical studies and particularly in early half path, meaning the type that may be associated with intermediate half peth risk scores and an echo that, you know, doesn't bop you over the head with, you know, grade three diastolic dysfunction in an L A that's like, you know, bigger than the L V exercise hemodynamics are going to be much more telling than the echo or B N P levels. And so I wanted to spend uh all of this time talking about the definition and how to rule this in because ultimately, even though we've got some therapy. Now, if we don't recognize this disease and label it, we're going to miss the opportunity to treat patients. So, moving on. So what did the guidelines tell us about therapy? So, um everyone's aware that you know, the guidelines for all of heart failure were rewritten last year. The S G L T two inhibitor now gets a level of two, a recommendation for the treatment of half. And where did this come from? So, um folks are probably aware of the two clinical studies. I'm not going to spend a ton of time on this um because I want to spend time talking about therapeutics. But um two large clinical studies, each of 6000 patients looked at S G L T two inhibitors in a relatively preserved E F population. So Emperor Preserve looked at patients with an E F of over 40 plus two or greater heart failure and required either uh you know, elevated B N P levels and structural heart disease or heart failure hospitalization. And this was exciting. It was the first therapeutic um pharmacological clinical study in a heath population to meet its primary end point. And as you see the curves here in terms of lysin versus placebo separated relatively quickly. Interestingly. And this was the subject of a lot of discussion, the effect of the S G L T two inhibitor in this study was very much um associated with what the patient's E F wore. A third of the patients had an E F of under 50 which in my opinion, is not E E F a third had 50 to 60 and the third had 60 or greater. And in this, um you know, subgroup analysis, even in the group of 50 to 50 60 the hazard ratio was not crossed. And so, you know, I think we would all agree that, that, that's a half pa group, but it seemed as if the signal for half pa uh for S G L T two was to some degree associated with E F and with stronger um benefit in a group with EFS under 50 the liver study was a nearly identical study. Um again requiring an elevated B N P. But um you know, did not necessarily have patients who were hospitalized for heart failure, almost identical Kaplan Meyer curves, which is kind of what you want to see, you know, when you're making guidelines, you know, you want to see that the drug is, you know, uh a class effect and is to some degree causing um relatively similar response in similar patient cohorts. The outcome was driven almost entirely in both studies by a reduction in heart failure, hospitalization. It's not surprising that this drug did not have a um change in mortality because in general, right, the mortality and half in particular is largely driven in the disease by noncardiac um issues. And so oftentimes we won't expect to see a hard mortality end point. But what was interesting was that again, similar distribution of patients across E F T tiles. And yet in this study, we saw the exact opposite, the benefit of the S G L T two inhibitor was actually strongest in higher EFS and sort of null in EFS of under 50. I'm not totally sure we have an explanation for why these studies had somewhat disparate um uh uh outcomes uh in EFS um that being said, the summary in these 12,000 patients has led to um S G L T two inhibitors receiving a level of two A. And it would not be surprising. I think over the next several years, if we see even higher level of evidence for uh this class for half path. And so this is really um sort of standard of care now for half um uh to put these patients on S G L T two inhibitor, whether they are or are not diabetic, both studies enrolled a mix of patients. Now, what's interesting right is that the army um Cuba Valsartan receives a level of two B evidence. And so the question is sort of what is that all about? We all remember the Paragon study, which was somewhat disappointing and came out, you know, 3.5 years ago, which just missed its primary end point. So um Sacubitril Valsartan compared to A R B in half path overall did not meet clinical significance in terms of the combined end point. What was noteworthy in that study was that uh again, when we looked at the benefit of the army stratified by the median E F in that study, which was 57 clearly people with EFS on the lower end of normal responded to the army and those with higher end did not. And again, this isn't that surprising considering the, you know, robust data in half raft. What was more interesting? And I think is the subject of um ongoing research is that there were clear gender differences in terms of um how men and women responded to the army. And so this is data for both the primary composite endpoint at paragon and just heart failure, hospitalization. So with women shown in red and men shown I guess in blue or black, and what you can see is a clear, significant gender interaction where women seem to respond to uh Sacubitril Valsartan compared to the uh A R B whereas men did not and shown a different way. Um This is a figure showing kind of E F across um uh the bottom axis with um when the figure um when the line dips below the X axis, we see um benefit for the army and when it's above uh there's no benefit. And so for women, it seems that basically at any E F under 70. So basically any woman who's not hyperdynamic, there seems to be benefit for Arnie and in men, that cut point is really only seen when the E F is effectively, you know, under 55 or so. And so, again, subject for its own talk, there are probably a hormonal and other mechanistic reasons why this is the case. We know that men and women remodel differently in half theft. But ultimately, once we've started the S G L T two inhibitor, we should consider the army for women, particularly if they're already on a antihypertensive regimen or an A R B. Really at any E F if it's affordable. And for men, you know, if the efs are on the lower end of normal. And so I thought it was worth spending a slide or two talking about why folks invoke the army in an otherwise kind of globally negative um clinical study, the guidelines and position, you know, papers will remind us that after we've kind of done our rule in half paff start S G L T two inhibitor, we should spend a lot of time treating patient comorbidities. And what are these common comorbidities? A bib? We'll talk a little bit about that hypertension, managing to about 1 30/80 and using particular agents like we've mentioned A E or M R A when doable, particularly for patients who have a low potassium. We definitely need to rule out ischemic heart disease. A third of patients had ischemic heart disease and they do worse. So all of these patients should get a stress test of some sort, sleep apnea should be ruled out and obesity uh uh should be um um definitely uh looked into and addressed and we'll talk briefly about that. And so with the last, um you know, 10 minutes of this talk, I want to talk about what more to do besides G D M T. I think S G L T two inhibitors obviously are the mainstay but kind of where else is this field going? And we can, you know, have a, a discussion about phenotyping these patients. It's very clear that patients come to have half path, even if they have similar comorbidities for different reasons. And you know, again, a subject for an entire discussion about how phenotyping these patients may lead to tailored therapies that when applied to kind of a blanket half pa population have not um led to outcomes uh that are um uh uh improved. I think we're all familiar with the uh interatrial shunting device. Uh It's worth noting that um mechanistically this was uh discussed uh from Lambacher Syndrome, noted that patients with mitral stenosis who had a SDS did better. So the thought was OK. If he is the disease of the left atrium and elevated left atrial pressure and volume, let's offload it to the R A. And it made a ton of sense in um initial studies like reduced L A P one where one month after creating a one month interatrial shunt patients had improved uh hemodynamics with exercise. However, in a larger uh 600 patient sham controlled study reduced L A P two, which just reported out in the lancet in 2022. Um the outcomes were um not what we expected. And so, you know, this is a typical contemporary heath population, median age of 70 B M I of 30 you know, 90% hypertensive, almost a half had a fib history and you know, most were class three. And so these patients were randomized to the interatrial shunting device versus placebo. And what we can see in the bottom figure is that there was no statistically significant reduction in heart failure and points over uh uh the two years of the study, which was somewhat frustrating, right? Because the the prelim data looked good when we looked at subgroup analysis, what we could see is that um you know, this was the somewhat heterogeneous group and in particular in patients with pretty significant right sided remodeling, meaning R A s that were dilated and P A pressures that were high with exercise. This procedure clearly harmed these patients. And it's not surprising because, you know, the volume that's offloaded to the right side with the shunt device has to be accommodated. And if there's derangements in the pulmonary vasculature or the right side, as evidenced by right atrial enlargement, these patients may not do well. And so um what was done in subsequent analysis was basically defining this concept of latent pulmonary vascular disease as defined by a exercise PV R of greater than 1.7. And so, if you stratified the patients in this study, that we can see that in patients with latent pulmonary vascular disease, clearly no benefit and actually harm. Whereas in patients who did not have this abnormal exercise physiology, they seem to benefit from this device and shown um uh in another way, if we look at the K C C Q sort of how did patients feel if they had a PV R with exercise under 1.7, they felt better. K C C Q went up if they had an exercise PV R greater than 1.7, they felt worse. And the reason I present this is, you know, again, negative clinical studies are negative, but it's worth again for a hetero G disease looking at who may respond. And importantly, because this is leading to a subsequent clinical study that will be participating at, at Penn called the Responder H F study enrolling patients with both he pa and I believe R who have um size PV R s of under 1.7 to see if they benefit. So more to come, let's talk briefly about a fib. Um Definitely see some E P folks on the line, I think A P A A FIB is a huge comorbid condition with half pa about a third of patients with half path have a fib and it um portends the worst prognosis if you have a fib and vice versa. Um drug versus ablation therapy, I think uh again, can be a subject of debate in all patient populations. But it's important to say that in the Cabana study, which was a ablation versus uh antiarrhythmic therapy. Even though in the um larger clinical study, the um uh benefit of ablation over drug therapy was not obvious in the heart failure substu of which the majority of patients had pe F there seemed as I show in the figure here to be clear benefit in ablation compared to drug therapy. And I'm not saying that every patient needs ablation, but rather that we should have specific thoughts about how to uh uh manage um or fib um in our patients with heath. And so I'll be curious to get some uh comments from uh our uh uh E P colleagues here. But I think this is very thought provoking. And again, suggests that patients with heath may, may require more thoughtful approaches, particularly because they may not be tolerant of uh aggressive rate control strategies uh in the interest of time. I'll skip a little bit over this. But it's worth noting that guide H F extended the criteria for implantable P A sensors to uh a broader um heart failure population for P F and ref all the way down to class two heart failure and um allows for us to implant this technology in patients, even without a prior heart failure, hospitalization, if their B N P is elevated, the guide H F study. Um although the end points were a little bit um uh uh more muted in the overall study in the pre specified pre COVID-19 analysis were clearly positive. And that's what led to the expansion of the FDA indication for this technology. And so this is a fantastic technology for the right patient who either has a clinically challenging exam, who sort of ends up in the hospital for A K I or heart failure often um very good um uh technology. And lastly, right, we recognize that even if an elevated wedge pressure at rest or exercise is sort of the of half path. These patients are symptomatic for very different reasons. And one of the pathologies that we recognize among many is chronotropic incompetency, chronotropic incompetency, regardless of how you define it has been shown in half path to be clearly associated with worsening functional capacity. So this figure here shows that the six minute walk distance is clearly associated with chronotropic incompetency. And the more chronotropically incompetent you are the less you can walk. And so this has been looked into this was a single center study, looking at patients with half, half on some amount of beta blockers who were deemed chronotropic incompetent by um the uh equation I just showed you if the chronotropic index was under 0.6 and it turns out practically, it doesn't take much to get there. So, a typical patient, you know, who's 70 with a resting heart rate of 65 that at peak exercise gets to 97 will have a severe chronotropic index of 970.4, which is way below their cut point. It's not that hard to have this and they randomized patients to be on and off their beta blocker. So everybody served as their own control and they did AC P T on beta blocker off beta blocker and a baseline. And what they showed is that um off beta blocker patients peak V 02 went up and their percent predicted V 02 went up and this was a small study. And so I'm not suggesting that we take patients off their beta blockers, but many people are on them for, you know, unclear reasons, hypertension, you know, other things S BT S that are very remote and it's worth thinking about particularly in patients who demonstrate chronotropic incompetency. Like the patients I showed you who we have to at least consider reducing their beta blockers or at least having a trial of it. Lastly, it's worth saying, you know, weight loss is really the holy grail in this condition. You know, 75% of people have A B M I of over 30 we know that weight loss leads both to structural and hemodynamic uh improvement. And we also know with increasing evidence that the G LP one analogs lead to sustained weight loss. And even though we don't yet have hard data in half path, we will soon the step half paff study that we participated in looked at some male in half pa um in both diabetic and nondiabetic patients. And at Penn, we were um fortunate to be able to enroll um the third highest volume in the Americas into this study. And so we'll be curious to see what the end points are. But for your patients who are obese and for patients who are diabetic, this drug class can be exploited for its weight loss properties. Um uh to our advantage, I think I'll skip over uh the date on nic innovation. It's kind of out there. And so in the last three minutes, I just want to talk about why we have a half P F program. There were calls to do this, you know, over 10 years ago from leaders like Sanji Shaw, Kavita Sharma, who I know gave uh grant rounds at Presby a couple of years ago. Um because again, this is an increasingly common condition that up until recently had no medical therapy. And so, you know, our half P F program has really built nicely over the last five years with a multidisciplinary um team that helps to manage these patients in terms of both their cardiovascular and non cardiovascular comorbidities. And why do we have this program? We have this program firstly to ensure that the diagnosis is correct. You know, ultimately, you know, with cathing patients, I think it's, it's less challenging nowadays. But I think, you know, many patients come for kind of diagnostic um you know, work up or, or, or difficulty there. But importantly, once we've made the diagnosis, right, we need to ensure we're not missing half peth mimickers. And we need to develop individualized treatment strategies for patients and dovetail their um clinical care with clinical trial enrollment because again, we only have really one therapy at this point. And I remind our fellows when they're rotating that half peth has a differential. And even though we're defining the syndrome by hemodynamics, we will miss mimickers if we, you know, think all half P F is the same and we can divide the differential in part by whether the echo shows L V H or not. And we're obviously diagnosing a lot of amyloid um in younger patients, we're seeing some uh evidence of storage diseases and also H C M when we get cardiac MRI S and these people who are thought to have, you know, concentric L V H or, you know, upper seal hypertrophy, which we're seeing patterns that are actually more consistent with H C M. The EFS are hyperdynamic. And as the, as we, you know, talked about these patients may not respond to things like S G L T two inhibitors or other conventional therapies if they're on the more hyperdynamic spectrum and may in fact, actually respond to things like mavica um for patients with normal thickened L V S, we think about, you know, wanting to rule out restrictive disease, pericardial disease. And so it's important to have a working differential. And SJ Shah came up with a Pneumonic called Help me. Now, um he's sort of a, a wizard in doing things like this and like the I need help criteria and he help me now is designed to remind us that even in P F, there are kind of red flags that should raise suspicion both for referring these patients, you know, for um work up and advanced um diagnostics, but also that raised suspicion for a half path mimicker. So B N P levels of over 1000 to me are amyloid until proven. Otherwise, it's very unusual in a patient with normal renal function. Um and garden variety half to have a B N P of over 1000. Um Similarly, if a patient is missing conventional risk factors, right, like they're 50 years old, they have no history of hypertension that's very, very unlikely to be garden variety half path. And then obviously, and organ dysfunction, non response to diuretics are concerning. And you know, I put on my kind of red flag signs, you know, pe pef under 50 very unusual high B N P I check patients for coal sign if they have coal sign. You know, it's unusual to see that in, in garden variety half path. You're more dealing with more deranged, you know, restrictive type disease. R V dysfunction, which is either very late half path or it's something like restrictive disease or um pericardial disease. And so, um you know, I'll end, uh here's an example of a diastolic stress echo. I had to like borrow this from a colleague and kind of call the images. I don't find this to be very practical, but here's an example of what it would look like, right? It's a patient who's resting prime is mildly abnormal. The P A S P is mildly abnormal and then you exercise them and both of those parameters get more abnormal. That's a a positive diastolic stress echo. It's not easy to do, but this would be diagnostic, high rates of amyloid and half pa. It's not surprising. And so again, just to come back to the therapy, right? S G L T two inhibitors now have a level two, a other therapies have lower degrees of recommendation and we talked about why. Um and I'll end there. I want to time for questions. Um I am excited to uh engage with everybody that was sort of a whirlwind Pef Pef tour. But I hope I've gotten everybody excited about this presented kind of a pretty straightforward algorithm for identifying this noninvasively. I think highlighted the importance of taking people to the Cath Lab because now we have therapies and we have more on the way and So I'll stop there. Um And uh answer any questions. Uh And thanks again for having me. Thank you very much for joining us uh and providing us with such an educational talk. Uh This was a great learning experience and I certainly learned a lot of very practical, good information. This is something that I can definitely take uh to the patients. I see. Uh and immediately I think be uh be better at providing care for them with E P P F. So fantastic, great practical talk, great job. Uh And thank you for joining us. Um I'm gonna circle back to the the patient you first presented. Um Yeah, I think this is a very typical patient, elderly patient who is tired short of breath, fatigued. Um can't cut the grass anymore or, or just has a hard time uh exerting themselves. And we go through the typical evaluations, an echo, a stress test. Um blood work A B N P. Um Where do you go from there? Who do you prefer for exercise? Um Who do you do a trial of medical therapy first for um there's such a large population of these patients and for someone that does exercise, right? Heart tests, it's labor intensive and, and I don't think we have the bandwidth to exercise all of these patients in the Cath Lab and really be able to do these formal studies. So I'm just curious that patient that you presented initially, what, what happened from there and how do you approach that pretty typical patient? So that's a fantastic question. And I think there's a couple pieces to it, you know, part of it is just partnering and having shared decision making with the patient in terms of their interest in kind of being aggressive. Um because ultimately, you know, his scoring system, you know, his scores were high, I think, you know, his um H two F P P score was more than diagnostic. So there wasn't an other reason to exercise him, I think to purely get the diagnosis. And I think you would be um well positioned, I think to just start medical therapy, including an S G L T two inhibitor and a patient like that. And to focus on patient comorbidities and addressing them. Part of the challenge though is that again, mechanistically, there are many features of each particular case that may lead the patient to be symptomatic. And in that particular case, the exercise was actually helpful. I guess it didn't have to be in the calf lab. We would have gotten the same result on the treadmill, but he was severely chronotropically incompetent and he was on a moderate dose of a beta blocker. I think he was on like 100 of a tool or something like that. And so in addition to putting him on medical therapy, we actually reduced and I think maybe eliminated his beta blocker, he actually felt much better in that, right. The other reason to calf patients is that it is prognostic. And so having an elevated wedge pressure on your calf is actually an a poor prognostic sign and it just may lead you to be more aggressive. Um, again, do you need the calf to do that? No. And so that's, that's how we manage that patient. And it's tough, right? Because he's got C L L, there's anemia, you know, it's gonna be multifactorial. But ultimately, all we can do is sort of try to pinpoint the players and the, the physiology and the particular patient and match the therapies accordingly. Um The next question comes from Ross Zimmer and he says, do you see a difference in clinical response in what appears to be two separate phenotypic groups of hef path, those with clear volume overload on physical exam or by resting, right heart path versus those that have a baseline, normal filling pressures. But the but develop he path or high filling pressures with exercise. Um Ross that, that's a great question. And I think the answer is the clinical trials don't inform that. And that was my entire point is that that latter patient who only has an exercise wedge pressure elevation is not included in any of these clinical studies, right? These are people whose B N P S are normal and are not represented in the S G L TT inhibitor studies or really any. So I think the answer is we don't know. My sense is that neuro hormonally, it makes sense that the patients with some degree of resting congestion, which is what the definitions kind of require, probably respond better to therapy in terms of symptomatic benefit. That's gonna be overt. What I would counter though, in that point I just made is that heart failure is progressive, right? I showed you data that even asymptomatic diastolic dysfunction will progress. And I think if we have some signals and we probably will see more of this come out in the data that even an earlier disease, this this drug class is helpful, it probably will be helpful. I just don't know that you can promise the patient this therapy is going to make them feel better necessarily when they don't have manifest congestion. What I would tell them though is that if we've ruled in this diagnosis by C or some other means it will progress. And so, um that's the reason to do it. So I hope that answers your question. But I think that's, that's where kind of investigator initiated studies like pay man and others are doing are important because we don't have data on that enlarging group. I know there's more data coming in terms of the weight loss medications. Um but I want to get your sense because, you know, weight loss is so difficult for patients for a variety of reasons and these medicines um have really made a huge impact for a lot of folks in terms of losing weight right now, how are you working that into your, your treatment um of a patient who's who you feel confident has heath and is obese. So it's a great question. Um It's important to always say, right, that the clinical um studies are important, right? We obviously got burned with um other preparations of G LP agonists and half ref right, the flight study actually showed that patients did worse. And so it's important that we have information from the half pep studies to inform the safety of this drug class in patient patients with symptomatic heart failure. And so it's important that we have that data for patients who are diabetic, you know, this drug class is approved. Um And so if they're diabetic, you know, and for example, they're on other therapies. I'm partnering with endocrinologists to try to get these patients on G LP one because everything's a risk benefit. But for this particular type of heart failure in general, I think it's highly driven by obesity. And it's worth considering for patients who are not diabetic, the only uh approved weight loss therapy is weight go V um And that we're having mixed um uh sort of approval um for um but it's still worth thinking about the hope is that um both the summit study uh with Terza and half and the um step half pep studies will not only give us the safety answers and the heart failure and point answers, but also, um, hopefully show, you know, the weight loss that's expected. So I think we're leaning on these, I'm prescribing them. I think it's a important drug class, but it's also something that we just need to be mindful of. At least in ref there was some pause that we should have had from the flight study. Well, Stewart, uh we'll, we'll stop there since it's uh 8 31. Again in review C M E code today is 84941 for everybody. Um Thank you for joining us. I thought this was a very practical, a very helpful clinical talk. And I think something that we can each take home with us uh to really impact our patients. It's a, it's a group of patients we all see no matter what sub specialty you're in now. And uh this is uh a great talk and hopefully in a few years we'll have even more data and uh and definitely have you back to give us an update at that point. Thanks so much for having me. I really appreciate the opportunity. It's great to see everybody. All right, take care, everybody have a great day and we'll see you in the fall for uh the next session of uh cardiology. Grand rounds. Everybody take care. Bye-bye.
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