So, I don't know if everyone can hear me. Thanks for coming out on Sunday evening. It's great to be with everyone for this session on Van Stuyren and amyloid cardiomyopathy. We're gonna be talking about best practices for successful outcomes in patients with heart failure. I just wanna thank the accrediting sponsor, which is the HFSA, the commercial sponsor AstraZeneca for providing an educational grant for the symposium and Vasmedica for providing our program management services. As no successful completion of continuing education activity includes a participation in the post-course evaluation. To claim CE credit, learners must complete a session-specific evaluation. And for that, the website is accessible by either the HFSA ACM 2023 mobile app. You can use CE credit kiosk at the registration desk or direct URL. To claim the credit, you gotta complete the following steps. You gotta log in by your last name and registration ID, locate the specific satellite symposium by title name and complete the evaluation. Please see the faculty disclosures information in the handbook. Representative slides are actually included with the handout and questions cards are located on the seat. And if you have any questions, please jot them down. We'll have personnel that will come around to collect the cards throughout the program. And please, if you could, silence all your electronic devices so we can move ahead. It is really absolutely my pleasure to introduce our first speaker, my colleague, Dr. Ahmed Masri from Portland, Oregon. He's gonna be talking to us about raising awareness screening and the diagnosis in ATR-CM patients with clinical heart failure. So without further ado, Dr. Masri. Thank you, Tamar. Let's see. All right, I think these are the wrong slides. That's okay. Yeah, if we can get the slides up. And as you can see, we can stop talking about amyloid. So thank you all for coming tonight and joining us. So go through these slides. We're trying to give you kind of a little bit of a flavor of what's been happening. This disease phase, as well as give you a flavor of how things are looking into the future. This is rapidly evolving. I think we meet again next year. You're gonna see a different set of key takeaways from any talk. So there are my disclosures. Well, that's on slide two. So, let's see if we can. Also the wrong slide. Also wrong slide. All right. Anyway, maybe we don't need slides. So, as you know, when we talk about cardiac amyloidosis, there are two major subtypes of cardiac amyloidosis. So we have a trans-diarrheic amyloidosis and we have light-chain amyloidosis. There are about, depending on which paper you quote, there are between 27 and 30 amyloidosis. And so these are not the slides. If you can pull up the early version that we had before we maybe managed the last version, would be great. But that's okay. All right, so talking about back to the amyloid situation. So, cardiac amyloidosis, you can have up to 30, 35 different types of amyloid. It's very generic. It's just anything that deposits between the cells that is protein material in origin. This is amyloid. But for us, practically speaking, most of the patients have either light-chain amyloidosis or trans-diarrheic amyloidosis. We're gonna focus on trans-diarrheic amyloidosis for today's talks. Let's see. Do we have any slides on here? I can keep going, but... All right, nevermind. So, and when we talk about, you know, how we wanna diagnose these patients, I think, you know, clinical acune here, this is one of the, probably one of the diseases that you actually cannot try just on your imaging, on your biomarkers, on, you know, on AI, maybe, and trying to find out patients. You actually need to listen to patients, talk to them, understand their trajectory over time. Orthopedic manifestations of the disease include carpal tunnel, especially when bilateral and without traumatic injury or rheumatological disorder. When you have, essentially, spinal stenosis, back issues, all of these things are really important because you're gonna put them to context of temporality, and temporality in this disease is really, really important. And the second point is, you know, we have so many algorithms out there. I think if you don't see a lot of these patients, I think the takeaway message that you need to remember is you need to explain all the ventricular hypertrophy. It is structural heart disease, not any different from chest pain, not any different from having mitral regurgitation or if you have structural heart disease, like left ventricular hypertrophy, you need to explain. And that's your pathway, as, you know, if you're taking care of these patients as a cardiologist, that's your pathway. So, we have the lights up. So we already talked about this stuff. We're not gonna spend more time on it. And so, and it is a prevalent disease. That's why we're here tonight and talking about this. I think 10 years ago, very few people had been talking about MLO or TTR cardiomyopathy. But since then, we've figured out something. So this is a study by Omar Abouazidine from Mayo showing that, you know, it is an age-related condition, obviously, when you find it. So the more, you know, the longer you live, the more likely that you can have trans-uratine amyloidosis. But it's really interesting. If you undergo a systematic screening strategy, look at the difference in the numbers. They're fairly impressive. If you focus on group who's 80 to 89 or above 90, that's essentially, you know, doubling, tripling, even 10 times more if you do systematic screening compared to clinical diagnosis. And that's important. The second point is that, you know, the more you look, the more you find. These are some earlier studies that we've had, but I think they're still seminal and we should essentially show them and talk about them. The first one was inpatient admissions for heart failure with preserved ejection fraction. 13% had TTR amyloidosis. And what's really important in that study, that half of them were women. We always say that women is extremely rare to have TTR amyloidosis. I think we're uncovering slowly that it's not necessarily true. And then another study looked at half of patients with biopsy showing that you have essentially about 15% or so. And then finally with aortic stenosis, Adam Castagno and Matt Horner did this a long time ago. One of the first reports come out with showing 16% of patients referred for TAVR having a TTR amyloidosis as well. So this is the bottom line that many, many studies, I haven't included more. I stopped counting two year ago. I think there are four more studies showing all the same thing. The prevalence is between five and 10%. 15 is a little bit of a generic stenosis, I think. I think you're more closer to, you know, seven to 10% if you focus on the group that is 70 years of age or older. Now we did this study a while ago now. It's not published yet, but hopefully it will be sometime soon. It was last year showing, you know, using very large claims database, which the problem is that it cannot confirm any of the diagnosis. But, you know, we had very stringent criteria for evaluating patients, and we did many, many landmark analysis, you know, truncating essentially the follow-up, constituting you have to have six months before, and then, you know, a lot of follow-up after showing that if you have concurrent diagnosis of aortic stenosis and cardiac amyloidosis, you have higher risk essentially of death and heart failure hospitalization. When we did our own studies as, you know, it was multi-center, two-center studies, looked at patients referred for TAVR. We saw that there is no increased mortality, but there is increase in heart failure hospitalization. These were untreated patients with TTR amyloidosis. So it's really important to pick these patients. You're giving a valve that is, the valve itself is $25,000. Procedure is $75,000. If you don't treat their TTR amyloid, they have it. Not sure that they actually changed something or not. And so when you think about amyloid carpal tunnel, especially bilateral co-existence and explain neuropathy, yes, as a cardiologist, you should ask about neuropathy. And I think it's really important as part of care. Also think about autonomic dysfunction. It's really completely out of proportion to your cardiac phenotype. Explain all LVH and think about using strain if you have it available for you as well. Strain is not diagnostic. I think that's where we ask too much sometimes of the echocardiogram. And so strain is good screening and increases your specificity when you're thinking about amyloid. But you shouldn't necessarily use it solo as a sole means of saying someone have amyloid or doesn't have amyloid. This is also from Adam and Matt, which it's one of my favorite things ever. You don't need to do strain. You actually can just look at something that is found and because if you go back 20 years ago, which is the S wave, you're all used to E prime and A prime, which are measures of diastolic function. S wave is a measure of systolic function. It's how much your basal part of the LV is moving in. If you have an MI there before, you can't use it. If you have a mitral valve replacement there, you can't use it. But otherwise, the majority of people you can use it and it performs very, very well. There are now many scores trying to look at ATTR and AS. And to me, that doesn't make a lot of sense to actually score things all the time for everything. I think what makes sense is just to put things in a clinical context and understand that no matter how good you think you are, it's very hard to differentiate two conditions that cause somewhat close phenotype. So if you have someone with aortic stenosis and LVH, it's not gonna be easy if they have, if they fit the right clinical profile, it's not gonna be easy for you to say that they have TTR or not. You just simply, if you wanna try to do the right thing, I think you just simply think about it. You don't have to investigate it if you don't think it exists, but just think about it. That's where we need to go. And so this is from Mazhana and Sperry, who we're lucky to have both here today. 10% of biopsies on carpal tunnel surgery showed amyloid deposits. 2% had variant TR, 2% had cleg disease already, and 3% were in children therapy. So it's a good strategy. The problem is that we don't know what to do over time. And we're learning, and you're gonna see more papers downstream, but we need to figure out what we're doing over time because if you take 10,000 patients that have some deposits in the carpal tunnel, for example, released latinocyanovium, how many of them are gonna be positive 10 years later? How much are you gonna do from screening strategy? How much money are you gonna spend downstream? All these are really important questions. We talked about this before. This is really important. We have somewhat of a suboptimal to poor history in taking care of minorities and patients of color. And this is really a chance to try and correct this, at least in the amyloid phase, where we have significant burden of V122I, which is a very specific mutation that happens of patients of Western Afghan ancestry and Afro-Caribbeans. And so what happens is you have this single amino acid change that leads to destabilization of TTR. It's age-related, so don't think about it in someone who's 20 year old. We actually do see this now, which is opposite of what we want. We see 20 year olds coming because they have V122I from 23andMe, and they have some numbness somewhere. They're thinking they have amyloid. That's not necessarily true. There are rare cases of homozygous disease. It can present early, but those are rare. The more common ones are heterozygous disease. And this is a study that was done by one of our fellows, Pranav Chandrasekhar, tried to put everything together because the literature is extremely confusing. But we're not gonna go through it, but I just wanna show the bottom line. You have many, many, many patients in your communities who have heart failure and have V122I, ATTR amyloidosis. So next time you see a black patient who essentially has heart failure or who essentially is struggling with symptoms, think about this in the age-appropriate group. And then this is a reminder also from Mazana that a fourth of the patients don't have, actually, of black patients don't have V122I. So if we thought initially we're gonna be smart, we can actually just use a strategy of V122I screening in these patients. No, just like white people, they can get wild-type TR. So the strategy should, again, go back to clinical evaluation, clinical acumen, and then TR gene sequencing. And this is why this is important. Whatever study you like to cite and look at, the mortality of patients, of black patients, is much higher than the rest. And so you have to keep an eye on that as well, both men and women. So why do we need to recognize ATTR amylosis early? Look at this in ATTR Act, which is, two months ago it was the only randomized trial. Now we have two randomized clinical trials for amylosis. But look at MHA class three in terms of CV hospitalization, for example. You know, it's very clear to us that you need to find these patients earlier so that you can intervene early and make them live longer and have heart failure hospitalizations. This is ATRIBUTEM, which is Acromedus, another trial that showed us that it was positive and showed there is somewhat of a similar magnitude in terms of relative risk reduction. The absolute risk difference was 6.4. Mortality is much less. So if you think about the placebo arm in ATTRACT, it was 50% mortality at 33 months. Here you have essentially 25% mortality at 30 months. So either we're great at taking care of patients or something is changing. And it's a combination of increased awareness, early recognition, less time from diagnosis to putting someone on therapy, as well as more importantly, we actually are educating the community to look for this and try to recognize that this is a treatable disease as a subtype of heart failure and you should seek it out. This is a study that we have done many here in the audience as well as the panel, our participants. We looked at the real-world performance of tefamilus and we essentially show that it's somewhat overlapping with how tefamilus was doing the trial there. We're not, just because of time and we started late, we're not gonna go through details. But what we wanted to get at is in clinical trials, typical takeaway is that people will do better in trials than they do in real life because it's controlled settings, all that stuff. Here we show that at least based on our experience, patients are doing either as good as they did in the trial or potentially better if we continue to follow them up over time. Just a quick reference, there is a whole other world out there outside of cardiology, believe it or not. And we have here four trials for puloneuropathy associated with ATTR early doses. All four trials show the same thing. You have stability of your neuropathy score if you silence ATTR production from the liver, something we didn't talk about quickly. There are two strategies right now, silencing and stabilizing. Stabilizing, you bind the TTR tetanus and keep it from falling apart. Silencing, you go to the liver selectively and try to shut down the production of TTR, transthyretin amyloid, or transthyretin protein by 8% or so right now. There is gene editing coming down the pipe. There is anti-amyloid therapy coming down the pipe which removes amyloid from the tissues. But these are not established therapies as of yet. Only stabilization and silencing is established commercially at this point in time. This is data we showed yesterday. Even if you look at the cardiac phenotype within the puloneuropathy trial, this is just an example of neurotransform showing stability of the phenotype. So while we don't have a cardiac-specific trial with mortality so far using silencing approach, we actually have one trial of cardiomyopathy using 6-MIT walk test, which is Apollo B, Dr. Moore presented before, and other sub-studies from it. And then we have a couple other of these neuropathy trials that had involved patients with both neuropathy and cardiomyopathy. And so I'm gonna speed up just one more MIT for the sake of time. You have many, many tools of diagnosing patients. Bottom line is always do free light chain in the serum. You don't need the urine. Free light chains in the serum. You do immunofixation of the serum or immunotyping of the serum and then the urine. So if you don't have urine, it's okay. Go with the free light chains and the serum as well as the immunofixation serum, and then you can get that later on if you feel the need for it. That, combined with bone centigraphy, PYP, HMDP or HDP are available in the United States, DPD available outside of the United States. Don't forget there is something called endomyocardial biopsy. We thought we're gonna just get away with that. I think we still need it 5-10% of the time. And most of the cases that become case reports and become case presentation in conferences are because the cardiologist did not biopsy the heart. So keep that in mind. We have so many imaging tools. The bottom line is that you have to think about the disease to get to these imaging tools. And you need to be able to look at your pictures when you acquire them. If you are not familiar with MRI, get a friend who you like and they like you and you can take them to the pictures, for example, because there is extremely variability in the readouts in the community for these things, as well as actually academic centers. And then technician pyrophagy can be very difficult. This is SPECT-CT. You can't say if it's positive or negative. Nobody can tell you. We did HMDP because we thought we were smarter by doing HMDP. I thought it was positive. That's after studying it for an hour. Somebody else essentially thought it's negative and reported it as negative. I was convinced the patient had amyloidosis, so I biopsied him and it was positive. But these are the challenges that you see. Clinical evaluation is the most important part, I think, of this disease so far. And then Dia, Smiley, and Matt Moller also showed that a patient who was a biopsy-proven disease, negative PYD, was passed on this new tracer called ATO1 evazomatide. And then later reported a study of 10 patients who were negative on PYP that were positive on that. So PYP is not the end of it. If you have clinical suspicion, don't stop at PYP. And then we're not gonna go through this, but this is a study that we showed recently about different organ involvement using novel tracers and its relationship to ECV and whatnot. But I'll stop here and conclude that ATR-CM is common and is evolving rapidly. It's a treatable cause of heart failure, specific cause that you can treat. This is not very common in heart failure in general. Early diagnosis is paramount. Avoid misdiagnosis. Natural history of the disease is evolving, and there are new imaging agents, hopefully, will refine our diagnostic approach. Thank you. Thanks, that was fantastic. So I'm gonna be talking to you about current and emerging therapies and some best practices. These are my disclosures. So just in general, the management of these patients nicely highlighted by European Society guidelines. Atrial fibrillation is very common. We anticoagulate these patients irrespective of their CHADS test score. We heard about aortic stenosis. If you're gonna fix it, please do a TAVR. Try not to put these patients under a pump run. Conduction disease is quite common. There's some belief that these patients actually need a biventricular pacemaker, and there's studies potentially underway. It's rare that these patients need, actually, an ICD because they rarely pass away from a malignant ventricular arrhythmia. And most of us spend a lot of time in the bottom corner there in the heart failure realm, trying to control a volume status and using diuretics. And so we'll touch a little bit about that. This is a typical phenotype. You can see here is a patient who has actually no ventricular chamber, right? The ventricular capacitance is gone. The atrium are twice as big. And this is a patient who, as we call in the physiological world, progressed diastolic dysfunction. Their EDPR, or capacitance, shifts upward and to the left. The end diastolic volume goes down, the stroke volume goes down. If your stroke volume goes down, so does your cardiac output, and hence your blood pressure. And so these are patients who often need medicines removed or deprescribed at a certain point in time. These are data from our group looking at beta blockers in these patients, and ACE inhibitors, long-term studies. Not a large group of patients, pretty sick at the time with advanced cardiac amyloid, and they did not have a mortality benefit. Surprisingly, in this more advanced group of patients who were typically treated with high doses of Carvedilol when we first saw them, when we deprescribed or removed the beta blocker, you can see there was a greater than 50% reduction in mortality. So we're removing beta blockers in people who are pretty sick and are actually living longer, at least when we saw this. These data are a little bit, I think, now in the controversial world. I want to tell you that beta blockers are always bad. NAC has recently published data in over 2,300 individuals, which they showed similar to us that ACE inhibitors and ARBs have no mortality benefit. Beta blockers overall had no benefit, but low-dose beta blockers, basoprolol, two and a half milligrams or less, so pretty low dose, was associated in those in EF under 40% with a reduction in mortality. So something to be considered about completely deprescribing beta blockers. Brett has nicely shown in TopCat study that those who were given aldosterone antagonists, aldactone or spironolactone, had a similar clinical benefit when they had a phenotype that was consistent with amyloid. And the NAC paper showed that across all patients with a TDR amyloid, MRAs were rarely deprescribed or well-tolerated and were associated, irrespective of ejection fraction, with a 23 percent reduction in mortality. These are non-randomized data, propensity matched, but it's the best we have at this point in time. We know in these patients, as they progress, they develop a cardiorenal syndrome. Their CVP goes up, the stroke volume goes down, the blood pressure declines, they get worsening renal dysfunction, and we tend to escalate diuretics. These are data from a group showing that when you index the dose of a diuretic that they're receiving and you add it to various biomarker prognostic scores, it's quite predictive of events. Here you can see worsening survival with increased diuretics. So you would imagine with the emergence of SGLT2s, we may have a real important therapeutic role to play in these particular patients, but there's not a lot of data. These are data that we are trying to get published at this point, so these are hot off the press and under review. These are 87 patients in our cardiac amyloid program. You can see 80 years age, predominantly male, all who are on background stabilizer therapy or silencer-based treatments, elevated antiprobian P's, and we use both SGLT2s that are typically on the market at this point. So what happens to patients when they start this therapy? You can see pre, and then at baseline, what happens with their diuretic dose is their median dose of Lasix was 40 milligrams. It goes down by about 8 milligrams or 25 percent. Their weight also tends to decline over time, you can see, and their EGFR drops, like we saw in the HF trials, but then begins to recover, and is no longer clinically significant. These are not associated with big changes. We use these agents at least at six months' time with biomarker changes. We're showing here antiprobian P-troponin, hemoglobin A1C, but they markedly reduce uric acid, as we've seen in other populations. It looks like these are agents that, I think, are combating the diuretic resistance we see in this particular cohort. And so, up front, many of us, I think, are now using MRAs and SGLT2s in patients with TTR amyloid. As you heard, this field has undergone a revolution. It's many different trials, and it's kind of unbelievable. Every one we do seems to be positive, so let's hope we keep up. You know, there was the Tafamin polyneuropathy trial. People remember in 2011 that led to its approval for neuropathy in Europe. We had the ATTR ACT results, and then we have various other trials that are either completed or soon to be completed, and have been shown to be positive, and so I'll review some of that data. The biology of this disease, I think, many people are familiar with, but just to review, TTR is a tetrameric protein made on chromosome 18 in hepatocytes, also produced in the choroid plexus and the retinal epithelium, but a majority produced in the liver. The tetramer in the setting of aging or mutations can dissociate into monomers that can form amyloid fibrils, so you can silent or knock down the protein with either antisense or small interfering RNA, or maybe CRISPR, certainly knocks it down, but we don't know about clinical benefits. You can stabilize the protein with ephamidus, diclunasol, off-label, nonsteroidal, and now we know acromidus is effective, and then there's this very exciting arena of anti-amyloid therapies that we're moving to. These are the recent ACC consensus pathway document that was drafted by colleagues, and it basically highlights that the only available therapy for TTR is tefamidus currently, and that for a.l. amyloid, we recommend collaboration with a neurologist and a hematologist, excuse me, and often use of daratubumab up front. Tefamidus, as we know, is a class of agent developed by Jeff Kelley. It fits in the dimer-dimer interface you can see here, as the cartoon shows, stabilizing TTR, and led to rather dramatic and meaningful reductions in morbidity and mortality in patients with a number need to treat of about seven and a half patients to prevent one death of 30 months and an NNT of about four to prevent one hospitalization. The drug doesn't make people usually, on average, feel any better. At best, it may stabilize the condition or slow the progression, and these are the six-minute hallwalking ACCQ data from the original ATTRACT trial. This all leads to what we heard before, which is one of the key things in this field is to engage providers like yourself, think amyloid, and try to identify patients as early as possible. These are relative risk reductions. There are wide confidence intervals related to the small ends, but as you can see in ATTRACT, we have only 37 patients out of 441, less than 10 percent, who are NYHA class one, but a relative risk reduction in mortality of 64 percent, 39 percent for class two, and maybe 16 percent for class three. So, you know, these are the last ESC, if you will, guidelines. I've adjusted them because we now have…they're not updated. VitruScan is approved for polyneuropathy, varying in patients with or without cardiomyopathy. Most of us will use a stabilizer up front for pure cardiomyopathy patients. That's what it's approved for, and we weighed data and made approval for several other agents. So we'll review some of the emerging data. Here's the acromatase data that was widely successful. I'll show you Pitiseran, a small interfering RNA, in a one-year short-term pilot trial, not a phase three trial, met its primary endpoint and is key secondary. And we have VitruScan in Heliosi, Planitursin, and Cardiotransform, which is, wow, the largest trial we've ever conducted, more than 1,400 patients enrolled with real meaningful endpoints being assessed. And then we have the CRISPR therapies that are planning to move, we believe, into phase three next year. So, Attribute enrolled 421 patients in the active arm and 211 in the placebo. It was a two-to-one matching, very similar to TRACT with certain differences, but a pretty moderately affected population, predominantly men, NT-proBNPs of about 2,300, where there were 3,000 at TRACT, and you can see the rest of the variables there, with some concomitant to feminist use in this trial, because after 12 months of therapy, people drop in onto feminists. These are the comparisons between the two trials. Patrons are getting older, as you can see. We're not finding a lot more women, but we're doing a worse job at identifying minority patients engaged in clinical trials and variant patients. I think that's disappointing, and we need to focus our efforts. These patients in Attribute are less ill, which you can see, Class III heart failure going from 32 percent to 17 percent. So, we're identifying people earlier, and therefore, I think you can expect changes in the phenotype and the effect of therapies. Attribute on a hierarchical ransom, like we used in ATDR-ACT, this was a four-port hierarchy, one on the overall endpoint of the RIN ratio of 1.77, and highly statistically significant 58 percent of the wins were due to the first two endpoints, mortality and or morbidity in C hospitalizations. These are some other data that were presented by Julian at ESC. You can see NT-PRO-ENP rising much more rapidly in the placebo arm than those on acrominase. Six-minute hall walk, finally, by the end of the trial, their Part A endpoint that they didn't meet, showing a divergence, but it took a long time, KCCQ diverging, but slower than in the sick patients we saw in ATTRACT, and with these agents, basically, serum TTR rises, so it's a nice blood test to show a patient that there's target engagement and the drug's working, though we don't know that that's at all prognostic beyond the biomarkers. The hypothesis, we all know, I hope, behind small interfering RNA antisense and CRISPR shown here, you're making a protein that becomes unstable, deposits in the organ and causes the phenotype, and what you're trying to do is reduce the unstable circulating of tetramer and monomers, prevent organ deposition, hopefully stabilize, maybe even reverse the phenotype, though we haven't really seen that that much with these agents. The APOLLO-B trial, which we reported last year in Heidelberg, and we presented 24-month data here at this meeting, was a phased study, a randomized international double-blind comparing patisserin every three weeks to placebo. Up to 30% of patients could be on background tefamidus, and primary endpoint to this trial, which was only 12 months, done during COVID, was six-minute hallwalk, and the secondary specified was KZCQ. The trial met its primary endpoint, you can see here in kind of the purple color, the placebo group with a decline in their six-minute hallwalk, and the patisserin group staying relatively stable, and while it was statistically different, I would say the clinical effect is, you know, less than impressive, and only 15 meters. Having said all that, if this were to continue two years and three years in the same course, you'd certainly get some pretty meaningful effects. Similarly, the KZCQ was very stable in those patients on active therapy or patisserin and declined in those on placebo, with, again, a statistically significant difference, and I think a debatable clinically significant difference. Probably most impressive to me was that at 12 months, the echoes look a lot better in these particular patients, particularly stroke volume and end-diastolic volume cardiac output, and that's not something we saw in other large-scale clinical trials, even after 30 months, so it looks like these drugs are a little bit more active earlier. Then there's CRISPR, single IV infusion, basically a lipid nanoparticle to deliver this to the patasite inside the lipid nanoparticle. It's a TTR-specific guide in the CRISPR-Cas9 system, single infusion, stops production of TTR permanently, and leads to, in the published data, a pretty meaningful knockdown of serum TTR that's greater than 90 percent. Very exciting, and something I think that needs to be certainly thought of in pursuit. And then finally, the real, I think, mind-blow to me, I was at the ESC meeting when Pablo Garcia presented in the published papers, published in the New England Journal, is anti-amyloid therapies, and these really have taken hold. There are two for AL, and then there are two for TTR, and one that's for all forms. These are agents that are moving to Phase III clinical trials very, very rapidly. Alexion is planning a Phase III trial early next year, or later this year. One agent is, used to be called PRXO-4-biprothena, and now it's Novo Nordisk's compound. Again, all of these are usually immunized monoclonal antibodies. They find a particular epitope on TTR when it's misfolded that's not present on the intact tetramer, and through antibody-mediated phagocytosis, you can activate macrophages and lead to removal of amyloid from the affected organ. And these were the data that I was mentioning. Here you can see with scintigraphy, at four months only, there's a decline, 12 months, though I'm not sure what changes in scintigraphy mean. It may be in discussion. We can talk about that. But the extracellular changes on MRI were quite impressive over a very brief period of time, and these are absolute changes of upwards of 15 or 20 points in ECV. So you went from 45 to like back to 30. So I would just say that we are indebted to our base science colleagues, our people from pharmaceutical industry who we tend to pick on. I certainly do for the cost of drugs, but without them, we wouldn't be in this enviable position where I think, because we now understand the basic mechanisms underlying this disease, we've developed several therapies that are effective in a clinic. And there's likely to be many more therapies, and I think we're all going to be in this very enviable position of having several therapies, and that we'll have to try to choose amongst them in a lack of really good data, and sometimes be costly, but a good position for our patients to be in. So I thank you for your time and attention. Thank you. It really gives me great pleasure to introduce my colleague, Brett Sperry. He's going to give us some case presentations on best practices for recognizing, diagnosing, managing patients with cardiomyopathy due to amyloid and heart failure. Thanks, everyone. So everyone's done dinner, and we're going to fight the postprandial food coma. Some cases here. But I tried to pick some good cases. Maybe we can have some discussion about them. You know, and I tried to pick cases that were recent, although the third case I just added earlier today, and it's someone I'd seen for a long time. So again, I'm at St. Luke's, Mid-America in Kansas City, and here are my disclosures. So this is the first case. This is a 61-year-old black gentleman who was admitted for heart failure. He came in with 15 pounds of volume overload. His encephalopathy and troponin were a little elevated. He did not have carpal tunnel, bicep tendon rupture, spinal stenosis. He did have some tingling in his feet and in his hands. He had some constipation on review of systems. He had 12 siblings. No family history of heart failure in parents or siblings. And so, I mean, obviously, we're all thinking amyloid here because we're in an amyloid session, but this is a type of presentation that you see very commonly. And as Dr. Masri said, you know, you really need to think about amyloid. It has to be on the forefront of your brain in order to actually make the diagnosis in some of these patients. So you add the echo, and these images aren't moving here, but you can see how thick the LV walls are and all the different views here. Oftentimes, this gets thought of as hypertensive heart disease or renal failure, but certainly in this race, in this age, with this amount of LVH, you really need to think about amyloid and take the next step. So here are his initial, or his workout, basically. He had a kappa lambda. Kappa was 9.4. Lambda was 40.9. So lambda was only a little bit elevated, and as I say, the kappa was normal. The ratio was slightly abnormal. The way ours comes back is we get our kappa lambda back quickly, and then we get the immunofixation back a few days later. So immunofixations did end up showing a lambda IgG in a urine and in the serum, and he had a PYP scan that was done. I think the PYP scan came back first of all these things. It was done as an inpatient. And so I'm showing you three images here. So the top image is, and this is SPECT CT. The top image are non-attenuation correction images. The middle were the attenuation correction images, not attenuation correction, but I kind of scaled it up to be able to try to see anything that I could in the myocardium. And then the attenuation correction images, on the bottom, I scaled up. And so this is a difficult one. I would say that I think I do see the heart there, but it's very faint. If you look in the right short axis, you kind of see a little things that look like circles in all the images, but it's very, very faint. Certainly would not hang your hat on this as far as a very positive study. So we call this kind of grade one study. And given the abnormal kappa and lambda, we went on to, actually, he got a cardiac MRI here, and I think this was done afterwards, but I just put in here just so we see. And I know Dr. Masri is our MRI expert here, but the ejection fraction was 32%. The T1 time was elevated, the ECV was elevated, and you see the LGE images on the right there showing pretty diffuse late gadolinium enhancements. Clearly, something is going on here in the myocardium, and it definitely looks and smells like amyloid, but how do you figure out what type of amyloid it is? What type of amyloid it is? So I think we all sort of know where we're going here. If you're not sure what's going on, you need to get the actual tissues. This guy went for a heart biopsy and actually had AL amyloid. When I first saw him and I saw his echo, I thought he probably would have ATTR given his race and his age. But that's why you go through the pathway, and that's why you try to get to the bottom of things. His bone marrow showed 20% plasma cells, conga red negative. He had this T1114 translocation here. So we started him on, there's sort of a second part of this case, maybe for the first part. Any comments from you guys on this as far as differentiating between AL and ATTR and when to go for biopsy? Yeah, I mean I think you should know 70% of patients with light chain amyloid have lambda clones. So even if everything looks normal to you, but your kappa is not higher than your lambda, you should definitely be scrupulous about looking at that. There are these overcalls, kappa lambda abnormalities because of real insufficiency. But I would urge you all to be very, very suspicious when lambda is even in a normal range, but it's higher than your kappa. In this case, he also had a S-pi and a U-pi that were positive. So that should really, obviously you can get all these things as the Europeans say simultaneously, which is perfectly fine. But 25% of patients who have AL amyloid will have a false positive if you will PYP scan. So the algorithm is you have to exclude light chains and then use the PYP. Once you have a positive light chain, you're done with the PYP scan. You can't use it to distinguish which type you have and you have to go on to an endomyocardial biopsy. We used to biopsy everyone prior to 2000 in our data set. It's like 700, 500, 600, everyone before 2013. And now we biopsy about 18% of patients. So if you're not biopsying everyone in your center at all, then you're doing something probably incorrect, right? You do need to, I think, have access to some endomyocardial biopsy. There's no role in my opinion for MRI in distinguishing type of amyloids. You can do MRI to confirm that there's a phenotype there, but it's not going to tell you whether you have AL or TTR. There's no... You can do an MRI if you want. But in the diagnostic workup, I guess what I'm trying to say is to figure out which type of amyloid he has. Before we got to the biopsy, we should be thinking this gentleman needs a biopsy is my point. You need tissue somehow. To get a diagnosis of AL, you need tissue somehow. So you're either going to need conga red positive on a FATPAD biopsy or a bone marrow biopsy or the endomyocardium. But I think this is a great example of when you should be careful. If everything is paying out right, 50-year-old, young, everything's playing for AL, you can use imaging for correct involvement if your bone marrow looks consistent. But in someone who's for high risk for TTR, at the same time, you probably should not only use your bone marrow as the reason to call them to have AL. You should probably go to the endomyocardial biopsy. Demographics. There are very few patients of both. But as we begin to take care of more and more people, I don't want to confuse things. We are definitely seeing patients, particularly people who are males over the age of, say, 75 who can have both diseases. That's pretty unusual. Having seen 1,000 patients with cardiac amyloid, there's less than five that I've seen with that. I don't think that's the main message. But there are people who could have both. The main takeaway here is your leak chains are abnormal. You need tissue to figure out. You can't rely on PYP scanning. It should be taken out of your armamentarium for the diagnostic work. That's not the right role for PYP scanning. It's going to lead to a lot of consternation and false diagnoses. If you get it, it's OK. But don't be staring at it. Think to yourself, I need to move on to get a biopsy to figure out what type of amyloid this is because I need to treat the patient appropriately. Ultimately, in this case, if you call it grade 0, 1, or 2, you still need a biopsy of the heart. So just to kind of finish this case, this gentleman started on therapy. He tolerated it very well for a year without any recurrent heart failure. I saw him in the office for abdominal fullness and leg swelling. And his ZKD looked like this. Oftentimes, these patients have very low P wave voltages. And it's hard to tell what they have. But we thought this guy had atrial flutter. So the point of putting this part in here is just to kind of speak to the management of atrial arrhythmias in these types of patients. And we, at least, are really aggressive about this because this seems to be, in a lot of patients, it seems to be a real turning point in their history. We just transplanted a guy a month ago who was very sick but was holding on until he went to AFib. And he had a clot in his appendage. And we could not get him out of AFib. And he was just done. He just could not function anymore. So the gentleman had a lot of right-sided heart failure symptoms. He had a 5-liter paracentesis. We cardioverted him. And since we did not put him on antiarrhythmic therapy, actually, and I just saw him a month ago. And he's still fine now. I mean, he's lifting weights. And he's doing really well. And his kappa and lambda are low here. They reverse the ratio of the kappa lambda, which is always good. It's hard to know how aggressive to treat these people that start with a very low lambda level, a very low-affected light chain level. He's been treated now on daratumumab monotherapy and doing well. Our plan was to treat him for two years with this and then repeat his bone marrow and kind of go from there. But did his EF drop when he went into? It did, yes. Yeah. And then recovered afterwards. Yeah, that's, I mean, one of the differentials, I think, of people who drop their ejection fraction acutely with this disease, which does always happen, is an atrial arrhythmia. Whether that be the loss of atrial tic or more often, you know, faster ventricular response. And then the other thing that we learned, which I wouldn't encourage to pursue very hard, we don't know how to fix, is that a lot of microvascular disease in these patients, probably amyloid deposition. That's another reason why people can do in the setting of an atrial arrhythmia, drop their ejection fraction, which is a very bad sign. So the second case here, these last two cases are shorter. Yeah. Yeah, I think you're right. I mean I hope many of us here help write the guidelines. It's a little bit discordant I don't have I mean I think it's very imperative for everyone to know that you know The first and best test to order for someone with suspected amyloid no matter what's going on. It's a free light chain assay That's what you need to do is when someone calls me and says a PYP scan I'm like, what's their light chain assay and they're like I didn't do it I'm like do it, you know and in places where people are allowed including my center, you know Not in the amyloid program, but clinical we have a rate of only 40% We publish 44% of people order the light chains the Cleveland Clinic As if he's here is put in an or set you can't order a PYP in their system without getting the light chains It automatically pops up. So I completely agree with you There's some expedition. I don't have a problem with people doing both the same day But I don't have problem with an insurance company saying sorry, you know You can't order X because you know, you didn't do Y first and that may be helpful We definitely have to get that message out to everybody. I see errors on both sides of this, right? I see people who just order light chains and then they end there Right, and then there's people who just order PYPs and then they end there So the key is really that that this is a there are really two diseases here that we're worried about And you need to really evaluate If It's but if the light chains are normal, you know, you can't just end there. There's another type of disease here that you do to evaluate All right. So the second case, this is a 93 year old gentleman per nature fibrillation CKD Stage three came in with a fall and it's heart failure We have this hospital in home program where the patient can then go in their home and we can bring the hospital to them So he went into that program. His BNP was elevated his troponin was elevated His troponin was elevated and he's improved with some diuresis. Here's echo. I don't have to belabor this but You know clearly abnormal here You know that he he had increased wall fixed measurements So the point here that I'll make on the echo is for the echo readers in the audience I think getting a little clinical with the echo. It was Echo read is helpful, you know pointing people towards the diagnosis that they need to be cured With the amount of LVH. Here's his PYP images He had a free Kappa that was a mildly elevated and a free lambda that was kind of borderline But the ratio is okay given his CKD and there are ratios with respect to CKD, we're gonna have a Increase in the ratio and an increase in the capital relative to the lambda, which is still okay So and he had negative immune fixations. So You know this guy he's NAC stage 2. He's Columbia stage 3. He was on torcimide 60 twice a day, NYG class 3 He's 93. He has a recent fall walks with a walker you know Genetic testing and prescription. What do we think about this? I'll tell you I I did Order genetic I did approach genetic testing with him and his his family members and I gave me a strange look about doing this but at least my view is that you know and realistically, I think people who are in 90s are not gonna have not gonna have hereditary but I think Martha Grogan if someone says that they Should maybe old but their family members are not old and genetic testing is really free at this point so low barrier to get them tested and then and then Deprescribed treatment for for a patient like this. Who's how do you deal with patients who are kind of outside the trial trial data It's not easy, I mean, oh, I think you have to have conversation with the patient my experience no one doesn't want the therapy It's not toxic. I can recall we did the rollover for early access We had 148 people enrolled within like six months for two families. We have people lining up outside and there's only one person No, I claimed to him. You're not gonna feel any better But it may make things slow down and he said no, thanks, but most people offense in America don't say no Thing I made this statement a few days ago. I started a hundred three-year-old lady on to famineous People criticized me but she came to clinic I don't know why in clinic they give the patient the name in the room And she came to the room and she said to me my name is Helene not Helen they left off an E so she's pretty functional 103 years of age that she could see the piece of paper and you know, so No, she's not gonna get better but it may slow what That true and that's what That's a good question. That's what you have to you're completely right I think I think you have to counsel the patient about the reality of what you're offering them and Then let them make a decision in concert with everyone. I'm pushing if she said, oh, you'd be perfectly fine by me Yeah It actually the class three patients It took five years almost the paper the date is published in one term extension It's actually a pretty statistically significant even survival benefit, but you have to wait on time But to your excellent point, you have to be able to live that long. So Yeah, I don't I agree with you in that regard Cleveland Clinic had a Retrospective observational study and the patients above 90 and You know some people benefit and if it and they they stay, you know And then the second thing to remember from the track is that it's not just a mortality You look at heart failure hospitalization granted not class three necessarily, but six-minute walk test KCCQ Not quality of life. It's earlier than one and a half years much earlier within the first year And so I'm just individualized I think at this point in time And just what we have a sec because this is relevant. Someone asked a question. What's expected increase in life and with Stabilizers my experience is it literally is double people survival So we had people who were basically, you know Dad at two and a half or three years and now people are living at least five not seven years on average So, you know, these are you know Challenging and to expense therapies in that regard not toxic, but they're not talking about an extra week or two of life We're talking about pretty long Slide actually was slide on this. It's published. You can look it up Rosenbaum if she was in fact We looked at mark of modeling and looked at that and you can see for in my check last one, too It's very different from three so you can take a look at that All right, I'll do do one more here This is very quick. So this is a 60 year old black gentleman Initially diagnosed with hypertensive heart disease came to the hospital with a thin RVR There's a suspicion for amyloid his PYP was positive tested for plasma cell disorders negative v122i on genetic testing This was before to feminists was available. So he was started on all the things green tea extracts turmeric Dexacycline diphenyl is all Famous was approved but there were issues getting it and in the first several months since when I saw him He decided to stand above therapy Feeling really minimal to no symptoms very active guy former police officer He eventually transitioned to to finish when he became hypertensive Probably related to the type lunisol and were aware of some numbness his fingers in his toes. And so You know, what do you what do you think about this type of case? You know, he's has numbness in his fingers and toes. He has v122i Do we refer someone like this in neurology? Do we refer everyone with hereditary to neurology no matter what? Does v122i have polyneuropathy associated with it and What are the thoughts there? I think that's challenge. So the first question is yes, I think everybody with You know variant disease that is not v122i Necessarily should go to Neurology for your v122i who only have cardiac symptoms nothing else whatsoever I think there are way too many of them to line up at the neurologist office given their very very long with time So you might just like, you know use some discretion there but I think honestly everybody who has a potentially neuropathic mutation should get You know annual or once every you know year and a half or so, you know visit to the neurologist office In terms of Does v122i have polyneuropathy? You know, everybody have seen patients with neuropathy with v122i. The challenge is that you know, it's hard to prove causality there and You know, sometimes you have idiopathic neuropathy You have to assume that it's related to transtheiritis, but the reality is when you're dealing with patients above the age of 70 It's it's very hard to to to to say for a fact that this is related You know but I think we're at a point in time where we have to give the benefit of the doubt to the patient and Be on the patient side and if you can't find the other reasons for someone to having polyneuropathy You might want to treat them as such My clinical experiences complaints the hands are often due to carpal tunnel localized disease things in the feet are usually not and so toes bother me many of the patients who have Neuropathy often have autonomic dysfunction And so we've gotten to use a compass screening questionnaire and we tend to identify a word of people who you know Might to your point might benefit from referral to a neurologist Depends how old they are, so, you know, if they're 20, I'm not seeing them again for, you know, 30 years, probably, because, you know, men don't dial up the disease until at least usually 50. Women over 60, it's what penetrates, it's an age-dependent penetrance. We think penetrances probably have been under-reported in the literature. I can tell you there's a famous paper in the New England Journal that said echocardiographic penetrance is 8%. We have a screen study where, by PYP, it's, you know, 40%, and I bet, by these agents, it's going to be 80%, right? I mean, I think the disease does show up, and there's no way it can't show up, because every large study, epidemiologically, would suggest it's an independent risk factor for heart failure and mortality. So, even if your echo or your PYP isn't showing it, something's going on that's causing these people to, you know, exit the world more frequently. I think it's much more penetrant than we think. We have no idea how often to screen them, but I would say, you know, more frequently, the closer they get to an age of onset. You know, in general, I would say, you know, every 3 to 5 years is reasonable, assuming they're not having any symptoms. I often offer these patients... Yeah, I often offer patients with variant carriers who don't have any phenotype but are worried, I offer them diflunasol if they don't have significant symptoms, right? They can take it, and it may actually prevent disease. There may be some prevention trials that are coming soon, too, for these particular patients, but, like Brett was mentioning, or Ahmed was, you know, the person who's 23 years old, who's considered 23, and me beckon people, are like, oh, they could have amyloid in the answer. No, they don't. I mean, like, that's not when amyloid shows up. Related to all this, someone asked about carpal tunnel patients. Your surgeon took out a little tissue and found it. Yeah, that's a great question. It's a perfect corollary to the prior question. So, you have someone who has carpal tunnel that has tenosynovium that's positive for amyloid. Congo Red is positive, and let's say it's hereditary. So, if it's hereditary, then I think we kind of take those a little bit more seriously, and, you know, you're not supposed to have amyloid depositing in parts of your body. So, that seems to progress a little bit faster, at least in our studies that we've done. So, same type of idea, right? As they're getting closer to their age when they may start getting it in their heart, and if it's in the carpal tunnel, then it's probably, you know, they're probably getting close to that age. Then you want to screen them with PYP scans every so often. It's not clear how often that is, but my practice has been about every three to five years, same, and probably every three years if they're hereditary. If they're wild-type, same concept. I mean, we're doing these carpal tunnel biopsies only in people of a certain age, so they're not getting them if they're 20 years old or 30 years old or something like that. So, I've been seeing them back, you know, every one to three years, depending upon if they have other cardiac issues, and scanning them with PYP every few years. One bit of data that I think helps inform this is we published a paper with a Danish group in which they have, you know, in these countries, national data sets. They took, you know, over a thousand patients who had bilateral carpal tunnel releases. They had them five to 15 years earlier. That's when the disease percolates, you know, and develops later. And so, if you were a man over 70 who was not fat, BMI was less than 30, one in four, one in five had a positive PYP. So, the other question patients ask is, well, what's the chances this is going to show up? Right? And we don't know. Probably the longer you live, the greater the chance. But it's probably not, you know, a guarantee that you had it in your carpal tunnel. It's probably somewhere in the, I would bet, 25% or 30% range. And that informs the discussion about should you take diflunasol, you know, every day. If you're 40, I don't want to give you diflunasol until the time you're 70, because I think that's a lot of therapy for, you know, nothing that's really manifest at this point in time. But there's not a lot of good data to drive these decisions. Now, in my clinic experience, almost no one with amyloid is fat. But I live in the northeast. So, we published data that said if your BMI is over 30, your negative predictive value for having amyloid was 98%. But my colleagues in the Midwest tell me I'm wrong. We have some larger patients with amyloid, yeah. But your point is entirely right. I mean, the negative predictive value is high. If you have someone who's very obese, you know, it's going to be pretty unlikely that they have it. It's not impossible, right? Yeah, if they came from Florida on tefamidus with a positive PYP skin, it's a grade 2 for a year for second opinion. And they weigh, you know, BMI 36. My tentacles are up, and I'm getting them a repeat PYP skin, and I can count lots of people who had, you know, false positive blood pools and put on tefamidus and didn't have disease. And that's a clinical clue. Hef-pef is obesity, metabolic inflammatory phenotype. And this disease, I don't know exactly why, but not associated with usually a very big weight. You know, people lose weight. Yeah. I would want to get them, I would want to really prove that they're asymptomatic, you know, put them on a treadmill, do a six-minute walk, do anti-proBNP, intraponin, these types of things, really, really try to prove that they're asymptomatic. You need to have symptoms to get to at least the inclusion criteria in the studies, but I would really try hard to prove that they're truly asymptomatic. It's in the heart, I mean, we know the progression of what's happening, right? So eventually they're going to get symptoms. If you have a positive EYP scan and your anti-proBNP is 200 and some insurance company tells you that they can't get stabilizer, that doesn't make sense to me because we're telling everyone to find people early, so congrats to you who found them early. And we published a paper about those patients, you can cite it, it's a multinational collaboration, but over three years, those people who didn't meet the BNP cutoff, they developed pretty significant worsening heart failure, for pacemakers, bad things happen to them. So you can probably pull that paper out, probably got to write a pre-cert or whatever you do, but you can advocate. And if you can get a decline response, if they qualify for income-based assistance, they can get free drug from the manufacturer or sponsor, that's one. The second thing is, if somebody cannot get to families afforded, we do diathlonasal or clinical trials. So we don't have a single patient who is not treated for the last three and a half, four years. I mean, it depends what you cite as, you know, meaningful yield, AFib has been shown, you published, not to be that great a yield, my sense, but... Yeah, we looked at that and we did two stages of screening, 1.2 centimeter and 1.4 with some other, you know, richer, and it's not a great strategy for AFib only. The fellow was supposed to do the next step, which is AFib and heart failure and, you know, thickness, but they decided that it's too much work. So we didn't end up doing it, but the two phases we did, using AFib as a screening strategy is not a good idea. And I also think that, you know, we can't screen everybody, I mean, the fast-growing segment worldwide populations over the age of 80s, I think we have to have some of these risk factors and so forth. The other thing I would just point out is I'm a little worried. PYP has a pretty low sensitivity, even the seminal studies that we published, the sensitivity is 70%. So one thing I'm starting to get afraid of, and that's in a population in which they were seen in amyloid centers and 50% had amyloid. So if a test can't find the disease when half the people had amyloid, imagine what's going to happen when you have prevalence of 2, 3, 5%. And PYP is not going to be the standard way I predict in five years we're making this diagnosis. We're going to have to do a little bit more MR, and we're going to have to, I think, get better pet agents or something else, which I thought was too much money, but if we're going to spend $2,000 or $3,000, $100,000 on the drug, we can spend a few grand getting a pet scan to make sure they have the disease. Do you want to tell us what the patient is? Oh, yeah, sure. Yeah. So the patient was referred to a neurologist, a nerve conduction study, which did show lower extremity axonal sensory polyneuropathy, and so we actually were able to add silencer therapy here. And this is like a whole other talk that could be a whole other hour, but the end part of this is, is this the appropriate thing to do, how do you differentiate between mononeuropathy from a compression, entrapment-type carpal tunnel versus a more dense polyneuropathy? And a lot of questions through this, and I think a mononeuropathy is not a polyneuropathy, and these agents are approved for polyneuropathy, so I think it just highlights the importance of getting them to a neurologist and getting a real expert opinion on what exactly do they have as their diagnosis. Any final questions from? I'll let you go. Thank you all for attending, and wrap it up. Thank you.

amyloid cardiomyopathy

heart failure patients

ATR-CM

clinical evaluation

imaging tools

minority populations

TTR stabilization

tafamadis

CRISPR

emerging therapies