 Thank you again for coming out to this inaugural ASU cardiac amylidosis update. I think it's really a testament to all of you as well as the individuals who organize this event. Dr. Chris Vijay, Dr. Sandesh Chev and Janice Guzman for putting on such a spectacular event. I have this distinct honor and privilege of presenting our keynote speaker who I believe really does not need any introduction but here is Dr. Matt Maurer. For those of you who have paid attention this morning, you would see that there's not an amyloid project that Dr. Maurer hasn't touched over the last several decades. And it's really a pleasure and honor to share this stage with him today. He's someone that I look up to as I'm sure many of you in the audience do. So with that, Dr. Maurer. So it's really great to be with everyone and give this address. I say I'm really excited about everything that's happening in amyloidosis, but we do have a lot more work to get done. I'll try to highlight that and I have support from lots of places including your government. So I just wanted to recognize Claudio Rapetzi who was the co-chair of the ATTRAC study with me who unfortunately passed away suddenly. He was a lovely man, very curious, a real master of medicine, credited with a paper in 2005 in Jack using dbd scintigraphy. And if those of you knew him, he had what we call Rapetziism, these ways of kind of making associations that were kind of unbelievable. So a great loss for the community. There he is presenting the ATTRAC data at the ESC in 2018. So this is a disease that's undergone a transformation in a very short period of time. We've gone from what we thought was rare to one that's pretty common, one that required an invasive endomyocardial biopsy to one that you can diagnose with scintigraphy to one in which we had no treatments to one in which we'll have a plethora. And so with that background, this is a patient that we saw at Columbia with one of our fellows who became interested in amyloid at the time. It's really a typical unfortunate case of a 62-year-old African-American gentleman who had acute decompensated heart failure, had bad hypertension and aortic dissection, and then had multiple admissions we heard from one of our hospitals earlier. Later on he had a phenotype with a pretty low blood pressure, orthostatic, as you can see, he had an increased wall thickness, no aortic stenosis even at RVH, and someone had done light chains on him and they were abnormal. These are in milligrams per deciliter, his Lambda is 29, his CAP is normal. He has elevated troponin in BNP and they order a PYP scan, which literally makes no sense because once you know that they have light chains that are abnormal, a PYP won't help you. And basically we met him, you can see the timing here, and many, many years after all these tests were done and within about a few days of our evaluating making a diagnosis he unfortunately passed away. And here's a patient who I actually, one of my first cases, this was a 62-year-old gentleman, a progressive shortness of breath for two years. He had what people thought was a silent MI because his EKG showed pseudo-infarcts. He initially had AFib that became persistent after a few paroxysmal bouts and he had a cath to evaluate for coronary disease, didn't have much, but he had an elevated LVEDP. No one seemed to notice that. They gave him ACE inhibitors, beta blockers and diuretics. He told all the doctors he felt absolutely miserable, no one seemed to care. And basically had an echo with increased wall thickness and a preserved ejection fraction. Actually progressed to develop big right pleural effusion that they tapped, thinking it might be malignant. And two years later now he's in persistent AFib, his EF has declined and he gets crazily an avianode ablation and a bivipace maker. And so this was a guy seen by one of my bosses, Mil Packer, and he called me and said, I don't know, everyone I thought who had HEFPEF is an elderly woman with hypertension. And I got this guy who's, in my mind, middle age. He's only in the 60s. He's a man and he's got low blood pressure. And if any of you know Milton, he could really kind of summarize some key clues to things pretty quickly. This is the guy's EKG. For those of you who can't see, it's got atrial fibrillation, diffuse low voltage, not only in the limb leads, but pre-cordial and pseudo-infarct pattern with poor pre-cordial alloy progression. And this was his echocardiogram at the time we were seeing him. So he's got wall thickness like 25 millimeters. He's got no LV chamber capacitance. His endiastolic volume is non-existent. His atrium are like twice the size of his ventricle. And this was years ago, so we didn't have PYP. We're talking, you know, 2000 and two or three. So we did a right heart cath and a biopsy. These were his filling pressures, which are high. I just point out he has no stroke volume, right? So if he has no stroke volume, even though he's tachycardic, you can see his cardiac index is 0.97, right? You know, and that's why his blood pressure is low, because blood pressure is determined by both flow and resistance. So if you have no flow out of your heart, you're going to have a low blood pressure. And we did an endiocardial biopsy as we heard a relatively safe procedure, especially in amyloid. And you'd see pathology like this, with a diffuse hyaline material that stains a bipolarized microscopy, congo red. And if you're really stuck, you can kind of do EM on the bottom right to look at the amyloid fibrils. So this is two cases that I wish I could tell you are rare, but they're not. And these are data from Isabelle Lusada, who runs the amyloid research consortium. And she surveyed patients, and this is what they said. I had to wait a long time. I had to see lots of doctors. And unfortunately, the provider that misses the diagnosis most often is a cardiologist, who basically say these patients often have hypertrophic cardiomyopathy. So we've heard this morning, but just to remind you, amyloid is a disorder when systemic that is characterized by extracellular deposits of a protein. These proteins form fibrils. The proteins get stuck in the organ. They make the organ not work. And there are, as we heard, dozens of proteins that can form amyloid in various organs in vivo. But as I like to jokingly say, but probably not untrue, cardiologists are not the brightest folks in the, I don't know, the brightest tools. So we only need to know two types of amyloid, really. AL and TTR, as we saw. And TTR comes as either variant or wild type, which for some reason we used to call senile cardiac amyloid or age-related. And again, the key here is to make sure you distinguish these two disorders that they differ not only in the biology and the precursor protein, but in their outcomes, the prognosis, the genetics, and most importantly, how we treat them. So just to highlight, AL is a disorder of the plasma cell. It affects people of all ages, but I just has an equal male-to-female distribution I was mentioning to someone earlier. If someone calls you with a case on the phone, it's a 40-year-old woman who has amyloid, right? It's AL amyloid, until proven otherwise. Epidemiology does matter. It's affected in two-thirds of the time. The kidney, two-thirds. So there's a lot of multi-systemic involvement. And this is the disorder we saw, the survival curves, where mortality is very, very bad, especially with advanced disease. All the way to the right is wild-type TTR, a disorder to date of older adult men, probably underdiagnosed in women, all of these orthopedic manifestations. And we have, as we heard, stabilizer therapy, though probably silencer therapy will work here, too. And then we have hereditary or variant disease. There are 130 different variants in the TTR protein. So the phenotype is very dependent upon which mutation you have. But it seems to like, as we heard, the heart and the nervous system, as well as sometimes ligaments. And here we have advantages of silencers and stabilizers. So these are our reasons, and these are five ways to avoid missing the diagnosis of a cardiac amyloid. So we'll go through each of these. First is you've got to think about it to diagnose it, and it should be included in your differential. So this is a really famous article by a famous educator named David Eddy. It's really great if you've never read it. In the New England Journal, he analyzed the pathological conferences in the New England Journal. If you read them every week, there's a case. And he analyzed, you know, 50 of them, and he came up with certain conclusions, one of which was he said this was fallacious. I don't know how many to do, but more often the diagnosis was correct from someone from Harvard, and they heard it in the hallway. But it's kind of embarrassing to do one of these cases in the New England Journal to actually get it wrong. And when people got it wrong, which happened, the problem was that they didn't follow what he thought were these main six steps to, you know, basically making a diagnosis. You listen to the, you know, chief concern or complaint. That gives you a pivot, and you generate a list of causes, and then you kind of hypothesis test. And the key he said was when you have a very short differential. You're in the room, it's a thick walled heart, and it's hypertensive heart disease, and you're done. You didn't create a long enough differential. So I urge you to put amyloid on your differential. Second is there's misconceptions. So we think it's rare, and we think we got some good screening tests, and we don't. So this is the impression of most providers who are looking for a needle in a haystack, and these are the data we heard today, right? 16% of patients undergoing a TAVR have amyloid. 13% of patients with heart failure and a preserved DF and an increased wall thickness. 6% of HEF-PEF patients in the community, 5% overall of HCM patients, but if you're over 60, one in four, and I like to jokingly say if you walk out on Broadway and just scan someone who's 75 or above, we just saw it was one or 2% of older adults going to be asymptomatic but have it. So this is not going to turn out to be a rare condition at all, even though Tephamidus got approved under the FDA designation of a rare disease. So these are the data. I don't want to rush too quickly. So this is AL amyloid. It's a disease that affects one person in 100,000 or 10 per million, so you can do the math. There are about 3,000 to 5,000 new cases in the U.S. Even if they all live 10 years, they don't. You know, there's not going to be a lot of cases. This is definitely a rare disease by every designation. Variant TTR is not that rare. We heard 3.4 to 4% of African-Americans carry a variant depending upon if they live to be the age of 60. There's estimates that there are 25,000 to 120,000 African-Americans who have variant TTR, and that's not included in the other mutations we heard about. So I would say not so rare. And wild-type disease is just going to explode because the fastest-growing segment in the worldwide population are people over the age of 80. So definitely not rare, I think. I always ask people which patient has amyloid. Who says the red EKG? Just raise your hand. No one put their hand up. Dr. Steadley did. And who says the green EKG? And most people, and the answer is both of these people, have amyloid biopsy proven. So we taught people that low voltage is something to look for, and it is, but it's a very late-phase phenomenon. If you want to identify amyloid with someone as two feet in a grave, that's when you look for low voltage. But as you can see here in 210 biopsy proven amyloid patients, low voltage is prevalent in less than a third. So it's not very sensitive. Much more sensitive is pseudo-infarcts, looking formally at the voltage criteria or doing what we ask all clinicians to do, which is look at the EKG and integrate it with the wall thickness on the echo. So this is Christina Cuerto, who's a famous amyloidologist, PhD thesis with Claudio in Bologna. They took 1,000 patients and they quickly, a third of them had HCM, a third had hypertensive heart disease, a third have amyloid. Basically, if you look at all 12 leads of the EKG, usually every lead has 10 millivolts. So it's pretty simple, it's 120 millivolts. And if you divide that by a normal wall thickness, that is a number of 12, right? If you add up all 12 leads and divide it by the wall thickness of 17, and it becomes seven or six or eight, anything below those cut points are basically amyloids. So this is a very simple way. And as you can see, low voltage, not very sensitive but specific, increased wall thickness, very sensitive, but not specific could be anything, but the two together are much, much better. The other thing I would just note is that AL amyloid can be diagnosed by a fat pad as we heard, but if you have a clinical suspicion for AL and the fat pad's negative, you can't stop there. You need to go on because the sensitivity, while we talk about it being 70 or 80%, is nowhere near good enough for a life-threatening disease. And so, fat pad biopsy negative, you think something's going on, gotta keep working them up. You should know about the clinical clues. We heard about them all this morning, but once you know these clinical clues, it's really easy to make this diagnosis because there are a lot of them for a prepared clinician. So we talked about this, but this is a disease of heff-paff usually without, and it's later stages hypertension, typically in men. You can see pressure volume loops to the upper right. For those of you who don't remember, this is how we study physiology, but we are increasing the EDPVR and upward shifting it. And what happens then is the endiastolic volume goes down, and so does the stroke volume. So your EF stays the same because the numerator and denominator are both going down, so the EF is preserved. But the cardiac output, as you can see in the black line, goes down, and what happens to their blood pressure? It goes down over time. So you're removing anti-iprotensives. They're getting on less and less medications. These are patients who will always have an elevated JVP and right heart failure. As I said, I'll show you some data that don't like ACE inhibitors or beta blockers. If you're looking for a big tongue and periorbital purpura shown here, for TTR you're never going to find it. It doesn't exist. It exists in AL amyloid. But for TTR, as we heard, there are lots of orthopedic clues. So we know about bilateral carpal tunnel syndrome. This is lumbar spinal stenosis. I call it carpal tunnel of the spine. I'll show you data about a third of patients with TTR have it. This is the famous Popeye sign, so you can look like Dr. House with the residents. If someone has a biceps tendon rupture and their biceps muscle looks like that and they have a thick walled heart, you don't even need to do a PYP scan. Literally, it's diagnostic. You should do it and you will do it, but you could look pretty erudite on rounds. These are the data I was mentioning before that we recently published with Mazhana in which the big new news here is 83% of wild-type patients have an orthopedic manifestation and in addition to hip and knee replacement, shoulder surgery and shoulder issues are very common in these individuals. And you can see the hazard ratios, there are odds ratios compared to population-based samples, much, much higher for knee, hip, and shoulder arthroplasty. Most of us unfortunately don't diagnose things by history anymore or physical exam. Unfortunately, we wait to the image and so if you're waiting for that, which is fine, there are also lots of clues which we'll run through. So these are the still frame echo images that we are all looking for. So there's increased wall thickness, always usually in amyloid. It's not symmetric, by the way. By MRI, it's symmetric in 17% of the patients. So just because it's asymmetric doesn't mean it's not amyloid. They have, as we heard, a thickened intraatrial septum. They have valvular thickening. Their atrium get big. Early on, they have diastolic dysfunction, but if you miss the boat, like in our patients, they'll end up with a low ejection fraction. So that's clearly a late phase phenomenon of the fusions. MRIs are very useful. This is what I used to call the peak in the squeak test. A colleague in New Jersey followed someone with a myopathy for years. They didn't know what it was. They got an MRI. It showed a relatively preserved LV systolic function and diffused enhancement at the bottom. It said, think amyloid and they went, and they referred them off to the amyloid center in part because they were unsure what to do and also a little embarrassed to sort it out sooner. So this has become a source of referrals. This is the apical sparing we heard about. Highly sensitive and not so specific. You can see this in chronic kidney disease and hypertension, but quite useful, which lead to the apical sparing. So lots of clinical clues. And you should really understand the nonbiopsy diagnostic approach because that's critical, but there are a few pitfalls and we're seeing this more and more often as awareness goes up. So again, endomyocardial biopsy is not a bad test. It's really hard to do the worst thing in an endomyocardial biopsy which is perforate someone when they have amyloid, right? It's a thick-walled heart. So if you're ever in doubt, I'm sure my colleagues who are nodding their head who do this all the time agree this is a pretty low-risk procedure. These are our data that people highlighted previously looking at PYP scintigraphy. We wanted to use DVD. It's not available in the U.S. It's actually not true that the only isotope is PYP. We learned during the sourcing pandemic issues that HMDP is available in the United States and can be used. And those of us who knew that kept doing scans and those who didn't were like, oh my God, what are we going to do? So both are fine. MDP is not fine and doesn't work, so don't use MDP. And this is how these scans are graded, right? One is uptake less than the heart. Two's and three's are positive, but the bottom line is you can't use planar imaging anymore. You must, must, must do spec imaging, right? You have to know that the uptake that you see on the X-ray, the planar imaging is actually inside the myocardium because it could not be. It could be, as we heard, blood pool. And so these are the current, you know, diagnostic criteria and I highlight the important things here. You can make this diagnosis noninvasively with the MDP scan if they have a phenotype that's consistent with amyloid, right? Don't scan someone whose EF is 10 with an 8 centimeter ventricle and a thin walled heart. That's not amyloid. That's not what it looks like. It doesn't have amyloid that way, right? So you should have a phenotype that you're suggestive or they should be a variant carrier, right? You must obtain monoclonal proteins. You can't order a scan without ordering the monoclonal proteins. If you do and you do it without monoclonal proteins, you're committing malpractice and I jokingly say to people, I will now testify against you, right? Because it is malpractice, right? You can't interpret the test. If the monoclonal proteins are positive, you can't use the PYP. You need to go on as we heard the biopsy. And you have to have grade 2 uptake, but you need a spec scan. So we tried to highlight some of these errors in a paper in Jack. Maz Hanna led the charge here with Amartha, Grogan and others. This person has AL amyloid. Turns out 25% of patients with AL amyloid are going to have a positive PYP scan. That's why you need to get monoclonal proteins. Then there's, and this Venn Diagram is the embarrassing one from Columbia that we published. These are people who came for our center for clinical testing and you can see how many got all three of the appropriate tests in the middle, only 40%, right? So doctors are ordering PYP and not ordering the monoclonal proteins. Second one is, I just highlighted here, there is a grade 2 scan, but when you do spec imaging, what do you see? The isotope is inside the chamber. This is not in the myocardium. This is a false positive PYP scan. And then if you do this long enough, you will run into some unusual mutations or variants that don't uptake PYP. So this is a paper we published about PYP use at our center. Now we're up to like 300, 400 scans a year. As Dr. McPhail was saying, we don't need to do a lot of biopsies. It's under 10% of the time that we need to do a biopsy for a patient and it's a pretty good test I would just point out because about a third of patients you can see in the line are positive. So what tests do you do in medicine where 30% of the time you're making a clinical diagnosis? It's not perfect though. So people who had grade 2 scans when we used spec as the quote unquote gold standard, 64% of them were blood pool, not positive scans, right? Not positive. In the community we're seeing a lot more of this planar imaging people getting on tofamidus and they don't need tofamidus. It turns out the overall false positive rate is almost 10%. So screening is great but you'll see screening could be associated with some problems. So this is what I call the amyloid cascade. For decades we were kind of all the way up here looking at symptoms and the EKG and low voltage. We used the echo once in a while but now we have techniques that are a lot more sensitive. In fact we have a lot of people who have a low wall thickness and a positive PYP scan and you would really identify someone who's asymptomatic and early in the course of the illness. So these are very busy, I apologize, but this just shows you how much PYP enables in earlier diagnosis. Everything about the patient tested in our lab with PYP versus biopsy is better. New York car class biomarkers are low or all of their staging systems are better. Blood pressure is higher, stroke volume is higher. PYP scanning is doing anything interventionally. It's just you're finding people in an earlier stage of disease which is where we need to find them to leverage therapies. For those of you who don't know, there's a fantastic paper by the London group in 20 years, like 2,000 patients and they showed this unequivocally. Why? Because defaminus is not available in the UK because it's too much money. They didn't pay for it. You are, like all things, the greater your mortality per year. If you have variant disease, you tend to do a little bit worse. But you can see, if you're diagnosed by PYP, you have a lower mortality and stabilizer therapy is in this multivariate model still highly effective. So all of these things are leading to much better outcomes. So the algorithms, I'm never a big fan of algorithms. I quote Joe Alpert from Arizona, the editor of the Green Journal said, if you don't have a monoclonal protein, you don't have a monoclonal protein. You don't have a monoclonal protein between every algorithm and a patient needs to be a provider with a brain. Make sure that you know what you're doing because every algorithm, if you follow it blindly, could lead to problems. But this is pretty simple, right? You basically, you know, check for monoclonal proteins, do a PYP scan and do genetic testing. And that doesn't go down the other pathway. And then, you know, I think we really want to, as we've been talking about today, figure out ways. I give you credit at this meeting because it's one of the first to think about what I call active ascertainment. I'm not so sure this is screening because people have this disease, per se, but maybe it is. And all these therapies work better when they're started earlier. So, sorry, this is the landmark defamitus paper we heard from Dr. Rosenthal about how it works. It binds in the dimer-dimer interface. You can see here, and it prevents the protein from dissociating really an unbelievably effective, well-tolerated drug. Unfortunately, it costs too much. But this is probably the most important unpublished data from the trial. So, in the trial, there were 37. So, 441 people in the trial, 37 with NYHA Class 1, less than 10%, right? And they had the confidence intervals in this example are wide, but just look at the point. They had a 64% reduction in mortality. Whereas those with Class 2 had a 39% reduction in mortality, and those with Class 3 only had a 16%. So, very clear evidence that if you start this drug earlier, I mean, where else do you see more than a 50% reduction in mortality, right? I mean, like, kind of amazing. And so, this success of the ATTR act trial has led to, as you can see, over the timeline here, just the plethora, as we heard about, of new therapies that are coming down the pipeline. So, what can we do for screening? This is one of the first papers we got interested in with Adam Castano. This is what we called the unveil study, in which we took consecutive patients undergoing a TAVR. And we found out that a 16% overall had amyloid, and 22% of men had amyloid. So, you could start screening all the patients who are getting a TAVR. Becky Hahn, a famous echocardiographer, taught me that you can just look at the echo, and if the S wave on the echo is less than 6, everyone who has amyloid has an echo less than 6 in this trial, because she helped us read the echoes. And you got rid of 50% of the patients who didn't need to get screened. So, this now brings the yield to 44% in men. So, you could, that would be an approach, everyone getting a TAVR gets an echo. This is a study we did more recently screening with colleagues, Finn Gustafson and others in Finland. And you can see here, they have a national healthcare system. We basically found 1,179 people who had bilateral carpal tunnel syndrome. We called them up, and we said, hey, you have this surgery, you know, 10 years ago, do you want to come in for screening? And we heard that in men who are over 70 with a low BMI, by the way, clinical clue, no one with amyloid, almost nobody is fat. Almost nobody. We published the data. A BMI over 30 has a 98.5% negative predictive value. Hepheph is a disorder of older obese individuals, but not amyloid in our experience. But you can get 1 in 5 men who has this particular phenomenon. Definitely a very high yield, I think. They summarize the data here. You can see this 1 in 4, 1 in 5 prevalence in older adult males. We have a screening study that was funded by your government called scan NP, in which we're focusing on minority populations, in particular because they have the variant that we talked about that's common. It's called scan NP with Rick Ruberg, and we're trying to again advance early diagnosis by screening. This is an 800-person prospective cohort study. We have three sites, Columbia, affiliate with Harlem Hospital, Boston Medical Center, and now Yale University. And we're doing phenotyping on patients with increased wall thickness who are over 60 who have a clinical heart failure syndrome. Can't tell you all the details yet, sorry. Still actively ongoing. We're at about 480 of the 800 subjects. This is a study we did with NIA funding that led to a grant that we're thrilled to be working with Mayo Clinic and Ellen McPhail on. So in 47 patients at our center who are undergoing back surgery, we basically said to the surgeon, please don't throw it in the garbage, just give it to us. We stain the tissue, and as you can see 34-35% of patients had amyloid in their spine. When we sent the tissue to the Mayo Clinic to figure out what was a TTR, we found out that two-thirds of it was TTR. Much more commonly TTR as they got older, but not everything in the spine was TTR. Many of the times, a third, it was undefinable amyloid. Who knows what that means and whether those patients are going to develop TTR. If they're not, we're going to start screening lots of people who have amyloid on biopsies and congo red, and it would imply a critical role for mass spectrometry to figure it out, or maybe they will develop amyloid and then it would be a critical. We have hopefully going to start soon a prevalence study in these individuals at five centers, and then amongst the patients who we find amyloid in, they've had back surgery on average 10 years earlier. We're going to call them up and say, hey, we found some amyloid in your spine, why don't you come on in and get tested to see if you have it in the heart. If the data in Finland are correct, we're going to find lots of patients who are relatively asymptomatic but have a disease. Rick Rubberg and I wrote this, though, and I think it's really important if you're thinking about screening, and that is the following. This is the validation studies that have been done. So the Gilmore paper that we all cite from Julian and me and colleagues, half the people in that study of 1300 had amyloid. It's really easy to use a test when one in two people walking into your office has amyloid. So PYP scanning, we saw 90% sensitive, 100% specific when you exclude monoclonal proteins, but one in two people in the study had amyloid. So the pre-test probability is usually high, so your positive and negative predictive value are very high no matter what test you have. If you start screening people and they have a 5 or 10%, you will have a very high negative predictive value but your positive predictive value is going to go through the roof. You're going to start finding people who you think have amyloid and they don't. So it's going to be really important to use clinical features to increase your probability and to make sure you're doing the scanning test really, really, really appropriately. You need to scan with spec, you need to probably scan at three hours to avoid the blood pool at one hour in low pre-test probability populations. So the second thing I was asked to talk about which I'm going to try to run through quickly is this very important question. Now that we have all these patients and we're taking care of them, how do we follow them? And the short answer is nobody knows, exactly how we should be following these patients. We don't know that and we really do. But this is the most common question we all get which is, hey doc, how am I doing? Is this the feminist thing working as the other drugs? So there's a good rationale for screening for following patients. Hopefully you're going to alter, intensify, maybe you're going to get rid of certain therapies. Lots of these patients develop conduction disease and need pacemakers. We're actually trying to apply right now for a multi-center grant for BIVI that the government is interested in around the country for patients who have amyloid. We have reasons to think of a BIVI pacemaker. People who develop atrial fibrillation may need to go and sign this rhythm. And then the thing is, if we have three or four therapies approved, how are we going to switch? Which one are we going to use? If you think insurance companies are going to let you give two drugs that cost three quarters of a million dollars a year for an 80-year-old, you're dreaming, right? I mean the pre-certification process will be cuckoo. So let's just talk about some of these therapies that we have. So this is the patient I showed you before who you can imagine has a blood pressure of 80 over 40. He has progressive, as we saw, diastolic dysfunction, reduced what I call LV capacitance, his ventricular chamber is small, his EDV and his blood pressure is falling. And so there's an essential role in this patient to stop medicines, right? Be a geriatrician, shut off the heart failure therapies because they're not tolerating them. And we investigated this in our database with Richard Cheng. It's actually been done. And these are the data on outcomes in 150 TTR patients for beta blockers and ACE inhibitors. For mortality, the answer is no benefit. But Richard, of course he's astute, found this. You know, I see patients they weren't feeling well. I shut off their beta blocker. So in blue are the people I shut off the beta blocker, and in red are the people I didn't. By the way, I would usually shut off a beta blocker in sicker patients, you could imagine. And the hazard ratio for deep prescribing the beta blocker is more than 50%. I saved more than 50%. I reduced the chance of dying by more than 50% by simply stopping the beta blocker. So you want to kill your amyloid patients, give them a high dose of beta blocker, that would be a sure way to do them in. They have a low stroke volume, and they need a faster heart rate. Don't assume you're smarter than the physiology of the body. I think there's a big role for SGLT2 antagonists personally. We don't have a lot of data. One of our fellows is conducting a study right now. We now give this to everybody with amyloid. And the reason is, as Richard showed, one of the things that predicts mortality in these patients is the dose of their diuretic. And you can see survival is much worse the more loop diuretic you're on normalized for your body size than obviously one way to keep them uvelemic might be and protect their kidneys might be in SGLT2. So food for thought, and people are interested. These are the data from a patient and my colleague, Dr. Nebobian's open-label study. This is a 90-year-old lady who has an anti-probian P of 10,000 over 12 weeks. Her anti-probian P went down to about 8,000. She basically, the red is what would have caused us to stop. So if her creatinine, which was already high, would have went up by 30% or EGFR, we would have doubled in the stopping rule. And you can see in this study, her creatinine remained stable and she required actually less diuretics. And that's what we've observed in this 15-person open-label study so far. That we usually get rid of the metallozone high-dose or cut their torsomide quite a bit. These are data from Brett Sperry in which he took the Topcat trial. No one knew in this trial, a Hepheft trial who had amyloid, but he looked for features that were suggestive of amyloid, low-tissue Doppler signals, and he then analyzed the outcomes of patients who got aldactone, who he thought had amyloid and didn't, and aldosterone antagonists had a mortality benefit in patients who had a phenotype that looks like amyloid. So we often give them MRAs. One is pacemakers and bradycardia. So this is a new focus of our attention. These are data from Claudio's group again, poor Claudio. But these are three risk factors for developing a pacemaker and need a pacemaker and amyloid. A, atrial fibrillation, B, first-degree heart block, can't have the two at the same time, but you could look back at their historical EKG and C, and C, do they have a wide QRS? And just to highlight, if you have all three of those things, you have a 40 percent chance of having a pacemaker within 12 months. So those are people who you should start maybe doing long-term monitoring on and check. You know, this would be, I think, a really good place to think about a bi-v pacemaker. Why? Because these patients become pacemaker dependent like the minute you put the pacemaker in, right? And like, the electrical conduction system is frayed with amyloid. They have a stroke volume of, you know, 45 mLs, index is 25 mLs, and now you start to rv-pace them. So their cardiac index, which was 1.8, now goes to 0.8. You know, they don't feel well. And there's data shown here to say that physiologically it makes a lot of sense. And there's even a case control study, not the greatest, you know, evidence in patients from the Cleveland Clinic showing there's a survival benefit. So we think this is the right thing to do, and that's why we're advocating to the government to fund a bi-v pacemaker trial, in which everyone will get a bi-v upfront, but for six months we turn it on and turn it off to get the information. So this is the bane of everyone's existence in general cardiology. I call AFib the most overtreated heart rhythm in the world, but should we restore normal sinus rhythm? I have no idea. This is my approach to AFib for all patients, amyloid or not, and that is the 2x2 table of are you really symptomatic or not, due to your AFib, yes or no? And are you likely to stay in normal rhythm if I jump through 15 hoops, right, and start, you know? And so, you know, it's very easy for someone who's really symptomatic, right, and highly likely to stay in sinus rhythm, but no one with amyloid is highly likely to stay in sinus rhythm. It's really easy for someone who's got amyloid who didn't notice that they were in into AFib and nothing's different about them. I don't do anything by the X, but there's a lot in the other groups and the question really here is you just got to get down to share decision making with the patient and chat with them. These are the data over, you know, 40 months about who's going to stay in sinus rhythm and might stay in sinus rhythm after cardioversion or AFib ablations, but patients with advanced amyloid almost never do, so I don't rush to do things. And then this whole question of, you know, well, what if we had two or three treatments on the market which we may soon have? You know, how are you going to decide what to switch or what you're going to do? And so, again, you know, these are the current across the spectrum of disease we use to famine us, but certainly for those who have neuropathy with a cardiomyopathy, I and I think all my colleagues in amyloid use silencer-based therapy. We think it's potentially going to be better. So, um, this was a paper that was written by very famous and important folks in the world of amyloid. I wasn't a co-author. I don't want to pick on it, but they made this up. It's a reasonable starting point, but there are a lot of holes in this, so I just want to... But these are the things they suggest about monitoring patients. You should look at them clinically, you could look at lab, and you could look at the EKG. So let's touch upon each of these, the clinical ones. So New York Heart Class, a recent hospitalization, are they taking more diuretics or performance-based measures? So New York Heart Class, fantastically prognostic, you can see there, right? Like the dose of diuretics, fagnastically prognostic. So we use those to modify the Mayo and the NAC staging system, and it turns out they really improve the AUC. And so this is what we call the Chang or Columbia score after Richard or our data, but it's much, much better than the others if you wanted to refine risk. And the two things we're adding are New York Heart Class and how much diuretic they're on. So it's really not terribly complicated. It's a score one to nine, and you could put people into early, middle, and late. Sixth Mental Hall Walk, well, that would be great if we could get the staff and everyone to agree to do it at a set period of time because their Sixth Mental Hall Walks definitely go down quite a bit over time. And as we saw, while Tephamidus doesn't make the Sixth Mental Hall Walk better, it prevents the decline. So I endorse that. And we know that this disease is not linear in its progression. And so probably when we're doing testing, we may need to do testing more frequently, you know, at a certain point in time. So you can see here people are pretty stable on this curve. Functionally, we're here, people are falling off the curve. And so probably as people progress, we may need to change the frequency by which we monitor patients. Frailty, very, very common in these individuals. This is what we call the clinical frailty score. After the Dahlhaus University, one to nine, and you can pick. And this was evaluated by the group in Canada and Sir Cartfeller. And you can see there were people here who were not frail in CFS one to three, pre-frail four to six and frail. And everything about them was much different. But interestingly, tert-tiles of frailty score were independent predictors of, you know, outcomes in these patients, independent of their amyloid stage in New York art class and treatment with Tephamidus. We've actually become really interested in this, which is called the short physical performance battery in my lab. This is a marker of physical function, involves three items. It's your balance. Can you put your feet together and hold it for 10 seconds? Can you put one foot slightly in front of the older 10 seconds? Can you do a tandem for 10 seconds? You got four points if you can do all of that. Second is we do gate speed, right? In meters per second. And then the final thing we do is chair stands. So the reason we like this is we don't have to get a hallway. We don't have to block off things and so forth. It takes about, you know, five or ten minutes to do. And it's very, very predictive of what happens to patients. For those of you who read the rehab HF trial in the New England Journal, Delane Kitzman used this as the primary endpoint. So these are data just from our center that we're collecting, you can see. And here in ATTR patients, one of the biggest problems they have is the chair stands. They have a lot of different kinds of problems. And I think that's the one that I was mentioning, muscle loss before. But they seem to do much worse. And we're measuring it in scan NP as well. Laboratory tests. We have lots of biomarkers and we can easily not only risk stratify patients, but we can follow them. So these are the two staging systems. One developed by Martha Grogan using NT-PROB and the other staging system is the Gilmore staging system, which uses the same NT-PROB and P-CUT off, but an EGFR renal dysfunction above or below 45. So you can tell someone, you know, early middle or late, I would make sure patients want to know their prognosis before you tell them, right? Many people don't want to know. Often the wife wants to know, but not the husband. You know, you got to be a little sensitive to all this. It turns out these, no surprise, biomarkers are highly prognostic over time. And so you know, these are changes in the next day to six months, one year and two years. Stage changes, people do worse. And you can see the hazard ratios here for changes in NT-PROB and P-CUT. So a 10-point change in their NT-PROB and P-CUT and the weekend call on Saturday was, what does it mean? It went from 1,000 to 1,010. It means nothing, right? You know, but a 500, 1,000 or 2,000-point change, those really have meaning for patients. If you really want to get into the weeds, it turns out uric acid is in these patients and is prognostic, independent of their diuretics, maybe SGLT-2s will modify that risk, because they lower uric acid. And if you want to prove to a patient that defaminus is working, they always want to know, is it working? You just measure their prealbum and before they take defaminus and after, and it goes through the roof. Obviously, if we start silencer-based therapy, the prealbums are going to go down. It's going to be confusing. But these are the changes that we see in patients that we published on. Not finally, but we can always use, you know, all these sophisticated cardiac testing. So EKGs, well, there's lots of AFib, there's lots of conduction disease, and then there's lowering voltage over time. And these are some of the findings that you could look at and see. This is the data I showed you about Claudio Rapetsis about who needs a pacemaker. So pretty common, I think that's going to be the new horizon. These drugs work seemingly well for heart failure, but they're not really affecting, in my opinion, the risk of AFib and the risk of needing a pacemaker. So it's just that they're just plotting along in that regard. This is what my nurse practitioner won the Heart Failure Society Nursing Award for. We stuck xylopatches on 50 patients, expecting to see lots of heart block. We saw a nuance at AFib in about 8%. New heart block that was bad enough that we're like, hey, buddy, you should come in. You had an eight-second pause. You need a pacemaker like soon in 8%. So a yield of about 15%, which is amazing. Oh my god, what's happening? VT in like 70%. And that has no prognostic significance. So you can order this test, but you better be prepared not to start sticking a defibrillator because you're going to put a defibrillator in 7 out of 10 amyloid patients because they have a lot of VT. So I think there's a useful thing to do, and the frequencies probably should be modulated based on how severe the phenotype is. What can we do to measure amyloid load? So patients always want to know how much amyloid do I have and where is it and what's happening. And the answer is this is not yet, I think, ready for primetime outside of research, but these are the things we could do, and as you can see, as we do more and more, it'll get more and more costly and will be less widely available. But if we're going to spend a quarter of a million dollars a year or a half a million dollars a year, we may see things really better or worse in this regard. So these are the data from the ATTR act trial just to share with you. This is the wall thickness change between Tefaminis and placebo. We're talking about less than a millimeter change in both so you could stare at the wall thickness and if the patient is asking you what their wall thickness is, you can tell them, but I usually say if your wall thickness changed a lot on the echo, it's because a different reader read your echo, not because your wall thickness is different, but because the patient is a patient, so you can't use that. EF didn't change. Stroke volume is where the money is, as I said, but you could look at that, but these are pretty small changes of over a long period of time. And GLS, everyone talks about, didn't change. It turns out that the things that did change are circumferential and radial mid- strain. So we're not even measuring those usually clinically, but we could look. Maybe that's a good idea. There are ways using CT to quantitate, and these are provocative data from a center showing that the PYP scan with CT quantification and so forth tended to change over time. Maybe that'll be a marker, but we're just starting to. I don't have a lot of confidence per se in that. There's also these reports that are coming out with silencers, particularly that PYP scans can become negative. They go from a half. So I'll touch upon that in a minute. These are data from the NAC to the left with patissaran. Patissaran didn't change the ECV, whereas patients who got placebo, they got worse. So things weren't getting better, but you could use ECV. And these are data from a center also looking at Tephamidus versus historical controls, where they also measured MRI and there were some changes. But these changes are pretty small on group averages. Maybe as you're following them, you'll see that there's a difference between the two. There's a difference between the two. There's a difference between individual patient. It could hold some promise. These pet imaging agents, I think, are really where the money's going to be. So this is floor beta pier. And then to the right is what we're using a Columbia compound made by Jonathan Wall. It's a small peptide that he's labeled with I-124. And it images amyloid all throughout the body in every organ. So you can see that it's got a polysens. I don't think it's going to be like sarcoid that it's going to melt away in three months with just steroids. But this is an interesting patient, I just point out, who we had in the Helios A. Trial. And we argument here is we're going to need multimodal imaging. So if you can see in the upper, here's his baseline. You can see he's got a PYP that's positive. He's got a clear grade 3 scan. And you can see on the right is the PYP scan. So we did another PYP scan. All my colleagues called me and said why'd you order another? I was curious. I wanted to see what happened. PYP is gone. There's no uptake anymore. So this is cool. And it's about 30% of patients with silencers this is happening to. We then brought him in for the PET scan. This is his PET scan with the Jonathan Wall compound. His heart's full of amyloid still. So we never knew what PYP was before. It's microcalcifications. It's not measuring the amyloid load. And so the changes that we're going to see with CT scans and those I have a lot of suspicions about and worry that we're going to make some mis conclusions. And so these are the things that we could do. But I just point out I think there's a big thing that we're missing. And that is remember where all doctors just talk to the patient. Just ask them how they're feeling. And these are the things that I've seen in erudite patients I've ever encountered in my career in cardiology. They know what's going on. They can monitor their biomarkers. And so just provocatively these are not amyloid data. These are serial KCCQs that were given to patients remotely in an ARNI trial paradigm in which they just measured it. And guess what the patients when they were feeling worse on their KCCQ that predicted their hospitalizations. And they got better after them. And so I think there are ways that we can really all of this testing and everything that's going to require as you have at your centers a bunch of experts. And it's amazing to see all the individuals whose expertise is essential. I mean you can't do this without a hematologist and a fantastic neurologist and pathologist. It's not a cardiac disease. So it's going to require multi-disciplinary care. So I'll just stop by saying early identification of patients is feasible. We don't know what the best strategy is. So you want to create a screening program? Great. But don't tell everyone you've got the best one where we have five or six that are ongoing. I'm convinced that there'll be a screening study strategy in a guideline but I have no idea is it. Lumbar spinal stenosis is a carpal tunnel. What we need to do. That's an area of science that should be checked out, determined to be cost effective. Even more in its infancy are how we monitor these patients. So I encourage everyone who's taking care of patients to just get a database together and record what you're doing and see because you may teach us all that there'll be a better way. And certainly we're going to need that in order to optimally take care of people because if we've got to choose between therapies, we're going to have to have convincing or add a second therapy, we have to have convincing data. I think we've got a lot to learn from implementation scientists. I'm not those folks but they know how to engage patients a lot better. You're really in our shared mission of bringing the patients into all of this and they are really fantastic partners. So again thanks for allowing me to come out west. I really appreciate it. Well we can have some time for questions. Thanks for the fantastic talk. One of the things that at least I've struggled with on the neurological side is the asymptomatic or perhaps presymptomatic family members who have affected patients just wanted to get your thoughts on that. I think it's really, look, we have enough to do but remember as you're pointing out there are lots of allele carriers out there. I jokingly say to the companies in this space, who can we find in screen? I'm like just screen the family members. You want 50-50 yield? They have a brother or sister, there's a 50-50 chance. I think they probably have a phenotype more than certainly cardiologists know. I wish we had more bandwidth with, I mean my sense is that neuropathic findings are occurring much earlier than the cardiac findings. There are very subtle things. We try to do compass questionnaires in patients and they often report a lot of, as you were highlighting, autonomic symptoms that may be subtle. I'm professing we don't know. We just got a grant with, I didn't get it, Justin Groden for those who don't know is at UT Southwestern. Fantastic amyloid individual. Julie knows him well. He got an R01 for V122I patients in which at the Cleveland Clinic, Columbia and UT Southwestern we're going to be doing MRIs in allele carriers because he has some evidence that they actually have a phenotype in their hearts beforehand. Before we, you know, before all of these things change. And so if the goal is really early diagnosis that may be useful. The other intriguing thing that my former colleague Alan Castano when he went to industry, he was working with Eidos, who makes acaromatous. So acaromatous is the stabilizer. Acaromatous is the next generation stabilizer. They had planned, they bailed because of certain issues, but they had planned to do a prevention trial. So actually to give allele carriers, you know, these drugs. What do I do for patients? When I find someone who's got, you know, variant disease and is asymptomatic but is close to when I think the disease could penetrate, I talk to them about difluenosyl, every single one of them. And I usually give them if they're willing to take it difluenosyl. Do I know the right thing? I don't, but I mean I watch their parent, God forbid, I have a miserable disease. They watch their parent and they're pretty motivated. Now, if I wouldn't give difluenosyl to a 30-year-old who's got, you know, 30 years before they're going to develop the disease, but you could argue that there's probably a right time to do that. It's an individualized decision, obviously the risk to non-steroidals that you take every day and people have to be aware of that, but we're giving a dose that's below the non-steroidal dose. So those are some following thoughts. I don't know if that addresses what you're talking about, but I think early is the name of the game and with allele carriers, we need to be a lot more vigilant at really getting them into the multidisciplinary team and scrutinizing them because cardiologists miss it, I think, often. Can you come in on the on the patient, please? Yeah, yeah. So they get anticoagulated if they have atrial fibrillation, irrespective of their Chad's vascular, right? So you see AFib, they should get anticoagulated. It doesn't really matter whether you give it to an orphan in our experience. Merging data suggests that is true. Often all these patients go on a novel anticoagulant. Some interesting things that we've observed. So the London group has published this phenomenon of atrial electrical mechanical dissociation, which basically is they're not in AFib, but their strain on their atrium is non-existent, like they are in AFib. That is 22% of patients with TTR amyloid. 22%, right? So you wonder, you know, amyloid, as we know from data from the Mayo Clinic is very thrombogenic, AL more than TTR, but the worst thing that can happen to a patient is having a stroke, we probably need to anticoagulate them maybe even sooner than we're doing. So here's my quick observation. V122i is a much worse outcome than wild type disease. V122i almost exclusively affects blacks. Who has more AFib with amyloid? Blacks or whites? By far. Statistically significant. In the general population who has more AFib? Blacks or whites? Whites. There's actually a risk score for AFib. It includes race nationally published from many studies. But when you develop AFib in the general population and you're black or with amyloid, your risk of having an embolism is even worse, much higher. I think that African Americans probably have an atrial cardiomyopathy. They may be resistant to developing AFib and when they develop AFib, they're worse off. If all this holds out, I bet in 10 years amyloid may lead the way to a change in general clinical practice. I'm not sure we should be anticoagulating people just because of AFib. We should be anticoagulating people probably because of the atrial cardiomyopathy. We may get to a point where we really just look at the atrium and go, this is the person who needs it right now. We're doing something downstream. That's all hypothesis generation. But what happens in amyloid seems to mimic what happens in the general population. Thank you again. As a non-cardiologist I learned a lot but my question to you is I think there should be a standard of care for screening considering the high percentage of occurrence or prevalence of amyloid. So are we going to develop those criteria that you had listed, eco criteria and the biomarkers as a means of putting something into a screening plan. Just like I mean we have workers and we screen them for triplets. I think now time has come but with our aging population we may need to develop new screening guidelines. I completely agree with you. I'm just trying to profess to you that I think it should be scientifically based. There are lots of benefits to the screening. We all have all these clinical clues. It's somewhat of an unusual disease but we could find it early. It all seems to make a lot of sense but there are lots of things in medicine that made a lot of sense that didn't work out so well. So if you look from a screening perspective everything's been met except cost effectiveness. If you look at the WHO criteria but that's important. Are we going to have too many false positives? Part of the impediment to all this I've been saying for a long time is these drugs are way too expensive. There's no way that this could ultimately be that cost effective per se. So don't misunderstand. I'm 100% enthusiastic about a screening approach but when you say to me which one should you use the answer I think honestly should be no one knows yet, right? I mean try one in your center, see what you're going to do collect data and so forth. We're planning to pool the finished data our own scan NP data Omar Abedessi's data and try to put it all together. We have different things but no one's I'm not sure like anything it's going to be 100% exactly what you want to do for everybody set there may be different approaches as we heard when you're 95. He's not doing well. He's probably has amyloid we didn't screen him right we just were kind of like he's got too many other things going on my colleagues like I love you Matt but I'm not going to look for if he has amyloid I think she's doing the right thing you know I had a question to whatever your thoughts and experience are you using cardiac MRI to diagnose? Yeah I was a big naysayer I have to say years ago I made that joke about this week in the peak because I was kind of annoyed you know no one was really looking I think it probably does have a pretty big role I mean especially what I was trying to make a point on if I made it well is that when the pre-test probability is very low when you start screening you're going to look for one patient out of 20 or one out of 10 that's really low prevalence right not what we've done then we're going to need some better techniques and I don't know what the right ones are but MRI seems to be one that can really suggest the phenotype in a lot more specific manner so the biggest concern I don't have about screening like I said is given the current day that we have PYP scanning is going to be wrong 50% of the time if we don't do it really well if you're really looking at one in 10 people and it's not me making that up we've known that I mean here's an example right stress testing for coronary artery disease it looks fantastic when you stress people in 1970 all who had left main and three vessel disease and you know it was always positive but we've all taken care of women who have stress test is negative or doesn't reveal things so when your pre-test probability declines it's an old you know well proven epidemiological phenomenon screening test don't look as good so I think you just you as clinicians have to be a little cautious about you know you know who you're looking for I can't every month now I'm sure at every major center we see someone who comes in who someone suspected amyloid they don't have amyloid right or worse than that someone who's been on Tephamidus for six months spent the three or four grand for the first month a thousand dollars and now they spend ten grand or five grand whatever out of pocket and you tell them sorry you don't have amyloid like well why'd I get on this drug I'm like I don't know like so you know be enthusiastic but be I think sensible is my point I'm sure we have more questions can you explain again why the patients with cardiac amyloid don't do well with beta blocker yeah so I mean I wouldn't say at all beta blocker I would say high dose beta blocker for sure and the answer here is you know these are individuals who how do they maintain their cardiac output right remember your stroke volume normally is 70 your endiastolic volume is a hundred right so right 70 divided by 100 is 70% ejection fraction right 70 milliliters right times 70 a heart rate gives you 4900 milliliters a minute that's five liters a minute that's normal in amyloid let's make up the numbers give them the endiastolic volume of 50 half is small right small chamber their stroke volume is now 35 ml their EF is 35 divided by 50 is still 70% they got a normal ejection fraction right but their cardiac output even if they went at 100 times a minute right is 100 times 35 they're delivering 3.5 liters of blood as output how are they maintaining their output because they got a heart rate of 100 or 80 you start slowing them down their blood pressure falls they don't like that that's how they physiologically maintain the state they're in a state of I would call it subclinical cardiogenic shock the one good news about TTR amyloid no doubt good news right is it's a very slow and indolent disease these people have had this disease the time you've diagnosed them even if early for five years it's been percolating in their body in the ATTR act trial we had patients whose average age was 75 their average NT Pro BNP was 3000 their troponins were elevated their stroke volumes were 45 ml so their stroke volume indexes were 25 ml right and their wall thicknesses were 17 millimeters what was their New York heart class to why was it to because this disease developed so slowly that these people can acclimate in a big way so a lot of messages there but they name they need a faster heart rate usually to maintain their outputs and they don't usually like beta blockers very much the most important thing I do to a patient that I see when I first see them medically is if they're on Carvedo all I wean it off or shut it off it's a vasodilatory beta blocker or and I put them on a bio available loop diuretic they lose 10 pounds the heart rate goes up and they feel like normal again and then they realize you know I'm not the greatest doctor in the world because I don't have any more tricks up my sleeve you know a few weeks later but they're like they do feel a lot lot better so that makes sense yeah totally they became very differently than have patients once you start seeing enough of them it's very obvious I mean the BMI thing I told you is not not you know it unimportant you know they're almost never fat I mean I see a patient who comes in my office is referred in with a grade 2 PYP scan it's been planar imaging and their BMI is 35 my antennas are up that this is not amyloid right it's just not like I can look at them ago I'm pretty sure when we do our PYP here at three hours and we do spec you're gonna not have amyloid and I start talking to them about nah you may not need that to famine us or what you were taking you know kind of thing so screening is great but you don't want to miss a sign people to a disease that they don't have because this has emotional consequences financial consequences you know Eric last but not least okay so thanks Matt one of you mentioned the orthopedic data but the other interesting thing anecdotally that Dr. Rosenthal and I have been talking about actually Dr. Grogan at the Rochester is that a lot of these TTR folks see to be in their pre-morbid lives very athletic you know all American football players black diamond skiers you know 60 year old mountain bikers so two questions one do you think that orthopedic issues is somewhat your relationship to the fact they've led athletic lives if you believe that that observation is sort of correctly true than having a separate different question so you know Dan Judge also described data similarly so I give you the thoughts one would be it's a little bit of a fluke those are the most active people in the world and as soon as they can't run as far they're on top of it and running to see you and so they're just more vigilant that would be therefore it's non-association I do believe it though and the reason I believe it is a guy in London who basically is showing well how does TTR misfold and dissociate and certainly if you have a variation in TTR it's basically falls apart a lot easier but the kinetic stability assays that Jeff Kelly who invented Tefaminis has developed don't show that TTR is much less stable and wild type patients than normal controls we've published it no one seems to pay attention to it there's no doubt that if you more if used to feminist you'll prevent the disease so I'm one other way you can you know break up TTRs by sheer forces proteolytic enzymes and so forth so one hypothesis is that the organs that it goes into or ones that there's a lot of sheer forces in motion your heart's beating all the time so maybe you're shearing TTR aortic stenosis the blood's running through there maybe you're sharing it and the other part of your body that you move a lot is your joints and your ligaments I personally think there's probably an epitope something in those tissues like in the ligaments and also in the heart that attracts TTR so someone was interested smarter than me in biology they could take out those tissues and try to find I bet there's something that kind of brings TTR there first because TTR is made in the liver right and almost none of these patients no one gets liver involvement so why is the liver able to handle it on other tissues not but it's a great question a lot of athletes though I do see that yeah so as the number of TTR patients grow as we make these diagnoses how do you imagine we're going to sort of triage out these patients to those that are going to for the tertiary referral amyloid centers versus the amyloid programs that hopefully will become more widespread as we're showing here in Arizona there's interest a lot I mean I'm shocked in a great way that so many folks from around the valley are here and then you know back to the role of the primary care doctor so after the diagnosis of TTR is made and we start treating where do you see all the roles of those different groups of folks yeah it's a great question I mean look if we're right there's going to be you know hundreds of thousands of wild type TTR patients right I mean like I said you know on autopsy it's 20-25% of 80 year olds if that if you started I mean 80 year olds are the fastest growing segment in the worldwide population I mentioned I mean yeah so it could become overwhelming yeah I think I don't have a good answer it depends upon your local resources it depends upon what their needs are clearly they need a heart transplant they're not going to go you know accept the center of excellence I mean I think some of these therapies that are coming soon are you know patisserie would be great but it's pretty complicated I mean can you imagine if you have an IV infusions every three weeks can you imagine I have I have 840 people as of last week on Tophamidus I mean can you imagine if 400 of them wanted to get IV infusions of patisserie every three weeks I need like 40 nurses to put the orders and I put I put orders in for 10 patients in the Apollo B trial I spend you know so it could quickly overwhelm the health care system and I think that's part of this is only going to become a bigger and bigger part of healthcare how do we organize ourselves to best take care of people it's not rocket science I'm not a very brilliant guy so it really it's it's pretty you know certainly the TTR patients I think are the ones who could be cared for by community providers most of the time with some advice and counsel if need be a visit once or twice a year with a amyloid center but they don't need day to day especially in the early in the course of the illness they basically you know take Tophamidus a little bit of a diuretic and they live pretty functional and healthy lives someone asked before like how much does it prolong life it doubles their lifespan at this point people used to be dead in two years two and a half years people are now living more than five years so while I'm ticked at the pharmaceutical companies for cost charging too much and they know that they certainly they could argue and they do that this is much more effective than you know chemotherapy that we give people to prolong their life by a that doesn't mean two wrongs make a right where every drug costs too much but you know but I get that argument this is pretty amazing treatment therapy for these folks I think that wraps up our Q&A Dr. Mallor thank you so much