 Okay, good morning It's great to see everyone here This has been a long time coming and we're really excited about the turnout. We've had this morning. So I'm Sunday Stave. I'm the director of cardiovascular projects at the Institute for Future Health and I want to thank Our co-chairs jenice Guzman and Chris VJ and And this you know, this idea started this summer and the idea was for a local event to really start talking about cardiac Emily dosis and it really has blossomed into I would say a regional and perhaps even national event We have really a full audience here today And we also have around a hundred people or more on live stream And we have a great representation from all the Valley institutions, which I think is really Encouraging and Hopefully it'll be that first of many events where we can engage our community here in Arizona on this important topic I wanted to thank our sponsors. This was Supported by an independent education grant from Pfizer We also have support from El Nailam the American College of Cardiology, Arizona And the Institute for Future Health a joint venture of ASU and University of Arizona I also want to thank some of our out-of-town attendees raise your hand if you're from out of town We have a pretty packed agenda this morning. And so we're going to take questions during the panel discussion But feel free to put your questions into the YouTube chat Whether you're in the room or you're on live stream And if you do have a question on live stream, please write question And if you have a particular person you're addressing it to go ahead and put their name We'll have a coffee break at 9 50 and lunch at 12 15 If you'd like CME credit for in-person attendees will send a survey at the end of the meeting and now I'd like to introduce my Coach here dr. Chris VJ Dr. VJ has been really instrumental in helping organize this event and he's Multitalented position. He's qualified in a necronology nephrology Lipidology and heart failure and he runs a non-profit for the Tibetan community in India and Without further ado Chris. I'd like you to introduce our moderators for this morning Thank You Sandesh. Can you all hear me loud and clear? Okay. Good morning Thanks, Sandesh. Sandesh has done a fantastic job in putting it together along with the team Jen is April. Where are you? Without you this wouldn't be possible at all and thank you for really doing a phenomenal job and we're excited about the program Clearly, I think this is a very unique Opportunity for us to come together for the greater good of the community of our patients, right? That's what we strive to do every day to make sure that if I was a patient today or tomorrow Yes, I would like to know, you know earlier To detect the disease and then Hopefully make an impact with therapeutic strategies and then really have a good outcome So we're all in the same boat and to that end. I believe that Today is a very important day and I'm really honored and excited To have a great speakers great agenda great moderators. So then let's start off with the moderator introduction Let's go with Dr. Michael Castro. Please when I call you please call upon you come to the stage Michael Castro is a great friend of mine and known him for 25 years I've been in the valley here for almost 33 years and known him as long as he's been here And he's one of the finest internal medicine Practicing doctor both clinical as well as research and in teaching is also a Gerontologist, he's done multiple research projects and more recently. He's done some research with me doing Utilizing technology to actually make a better Patient outcome utilizing virtual reality and the Mercer technology and he was the principal investigator We just presented at the Cardi metabolic Health Congress in Boston that Michael presented recently So he's done some great work and so honored to have him here. He's also the associate program director for internal medicine program at a bravo and Such an honor to have you get Michael Welcome and Let's Janice, where are you? Janice goes man. I'd like to welcome another co-moderator Janice is a Again, a gerontological nurse practitioner based in Tucson. She she told me that she's based in Tucson and I heard She's baked in Tucson Okay, we were all baked somewhere or the other but Truly she's an amazing nurse practitioner who's doing some good work both in clinical setting as well as doing some very Fascinating research. She's actually doing something interesting. She's doing research in remote patient monitoring in veteran population in Tucson at the VA In hot failure. So it's going to be something very different and unique and see whether we can actually make a better impact on patient outcome So again, welcome Janice and again, thank you all for coming. I'm going to now hand over to Sandesh to introduce George and then it will kick off the meeting. Thank you all for coming Okay, I hope you have a large glass of tea. I have 32 pages of Dr. Post's resumé to cover But some of the brief highlights are Dr. George post is the regents professor in Dell web chair and health innovations chief scientist of the complex adaptive systems initiative From 2003 to 2009. He built the biodesign Institute at ASU and since January 21 He assumed leadership of the Institute for Future Health a joint venture of ASU and U of a and he's my boss From 1992 to 1999 He was a chief science and technology officer at Smith Klein beach him now. Glaxo Smith Klein and He was also awarded the rank of commander of the British Empire by Queen Elizabeth II for contributions to research and international security I think the thing I most admire about George actually is his ability to tell great stories and to integrate knowledge from so many disciplines So without further ado, I'd like to welcome you George Commander Well, good morning everyone. Thank you for taking time from your busy schedules to come on us on a Saturday and I hope what we will see emerge throughout this meeting is the not only the conceptual framework for The evolving framework for treating this disease But a greater recognition of this disease and the impact for for patients But a full recognition of very much consistent with my role as director of the Institute for Future Health Who is built in very large-scale programs and collaboration between? institutions and I say that as the only non-cardiologist in the Session and since the clicker doesn't work. I'm gonna have to ad-lib here for some reason But the it's completely dead Where's where's the sensor? Okay, great. Thank you Still not working Anyway, let me disease which is Under-recognized and therefore under under treated prevalence is clearly higher than has been Recognized hitherto as a consequence of that there's often an unacceptably long interval between The time a patient first presents and the definitive diagnosis occurs and in that interval a substantial utilization of essentially futile cost Before that diagnosis occurs the prognosis is Unfortunately a dire one as this audience certainly knows More recently we've of course seen the option for new therapies there a few to be their new therapeutics Whether it be for cardiomyopathy or polyneuropathy But by definition as in most disease states earlier detection actually facilitates Effective outcomes we're having some problems here And I think just one of the sort of simple being yet to show the interest in this Subject is simply just the rapid growth in both publications And the references specifically in the last few years to therapeutic intervention Data is however still fragmented. That's not unique in medicine That but certainly the data from Arizona Against those particular parameters is still a limited data set and to the third bullet there We have very limited data on our Hispanic population and certainly virtually no information on the Native American Populations and still most of the data is coming from highly specialized centers such as the ones that you all work in the Clear issue has been in most importantly a transition from invasive end of my end of myocardial biopathy to syntographic Imaging and but the same time with the increased prevalence of this disease Who do you actually then refer to a syntographic work up and we've seen the evolution of a series of? risk scores Evolving any one of a number of the parameters which are listed there put together and with the reach of machine learning and Artificial intelligence into many domains of medicine now apply in those types of deep learning tools to these multi-parameters does actually help in a Much more important Selection, but the same time is a need to still validate these evolving test scores risk scores a cost at the spectrum of the disease Obviously one goal certainly shared by this audience is to increase the recognition and awareness beyond the specialized amyloid centers There is a paucity of biomarkers, which is probably the biggest single area of research Opportunity particularly if you could migrate biomarker discovery into easily sampled biospecimens such as blood and urine because that would then Clearly expand the opportunity to do cost effective screening for earlier Detection at the same time rigorous diagnostic biomarker capabilities would if you had those that could also prognose and predict Any progression from polyneuropathy to cardio myopathy? biomarkers as in other areas of medicine to monitor therapeutic efficacy disease progression monitoring and the The low cost issue permitting you to screen asymptomatic hereditary variant ATTR cohorts for late onset disease due to the incomplete penetrance of variants in different cohorts we They're still having problems here April could someone else advance the slides for me won't do it off the keyboard either Then of course in the treatment domain. There is still the unresolved issue is efficacy greater for the Thyrate-retin stabilizers versus the silencers Proposals with regard to the use of combination therapeutics and this of course applies in so many areas now one in which I spend a great Lot of time is immunotherapy in cancer where combination therapies Increasingly the norm but the same time the What sequence do you give those agents? What is the unit dose titration and then the point which is going to come up in a moment well known to this audience is the fact that the extravagantly high cost of the agents in this arena is Certainly problematic another issue which we will eventually wrestle with is other thresholds for irreversible Progression which would predict lack of Rx efficacy and that leads of course to the grand challenge question of is This card in myopathy reversible will actually then require a new category of myofibral clearance agents next slide, please So of course, this is the issue we touched on a moment ago the high annual cost of approved therapeutics ranges from a century a quarter of a million to Half a million and if you look at the studies by ISA and others in the cost effectiveness domain This would require an extravagant reduction an extravagant cost Probably of the order of 85 to 90 percent to actually bring you into the quality adjusted segment of 50 to 150 thousand per cost-effective quality a threshold next slide, please and then of course if you go and look at the pipeline that is evolving in this arena whether it be for neuropathy cardiomyopathy or directly attaching the Aberrant TTR. This is a burgeoning a burgeoning pipeline and One has to then begin to ask the question of what will be the cost effectiveness of these new therapeutic regimens next slide and Of course the Will we will we in what time frame see a shift in the therapeutic paradigm in this disease that move him from lifelong therapy? Which is the dilemma today and me is this a bright star on the horizon? Which is using gene editing technology the work of the Intelliore and Regeneron are doing with the drug it's listed there They've demonstrated initial efficacy in the hereditary polyneuropathy Situation and now expanding into cardiomyopathy Certainly extrapolating from the studies in polymyopathy and neuropathy There's a thing there is indeed a sustained root knockdown of TTR Expression for six to twelve months, but the question were how that translates to clinical benefit remains to be Seen and of course in any gene therapy Framework it is the threshold of Transduction efficiency into your target cell population in this case the hepatocyte That will determine all and the dilemma which the FDA is always struggling with isn't in this emergent re arena Not just not just for amyloidosis But all gene therapy is one of the off-target effects because they in many instances may be often Delayed so it's likely to be the cost of post-approval studies next slide, please But that this is just a summary of themes which are well known to this audience What I want to do is breathe in the context of trying to create this framework for a pan Arizona Network because I think there are many elements of what you are facing In this that reflect the same elements that are shaping biomedical R&D and health care delivery at large next slide And that is the fact that we have Reflected in my own gray hair and increasingly aged population chronic co-morbidities in that population economically unsustainable Treatment regimens and major unmet clinical and social needs as a consequence of that that has to be balanced against what the general public and the Politicians think will be an inexorable tsunami of new innovations coming forward at ever lower cost With better clinical outcomes and quality of life, but the collision course between those two parameters is Going to be with us for some time and then of course in the era of precision medicine We now have multi-omic stratification of diseases into increasingly small cohorts of patients with different underlying molecular teleologies and of course that has been the price driver that if you've only got a small Patient cohort the recovery of your R&D costs, which can be anywhere between 500 million and a billion plus That derives this distorted element of market failure and periphery Drugs of this category March under the orphan drug status as you know, but the threshold for that is 200,000 patients so if indeed the prevalence of ATTR Neuropathies and cardio myopathy is in fact going to quickly move beyond 200,000 patients Then that will have to be reexamined and what will that mean then for the price structure and people's willingness to come in and In this of course if you are sub-setting patients on the basis of molecular stratification You also need a companion diagnostic so that adds further to the equation next slide And so this of course then leads to something again, which this audience lives with the entire time We're living in the environment of escalating scientific and clinical complexity and in short How do each of us stay current with our responsibilities? It's not it's the pace and diversity of innovation new concepts new technologies and an overwhelming burgeoning of large-scale data and the world in which I live is basically a fusion of three previously separate domains namely medicine with engineering and computing and then we're seeing new combination products diagnostics therapeutics devices and data algorithms coming together and at the same time with the pervade with the pervasive and rapid acceleration of machine learning and AI technologies in all areas of medicine Regulatory validation through the FDA so-called software as medical device will become an increasingly challenging issue and then back again to price Increasingly and if you look at the inflation reduction act It's very clear that the FDA's mandate which is currently limited to safety and efficacy is going to extend to value And so with or without Isis insertion into the equation CMS will become an equally potent blunt weapon in this debate next slide and So it's what I colloquially refer to as the s4 to m4 paradigm shift particularly if you're in academia For the most part academia is still trapped in single scientific disciplines or single clinical specialities But increasingly the problems we wrestle with our multidisciplinary and multispeciality Often conducted in single institutions where as the scale and sophistication was required requires multi-institutional collaborations Often if one is dependent upon the federal purse the resources are subcritical And at the same time you then got to manage the scale of these much larger enterprises And it is still frustratingly slow to translate innovation Interpatient benefit and we have to do better next slide And so another way of putting that is in fact silos subvert solutions And so the whole Metiae for the Institute which I run and many others around the country is actually making this transition from the s4 to the m4 next slide and So a quick vignette about Arizona for those of you who don't live here Where the third fastest growing state in the nation? Metro Phoenix is now overtaken Philadelphia and Houston as the fifth largest urban complex in the country We have unique demographics almost a quarter of our population is Hispanic We have the largest population of Native American tribes in the country constitute 5.6% of our population an intriguing feature is that in this five and a half million Metroplex health care is largely provided by only seven major health care providers Whereas if you compare that with Philadelphia or Houston, you're talking about 35 to 40 major health care providers So the question of herding cats in those situations is a lot more complex and trying to get seven major provider organizations to work together in Arizona and There has been very rapid growth in both universities as you you have a NNAU with now 1.5 billion in annual grant revenues next slide And as a consequence of that We've had a momentum in the last few years to do exactly what we're trying to do here These are consortia, which have been established in the last two to three years by bringing everyone together Across Arizona that's listed there the topics are self-explanatory But it's a momentum and so it is the question of what we've done here in these other Consortium which have been built over the last two to three years the penultimate one of course there was catalyzed by Covid but nonetheless it is this s4 to m4 transition next slide and So if one were to define theoretically what one would like to see in this network is the capability to build a substantial Biobank a longitudinal registry of patients Ethnic diversity in that patient group different stages Multi-organ amyloidosis for sampling both cardiac and non-cardiac and as mentioned earlier the ability to migrate to much more minimally invasive low-cost Biospacemins at the same time in the world ever increasing world of omics the last time I checked there were 400 omics Prefix suffixes attached, but certainly whole exome whole transcriptome Sequencing is now quite routine There are people in this audience who have published on proteomics Circulating micro vesicles or exosomes are becoming an intriguing Analyzed class and have been shown to be altered in ATTR and then of course what is the nature of the structural biology that gives rise to the Altered for protein folding then a whole series of analytical platforms Which are needed to support that and in the end you get to data high-performance data computing ASU has the is now in the top 100 fastest computers Supercomputers in the country. We're we're one of only six worldwide Dell high-performance computing capabilities that puts us in a top 10 of any university high-performance Computing capability and as we said when we talked about multi parameter risk scores bringing together all this complex Finitivic data yet alone the multi omic data is going to require though at that type of analytical framework and Last but not least is this again back to this issue of pharmacopharmaco economic analysis next slide and So the idea would be that the people in this audience could in fact be the catalyst to begin to build this statewide network of capabilities in the detection and treatment of ATTR amyloidosis We need to generate much more sophisticated epidemiological data in the state of Arizona Analyze what are the barriers and the promoters to implement evidence-based care apologies for the type Evidence-based practice and at the same time clearly. We're not an island. We would like to see Arizona Migrate into a national framework as a leading enterprise within this important area of biomedicine next slide and So just my disclosures and the most important thing is if any of you want access to the slides It's also a prompt to remind you that the slides from everyone's presentations are available But I hope at least with this superficial surf across a large landscape You've at least got a sense of what we hope will be an aspirational framework for Sandesh and his colleagues in helping us build this So again, thank you so much for taking time from your schedules on on the Saturday And I'm looking forward to a stimulating and productive symposium. Thank you Sandesh, do I into do I hand over Chris? Okay Morning everybody. I'm Michael Castro. I'm an internist in Phoenix, Arizona been here for about 25 years original from Puerto Rico. I lead As program director, I lead a Bras to help network in terms of residency program, which I think it helps me You know recognizing Cardiac amyloidosis and other amyloidosis and teach my residence about it. And so we are all aware of these ECSA Really really excited to be here. I've seen the faculty and what doctor Have put together. I'm really really happy about it It is my pleasure to introduce Dr. Chris Vijay. He's um, he's a man of many talents He's my mentor. He has challenged me intellectually through the years and I'm really really happy to see him here because I know he's passionate about disease process and identifying, you know Ways to help people in whatever ways are possible. He's a heart failure specialist clinical professor of medicine at University of Arizona And without further ado, Dr. Chris Vijay He does have 200 clinical trials and more than a hundred publications as well And I know he's humble about it, but I wanted to brag about him Thank you, thank you. Is this working now? Yes, no Yes, oh, it's moving. Okay. Okay. Thank you. Thank you for that introduction. Thank you everyone for attending this meeting. So My charge today is to really Articulate with compelling clarity Those red flags those things signs and symptoms that we can detect earlier Perhaps and then maybe make an impact on the therapeutic strategies and why are we here? We are here because amyloid doses is making an impact, right? So we know that we had some kind of an erroneous belief in the past that he we can't do anything about amyloid Because once you diagnose it We're just giving them the death sentence and there isn't anything we can do but that has changed because of newer Mechanisms out there and your therapeutic strategies is available and so many in the pipeline And secondly, we always believe that we need to send these patients out For a biopsy an end of my car will be up to the specialty center And that is changing because of newer modalities in imaging and we can detect non-invasively with higher sensitivity And specificity and thirdly we have what failure patients who now are being detected Primarily those who have have passed or what failure with reserve rejection reactionary now Realizing that many of these patients may well have amyloid doses Then maybe we ought to be thinking about it and that's my talk again And you know talking about all of this amyloid doses and the sub types and and what is the patient journey like and then What is the role of the subspecialism and we'll summarize with their case study? so as you see amyloid doses is is Aggregate of proteins getting folded into shapes and then they get Multiplicated into copies and then they stick and then they form fibrils and get Deposited in multiple organs and we are we thought that this was like starch So they called it amyloid, you know initially and then they said oh Maybe it's more like fat and then now we know that it's more like albumin or more like pre albumin And there are so many different proteins that are featured in different disease states that may well be amyloid as you see over here in this slide from alzheimer's to Parkinson's to encephalopathy to you know the even prolactinomas and and some of the Cancers like the thyroid cancer even atherosclerotic disease and patients with apo A1 May well have diffused atherosclerotic to the serum amyloid A in rheumatoid arthritis The finished amyloid dose is called the lattice corneal dystrophy or gel saline is the amyloid protein That is upregulated and then there's so many and all of them essentially constitute just about 5% or so And then the other 95% is for the two big ones that we're going to talk about the AL Which is the light chain amyloid doses and then the ATTR so So in the US as you see in this slide the the amyloid is it's not uncommon about 4500 new cases are diagnosed every year and about 50 to 80 years of age is where their Presentation occurs and it's caused by this bone marrow disorder the plasma cells that you see in this slide Actually form the immunoglobulins and then you know the immunoglobulins consist of four proteins their light chains two of them And then they're capa and lambda which is very important and then the two heavy chains and there's so many other heavy chain diseases and We know that even some patients with multiple myeloma There were 15 to 20% of them become amyloid doses They may be the AL one and then the Walden-Stromes macroglobulinemia and the treatment strategy is totally different for AL That's why we need to be quickly Finding out figuring out if the suspect amyloid doses is it AL first and then eliminate it completely so that now we go This direction completely dichotomized and because there are treatment strategies are totally different because for AL There is stem cell transplantation bone marrow transplant chemotherapy with the zoomeps nbr So ATTR is really a protein again. That's mutated from chromosome 18 q 12 point one It's been called what is called the Corino de Andrade's disease Endemic in North northern Portugal in a in a town called the VRD Kandy. It's along the way of The Santiago the pilgrimage the Camino de Santiago of many of you who are Catholics will know about it And there is a Skellefte Town called gold town in North Sweden where 1.5% of the population already have Amyloid doses and present in super centennials over 110 years of age again It's a tetramer that dissociates to monomer and then misfolds and aggregates and gets deposed either right So as you see in this slide, there are so many different ways of mutation Some of them are pure neuropathy some of them are mixed and then some of their pure cardiomyopathy the The top that we're going to talk about mainly is the ATTR amyloid doses as you see We said this about AL and ATTR constitute almost 95 percent of the population So ATTR is the again deposition as we talked about is it it's a liver produces trans tyritin And it's a transport protein that actually carries Syroxene also the retinine is the retinol protein which is the vitamin a and so the Trans tyritin exists in the serum in a soluble Tetramer form and this in amyloid doses becomes unstable becomes Dissociated becomes multiple monomers and then they now aggregate and then they form amyloid fibrils And they get deposited if it comes into the heart. It is now cardiac amyloid And as you see in this picture, this is how it looks in the by you know autopsy Amyloid heart very thick and muscle and once it's diagnosed in Untreated patients have immediate survival or somewhere around two to three point five years But again, it varies based on is it AL or ATTR and is it mutant or is it wild type? So what are the different types the wild type and the mutant or the or the Redditary so as you see over here in this slide the wild type is again idiopathic You know occurs in white men mostly 60 years of age the cardiac arrhythmias are very common like a Refibrillation they can present with carpal tunnel lumbar spinal stenosis neurological Where is the hereditary one? There are multiple more than 120 known mutations more both men and women can get it And as you see the afro-american population has a very unique Mutation called the V122 I which stands for the valine in position 122 is replaced by isoleucine so the V122 I in Ireland in a town called Donegal in Northern Ireland. There is a very high genetic mutation called the T60 a and So yeah, so we need to be thinking about when you see afro-american population and they have what failure have F And he has the question could this be amyloid Could this be cardiac amyloid so again We'll go through that in a little bit more detail So the genetic mission as he mentioned three to four percent of african-american Population is thought to have the V121 I mutation and again in a one retrospective study the african-american with ATTR Had high rates of heart failure 93 percent and and 47 percent had carpal tunnel syndrome and when you look at the patient's journey by the time They actually get detected to have amyloid osis is about 1.3 to 7.2 years and if you look at it They start off with symptoms are non cardiac and then they go to the primary care and then the cardiology and then they see another cardiologist Almost 30 to 40 percent of the time they got to see somebody else with a second opinion And they've seen multiple specialty even come to the pharmacy with different kinds of medications of the pharmacist as an Opportunity to ask. Oh my god. Could this be amyloid? They're on their carpal tunnel. They're on narcotic They're also having heart failure. They got discharge. They're on lasix and oh the pharmacist is good Actually, oh my god ask your doctor your cardiology that you could have amyloid. So testing diagnosed by the time they get there It's it's a trap so hidden in plain sight. So this is a very powerful slide So think about hidden in plain sight the H stands for the half path 16 percent of a have a GTR Of hot failure with the rejection fraction I is intolerance to many of the standard medication we use a is a RB beta blocker They can't take it a blood pressure is low if you're side effect profile D is for discordant on the EKG Many of them have low voltage EKG and yet they have a thickened Ventricle in the echocardiogram and that's the in the D stands for dysrhythmia the E stands for the echo abnormalities with LVH eutectonosis think amyloidosis in a younger person and Orby thickness by a true enlargement primary hypertension some pericardial effusion that he cannot really Figure out why they're having pericardial effusion They're negative for a and a and suddenly they have pericardial effusion for no obvious reason and in the end Sands for the all the non-cardiac which is on the other side of the slide They can present with carpal tunnel spontaneous bicep stendent rupture even statins can cause that Benpedoic acid can cause that but then when they come with spontaneously without really getting any weight lifting down and They get spontaneous bicep stendent ruptures think ATTR There are multiple orthoplasties the lumbar spinal stenosis GI peripheral autonomic nervous system They have all kind of orthostatic blood pressure drops and they're not able to tolerate many of the medications as well and some neuropathy So if you have many of this confluence of symptoms start thinking oh my god How suddenly you might have an epiphany? Oh, this could be amyloid Let me go and dig a little bit deeper and they have persistent elevation in NTPO BNP or troponin or both It's a prognostic marker the Mayo has a Criteria and UK has a criteria based on these Biomarkers that they can actually have a prognosis which can be worse if both of them are significantly elevated to Maybe just one and a half to two years in their longevity. The lifespan is decreased significantly The persistent elevation in the biomarkers again functional class like EKG and even cardiac Magnetic resonance imaging it can dig a little bit deeper as with Bob and be tall We talk about that too. This is the EKG where there is a significant drop in the QRS voltage But and then again the QRS voltage can vary and only about 20% of ATTR cardiomyopathy have a low-voltage QRS so don't keep looking only for the low voltage qr If it's not there don't assume the road this cannot be amyloid it could still be because even an AL amyloid 60% have a low-voltage QRS in the anterior leaving a sort of infarct pattern they can have a 5th You can have a V block at an earlier age Requiring a pacemaker for no obvious reasons start thinking about it and Bob will go through The echo finding as you see over here the cherry on top with the Global longitudinal imaging with apical sparing He'll go deeply into the and cardiac MRI as well as the accumulation of delayed wash out of the exogenous late Catalinum enhancement can occur increase extra cellular volume can be seen in the second row there and an increased native t1 signal for both AL and ATTR which can be detected before the presence of the late catalytic enhancement Which is a marker of increased fibrosis and so Screenings if one finds symptoms and science is about there are suspicious for ATTR then yes in hot failure Please do the screenings for amyloid is considered screening even if they're not in hot failure But they have all of this little thing little signs and symptoms and you start thinking maybe I should detect earlier Why because earlier it did I put them on therapy earlier perhaps? You can change the trajectory of their prognosis and their disease state and their quality of life and cardiovascular mortality Which will be discussed in detail again So how do you rule out a L again starts doing serum free light chain assay the kappa lambda ratio? Do the serum protein electrophoresis but with immunofixation because immunofixation is a lot more sensitive and specific or more than 95% same thing that you're in immunofixation and then once you know that is Not a L amyloidosis then we go beyond and ask the question. Oh, could this be a TT or amyloidosis? So what is the algorithm? Well, does the patient have a history the EKG look like I could be low voltage Do you have you ruled out hypertrophic cardiomyopathy constrictive pericarditis? They all can mimic amyloidosis Arcoidosis cardiac MRI consider that is suspicious again Do they the blood testing urine testing if positive then go ahead and send them to hematologist if negative then start thinking Should I do a PYP scan if PYC positive then ask the question or is it a TT or C. M Is to be no genetic testing and then there's a treatment strategy and that's defined over here In this algorithm as you see from the top to the bottom It may be a little bit tiny, but you can you'll have the slide kit with you So essentially talks about the same thing. I just put it in words, but this is in a flowchart format Exactly talking about the same thing that we just mentioned and in terms of the multiple subspecialties Or actually involved and should be involved in detecting and managing ATTR from beyond cardiologist In orthopedics should be thinking about it nuclear cardiologist genetic counselors involved Neurologies are to be thinking of their autonomic dysfunction. No obvious reason they can find that is very obvious GGI gain hematology pathology multiple difference of specialty Then each of them have a role to play as you see from recognition to early clues to knowledge about You know the ATTR itself and that's why we are here Hey, let's talk about amyloidosis again and again to increase the awareness Understand many of the symptomatology and recognize and provide consultation and support and and work together So let's summarize it with a case study So 66 year old african-american male recently discharged from the hospital. It has passed CPCP is follow-up five days. It's had the angiogram cardiology. They say it's all good You don't have any currently disease So they don't want to follow up many times because they don't have any more procedures to do and then Now they certainly they have a patient of that third-degree AB block a few years ago as a dual chamber pacemaker carpal tunnel syndrome surgery under when TAVR for aortic stenosis No bicuspid aortic valve on multiple medications not tolerating blood pressure dizziness The pressure is low, you know the BNP is a little high creatinine is borderline high LVH is present and you can actually put each of them in a separate silo and And essentially take care of those individual signs and symptoms and disease states and not put them all together in one box and Look at what comes out from a confluence of this disease state process and could this be ATTR Is a question that you need to be asking So what do you call an eight-foot creature weighing five tons with a large proposes used as a vestigial appendage with two large Tars two large ears and gray in color irregular in shape rough And if it is the opposite small white soft smooth regular and round then I would have to call it aspirin right so the elephant in the room That's what we are talking about today you have these confluences symptoms Can you quickly ask the question am I seeing this elephant in the room and Clearly early detection prevention prevention prevention we do too much at the secondary and tertiary care level We ought to be doing primary and primordial. What is primordial? Not even allowing them to have these risk factors such as blood pressure diabetes Obesity dyslipidemia and all of that we are talking about primordial Because too much has been done in late stage disease with treatment strategies As you see the bottom heavy model of cardiovascular care and truly we got to be addressing it Here in this action framework for a comprehensive public health strategy to do it earlier in the prevention And make this the social environmental condition make that favorable make the behavioral patterns and promote health At the population just not george posted a beautiful job and discussing All of this strategy that we're talking about and through this You know department of future health perhaps we can address all of these and then do it at an earlier And I believe that we certainly can with knowledge gain. We can provide inspirational transformational message filled with credibility Humility and the foundation based on empathy. So yes Aldous Huxley said the rung of a ladder was never meant to rest upon but only to hold demands But long enough to enable him to put the others somewhat higher again Epitomizing that sense of hope Thank you for your attention as they say in the Tibetan Buddhism Jalei Thank you. Again, my name is jenice guzman clark. I'm a nurse scientist at the va trained as a geontological nurse practitioner. I'll be Presenting our next speaker who you're familiar with already Santosh div is the cardiologist is a cardiologist at the southern arizona va health care system He's also the director of cardiovascular disease at the institute of future health and actually met him I think a year and a half ago when we started doing a project. That's now a va funded project using implementation science to improve Treatment or optimal treatment of patients with heart failure into va. So welcome sandage. Thank you, jenice All right, so I'm tasked with getting us back on track So I'm going to sort of give you the high level items from my talk And just to remind the speakers we have a Timer here for 15 minutes So you can watch that when you see the red light you can wrap up So i'm excited today to talk to you about epidemiology and population health This is an area that i'm very interested in as far as implementing strategies to screen patients and really bring The research into practice. So if you have any interest in that Please let me note And in fact We are looking for a couple of participants for a Focus group research study if you have a background in primary care or general cardiology Talk to me at the break So i'm going to sort of Go rapidly and skip some of my slides. So these are some of the abbreviations i'm going to be using It'll be on your cme quiz at the end So i'm really going to focus on what are the high-risk groups for this Disease and i think these are sort of the the current state of where people are really looking right now i'm also going to talk about a screening tool to help Identify high-risk patients So really we want to move the needle from You know looking at patients who are already symptomatic to patients with early symptoms Or even pre symptomatic So, you know, I some of the The cost data suggests that four percent of patients with heart failure of preserved ejection fraction Have amyloid and this paper. I think is probably where that data came from It was a relatively small Retrospective series of autopsies at the Mayo Clinic Comparing patients with heff-peff to those that were controlled without any heart failure And overall four patients had significant or severe interstitial Wild type attr deposition. So to my knowledge, this is probably where that data comes from So, you know, what's the pop? What's the overall rate of amyloidosis in the general population? And I don't think we have a perfect answer to that but In this series from italy about 12 000 patients had already received bone, excuse me, scintigraphy For a non cardiovascular indication. So oncology or rheumatology And so they went back and looked at what was the uptake in the heart and about one in 277 patients had incidental DPD positives scintigraphy So that's less than half a percent But you can see that there's a high association with increasing age and gender. So It was about 1.2 percent in men over 80 And then what's the, you know, current trends in cardiac amyloidosis? So this was probably the most contemporary series and this is from germany Looking at a large health insurance population inpatient and outpatient And they looked at any sort of code for amyloidosis Accompanied by heart failure. So these are presumed cases of cardiac amyloidosis with age greater than 60 And they saw a three fold increase in prevalence and two and a half fold increase in incidents Uh over a roughly 10 year period and the greatest increases were in men 80 years of age and older So this suggests that ATTR is increasingly being diagnosed And also was very interesting. They looked at the outcomes and the median survival was only 2.5 years Now they did not distinguish between ATTR and al amyloid. However, the uh, you know, the population characteristics suggest that It was mostly ATTR patients. So this survival is lower than, you know, typical smaller studies of ATTR patients So this is somewhat eye-opening And the the one year survival Overall was 70% And even in 2018 the most recent year of the study one in four were Dead after one year And there's a high burden of disease In the year after diagnosis the median number of outpatient doctor contacts was 40. So that's almost once a week There's also some evidence of geographic variation. So this study from 2000 to 2012 looked at cardiac amyloid heart failure hospitalization and you can see in the Panel a that there was a high hospitalization rate in red Around rochester minnesota as well as in northeast from boston to roughly washington And these are most likely areas that are associated with amyloid centers But it also suggests a disparity where you have very low rates of prevalence cases for example southeastern arizona and new mexico and if you look at the incidence panel b Um There's a similar trend although it's not quite as striking where newer cases are still being diagnosed in those large centers And the increase in incidence was also seen similar to germany Where you had a multiple multiple increase in prevalence rate and incidence rate Predominantly in men aged greater than 75 and in the black population again suggesting that ATTR is what is responsible for these trends As similar findings were associated when they looked at death rates from cardiac amyloidosis and panel 8 the red and orange are The total percent black population And so you would expect to see a very high rate of cardiac amyloid diagnosis in those states And despite that they had the lowest death rate in panel b So suggesting that there's a huge discrepancy and under diagnosis of cardiac amyloidosis in those states So so the question is well, what is the what is the population prevalence of attr In sort of the most common patient population, which is heart failure And so this study looked at 1200 consecutive heart failure patients in several counties in minnesota Age greater than 60 with left ventricular hypertrophy With preserved or mildly decreased ejection fraction And so all patients were offered systematic screening starting off with a pyp scan and One third of the patients agreed to screening the median age was 78 only a quarter had been hospitalized So this this was largely the ambulatory population And Impressively you can see in panel a systematic screening was associated with a five-fold increase in detection of attr And when you break it down by gender There was a 10 prevalence in men compared to a much lower prevalence of about 2 and women But interestingly none of the women were detected unless there was systematic screening approach So the sort of usual care or clinical diagnosis Did not lead to any cases diagnosed in women And again, there was a striking prevalence with With age and you really start to see things take off in 70 to 79 and going up to 889 And in greater than age 90 20 of subjects Had attr diagnosed, which is really amazing So overall one in 20 patients that was screened Had attr and the highest yield was in men older than age 80 so Patients who are undergoing evaluation for trans catheter aortic valve replacement This is another high risk population In this study looked at three different centers approximately 400 patients who were evaluated for TAVR And they wanted to see what was the outcome in patients with cardiac amyloidosis And they found that first of all many of the patients with amyloidosis were denied surgery There was a two to one higher likelihood of receiving surgery If you had lone aortic stenosis But that being said one out of eight patients who was referred for TAVR had a diagnosis of cardiac amyloidosis So that's written as ASCA So 12% most of those were a high grade And if the patient had been selected for TAVR Then the outcomes were were technically not different between the lone AS versus the ASCA patients So if they were healthy enough to undergo surgery, they had a reasonable survival Suggesting that these patients should not be denied surgery And the authors Developed a risk score and if you had a score of two points There was a very high sensitivity of 94 with the specificity of 52 So you can detect most cases of cardiac amyloidosis In in using the score and I think this is a great model for Centers and clinicians who are Evaluating these patients So a couple other populations are carpal tunnel and spinal stenosis And there's a really intriguing article showing that 10% of patients undergoing Carpal tunnel release surgery had amyloid deposits But interestingly not that many of them actually had active cardiac amyloidosis at the time And so the Cleveland Clinic is using this protocol Uh, so if if a patient has is a male greater than age 50 or female greater than age 60 And they have bilateral carpal tunnel. They are getting a biopsy at the time of carpal tunnel release And if they have just one of those tier one factors or if any of the tier two factors that combination also leads to a tissue biopsy And if the patient is congo red positive, then they undergo further screening for cardiac amyloidosis And this was a nice case example Um, in which they showed that a patient that had congo red positive at the time of carpal tunnel release had normal Syntagraphy, uh, and was essentially asymptomatic. However, uh, four years later, they had a positive Uh, PYP scan, although they didn't have any evidence of LBH Suggesting that these patients, you know, may be pre, uh, you know, have a Early detection of future, uh, cardiac amyloidosis And and this was a nice study that retrospectively looked at patients that already undergone bilateral carpal tunnel surgery looking back five to 15 years And five percent of the entire sample Had evidence of cardiomyopathy This was nearly 10 of men And if you were a man greater than age 70 with a normal BMI, it was a 21 percent Rate of amyloidosis. So that was really, uh, a good example of how to, uh, find these patients and, uh Dr. Mauer is probably going to speak on this but as far as spinal stenosis Similar findings where there's a fairly high uptake of Of congo red at the time of spinal stenosis surgery However, a very few of the patients in this series, for example, actually were PYP positive and received treatment So black patients because of the high rate of the v 142 i mutation are at roughly twice The risk of of heart failure. And so this is another high risk of population So i'll leave you with this risk score The male clinic looked at, um, population of patients had been referred for, uh, cardiac amyloidosis Referral into cardiology clinic and they developed this risk score using available Uh, variables, uh, so they excluded, um, some some variables that were not available such as biomarkers ecg Uh, there was some missing data. So they settled on this score, um, which combines age gender presence of hypertension ejection fraction posterior wall thickness and relative wall thickness which is the sum of septum posterior wall divided by the, uh, dimension lv dimensions And if you have a score of six or greater, there's a 93 percent sensitivity and a specificity of 62 percent And interestingly biomarker addition of biomarkers did not help the model So one of the nice things about, uh, this is that it has a good performance at different prevalence of the disease So even in low prevalence states has a good performance It is specific for ATTR and it uses widely available, uh, data that is available to any, uh, Clinician doing an h&p and echocardiogram So I hope you can see that there's some really, uh, I'd say prime time populations that are are ready for screening And I think the question is, you know, are we doing enough with what we already know? Next in the agenda is dr. Robert Burke Dr. Burke is a practicing cardiologist in scotsel irisana. He's with the honor health system Uh, he had gone to medical school in, uh, rwj completed his residence in internal medicine at mea clinic rochester Came back to irisana at both shipwrestling down here and did his cardiology and echo imaging fellowship down here His interests include cardiac imaging, especially with structural heart disease And without further ado, he will be talking to us about echocardiography and strain imaging cardiac amyloidosis Thank you, dr. Burke Well, good morning everybody and thank you for having me here. Dr. Deb, uh, dr. BJ. Thank you again So cardiac amyloidosis and echo. I think that we've all heard about this before and we're relatively familiar with the concept I think that echo has been viewed as the generally the introduction and primary screening tool for Um, amyloidosis going back for pretty much as long as we've been doing echo We do have guidelines that actually reflect this and we'll go through this very briefly I think this is probably the most important paper that we have to look at what we're supposed to be doing in clinical practice So again the algorithm here you've actually seen this before we're not going to go through this again Clearly we all understand that this is incredibly important And that we need to have echo as a primary tool to determine whether or not somebody should even be evaluated for possible amyloidosis So recommendations again, I'm not going to read through this. You all seen this a couple of times before So consensus recommendations for multimodality imaging and amyloidosis and realistically There's going to be a lot more than just echo But given the fact that echo is relatively inexpensive. It's very readily available It will still remain the primary tool from an imaging standpoint to say is there a problem? Or is there not a problem Again, I'm incredibly biased because I'm an echo guy And I anticipate that everybody's going to love the echo and start to use that as the the way to really help to differentiate what's going on So basic assessment Is the lv thick? Okay. Do you have an increased lv mass and low voltage ekg? We've already heard that that's not a hundred percent and it's not going to be something to exclude us Atrial enlargement incredibly important For those times when somebody does have a trans esophageal echocardiogram Looking for evidence of left atrial stasis or smoke, particularly within the left atrium. That should definitely elevate your pretest probability or suspicion For possible amyloidosis particularly in the absence of mitral stenosis Somebody has mitral stenosis. That's a different creature all together and they shouldn't be overlapped and it's pretty easy to take a look at Valvular thickening we can comment on that somewhat But again valvular thickening in the absence of a reason for it is incredibly important And that's actually been hit on already atrial septal thickening and pericardial effusion as was noted again by Dr Vijay a pericardial effusion with no reason Well, you know, you might need to start thinking about amyloid as the etiology So again standardized acquisition interpretation reporting for echo with amyloid These are the things that we're expected to talk about now For those of you who are practicing cardiologists Now you have to realize at least in part why i'm such a pain in the butt when it comes to structured reporting All of this is supposed to be on an echo report per iac. None of this is unusual This is all inherently there One comment that i'll have here is myocardial echogenicity And saying that sparkling or starry night appearance to the myocardium There's a caveat to that one and unfortunately A lot of what we have historically relates to fundamental imaging So now that we use harmonics in the vast majority of our studies We get more of that sparkly or hyper refractile texturing to the myocardium And it doesn't always relate to amyloidosis. So we need to just sort of take a little step back there I know that i've got a colleague of mine who likes to sing starry night every time that he thinks that something's going on with amyloid But you know, that's not always the case particularly with types of imaging that we use from a technology standpoint Atrial size septum effusion. We talked about that stuff again Any time that you're starting to see diastolic dysfunction in the absence of a reason, you know, this is not a hypertensive heart They don't have a history of terrible hypertension. You really should Perk up your ears a little bit more to say that there might be a problem there Again a couple of just things just from a very basic standpoint in this Panel a you can see that there's thickened myocardium. It does have a little bit of hyper Refactile or starry night type appearance. You can see that there's a little pericardial effusion You can see that there's overall thickening. So this all fits Now, do we see this commonly? Yes, we do. Do we often blame it on things like? Well, there's renal insufficiency It's a kidney problem. They're gonna have hypertensive heart disease Don't worry about it too much the overlap there is still significant and we need to be mindful that Just because somebody has hypertension and kidney problems doesn't necessarily get them off the hook and the underlying etiology could still be amyloid So again thickening here as you can see with the white arrow thickening of that anterior mitral leaflet We see that and we see it quite a bit again There's a caveat with this one that I would say the more we're going with harmonic imaging The more we're going with lower dynamic range or compression the more likely you are to end up with thickening of structures That's somewhat spurious. So just be mindful of that As an etiology the yellow cursor here what that's looking at is thickening of the inter atrial septum And that's what we've spoken about before So echo assessment functional assessment elevated filling pressures restrictive physiology and decreased strain So tissue Doppler the uh 555 sign out I don't know if you guys are familiar with that or if it's just an echo geek thing But all the tissue Doppler velocities being less than five centimeters per second That's very abnormal and that tends to correlate very well with restrictive type inflow patterns Because your ratio tends to be with your e prime in that 20 plus range and you start getting at 25 or more That really pushes toward this is restrictive physiology. Dr. Steadley knows this better than I do And you know, it's just one of those things that as soon as you see those numbers something's wrong And you really want to have a reason for that and it's just well, you know They got high blood pressure and they've got a bad valve. There's probably something else happening Strain now the interesting thing here is when we talk about gls or global longitudinal strain We talk about values less than negative 15. That's a little bit dependent upon the vendor You don't have to worry about that too much if it's low and oftentimes these are In the 10 to 12 range you've got a real problem That deserves an evaluation The cherry on top sign is not always perfect, but if it's there, it's a wonderful thing So again, this is our 555 sign. I'm not going to go into all the echo intervals And when we talk about looking at the cherry on top sign and strain Here you can see that really the apex is spared It has normal strain parameters and then that falls off as you get through the mid to the base That is entirely a non coronary distribution for a problem. Okay, so that's incredibly important Just keep that in mind. It's not always this pretty We saw another example of strain where there's going to be some more heterogeneity And there may be a little bit of basal normal strain. That's not uncommon Strain imaging is still somewhat technically challenging and it does depend upon whether or not you've got good imaging up front So there are times when strain I really can't give you a good strain number And I can't give you a great pattern because you've got intercostal spaces that are incredibly small We lose segments that kind of stuff So you don't have to go and say well, we couldn't tell it on the strain or strain looked okay You still have to keep an open mind Again, same stuff through here. This is actually looking at the left atrium and looking at left atrial strain And again, if you have infiltration of the left atrium, that's going to set you up for atrial fibrillation Those values will be lower. Your mechanical function of the left atrium actually drops off So reporting all this stuff as far as whether or not we should say is there any question of Hamillidosis things that are going to be very suggested Increased lv wall thickness. We talked about that with the relative wall thickness already increased lv mass and mass index typical strain patterns the 555 Thing on tissue Doppler atrial enlargement particularly by atrial enlargement and loss of a wave So the a the atrial contraction the left atrium is not contributing much to filling That's incredibly important because that is infiltration of the left atrium Goes along with potential for atrial fibrillation as well That's small to trivial pericardial effusion and pleural effusions that we can't explain So I hope I caught up a little bit on time and we'll have a moment for uh Some questions later, but thank you all for your attention Thank you. So next Our next presenter is Dr. Bital severe from the university of arizona basin twosong. She's an associate professor of medicine Of radiology and is the section chief of nuclear medicine Thank you very much. I will try to get the time back. So I just do come in so All right, there you go So I will not first of all I have a lot of disclosures in ecology I don't have a disclosure on amyloidosis. So I don't have that slide This kind of Introduction already being told so I'm not going to cover that but we all know That it is not coming from sugar like the name It is actually a precursor proteins that's going to create a very stable structure And uh, depends on when it will be deposited it will create a variety of diseases. So We're here to really speak about the way to delineate lychin amyloidosis that will come from the bone marrow From ttr. Amyloidosis that will come from the liver predominantly So this is an example of a normal staining and then a congo rates turning and we all know that back in the days that That would what we do if there would be already a suspicions like we're still before the elephant in the room People will go through biopsy and the goal today is to see how can we minimize that biopsy So we all are well aware about the bone scan and this is the bottom line This is sort of the last chapter of that the last page on that chapter That in order to delineate la from ttr. Amyloidosis we would basically Exclude the monoclonal protein in the body. We will use pyp If the uptake in the heart is either equal or above that of the bone It will consider to be great to a great tree highly sensitive highly specific and also We can quantify it by putting a region of interest above the heart And compare it to the contralateral area if the ratio is above 1.5 This is actually a ttr. Amyloidosis So that being said we have multiple tracers as you can see pyp dpd edge mdp and mdp For those that not doing oncology in the united states mdp is actually the one that we do So compared to the study was shown here before about the prevalence of incidental finding of a ttr It will be really hard to do because we're not actually using routinely any of the other tracers we're using mdp And pyp is the only tracer here that is fda approved That being said let's start looking at why the guidelines are the way they are So this is a small study that looked at in 2005 already looked at a ttr patient 15 al patient 10 and then a control group They did five minutes images. They did delay images at three hours. And then they said any cardiac uptake Even if you see the heart a little bit that would be considered to be positive And you can definitely see that group a with attr was actually significantly higher in uptake than the rest of the groups And a nice thing about it that al was equal to control and that was the sign that you can actually delineate those two diseases together Interestingly enough in this cohort, which is extremely small There is no grade one and we'll talk about the grades in a little bit later And that's where i'm going into the oncology bone scans in the united states, which is mdp You can definitely see here that On a patient with attr there is actually positive uptake in the heart It's so positive that there is almost no uptake in the bones And that would be considered grade three uptake However, you can see on al that there is no uptake and what you see there It's actually the sternum and the And the spine and look at that oncology mdp tracer. It's negative on both attr and al So we don't have enough data But the data we have on mdp shows that it is inferior and i'll speak about it at the end when we have shortage of pyp So that being said a very large study 1200 patients with positive and negative and you can see that among them They had a five hundred and thirty eight attr 181 al and obviously other kinds And um, this is a very nice study because some of them add endomyocardial biopsy The rest of them had either other biopsies or clinical determination of amyloidosis and the subtype of it And uh, they use again dpd pyp and hmp dp And you can see that they only did planar and we'll talk about that as well That being said, um, they did multiple region under curbs So the first one they took the only patient that they actually did biopsy and I say we're going to call Any little uptake in the heart grade one two three we're going to call it positive We want to call negative for the one that are absolutely negative on bone skin planar only again That being said now you have sensitivity of 99 but specificity of 68 To make it very clear Now we have patients and we think they have amyloidosis or not and we kind of call all of these patients attr Whether is true positive or false positive and that's a problem So they said, okay, let's see what's going on among the false positive They saw that they had tons of patient of lichen amyloidosis and apo eight one, sorry Amyloidosis so that being said I say let's take the entire court They included all the 1200 patients now and now since specificity in the larger cohort end up being 86 higher not enough So, um, now they went and say let's see what makes it um What what why is it so important to increase the specificity to a hundred percent? Because this is a patient that you may call grade one uptake and now you won't be able to differentiate between Al and attr and now those that need chemotherapy will not receive it and now it's a problem So that being said they said, okay, let's increase the specificity by going into only calling The one that we buy up see we know for sure With the verification of truth that grade two and grade three now would be considered attr only And now they had 91 percent sensitivity 87 specificity again not enough So they start looking at the entire cohort the same concept now Sensitivity decrease because again you do have some overlap when the cohort is high But specificity again 97 percent again may not be enough So let's look at the role of the monoclonal study. I'm not gonna spend much time This is on the agenda of today, but what they did they basically said let's take all our cohort that we know Have al and then they saw that 99 percent of the lichen amyloidosis actually had some kind of monoclonal In their either urine or blood So when they excluded this population They actually find that this is where they're going to increase their specificity The interesting part was they said, you know out of attr amyloidosis in their population 19 percent also had detectable monoclonal protein So you can already understand you're going to compromise your sensitivity So now when they included all of it with grade two and grade three specificity became 100 percent, but look what happened to the sensitivity But it's okay because before everybody would go to biopsy now you can find some subpopulation That you can exclude biopsy because now you know that if they're going through these parameters They're going to have 100 specificity with positive predictive value of 100 percent to have attr amyloidosis And the best way to delineate the two So they concluded that the only people that would actually benefit from pyp bone skin would be patient with negative monoclonal Need to have again you need to think about like we would say now use that term the elephant in the room And then have positive echo cardiac mr and grade two and grade three aptexyntegraphy Pay attention that the semi quantitation is only included here, which is essentially visualization and not the Quantitation So let me show you the quantitation extremely small study but very robust because They had 12 patients of al and then out of the ttr amyloidosis They divided them almost equally to the wild type and demutate They use pyp and basically they did images at one hour Followed by spect if needed compared to the protocol today that when you have a spect CT you do it anyway And they looked at cardiac retention. They looked to see how it's washing out from the system And then they actually saw that on the semi quantitation They had two patients again with false positive that they called attr Whether they had actually lichen amyloidosis, but they went into The quantitation they only had one attr false negative So this is where they increase the sensitivity in that cohort is 97 percent and specificities remain 100 percent And you can see the delineation that when you have region of interest on the counts And you have x on the heart and you compare that to the contralateral lung on the uh on basically away from the sternum You can actually see that Everything that is 1.5 and above in ratio Would be very very specific for the delineation of ttr from lichen amyloidosis So a multi central trial look at Multiple and again, you can still see the tracers. We don't have mdp the oncology tracer that we use here in the united states So you can see that the variety of studies and again specificity and sensitivities are very high Again, they didn't Certify those studies whether they use monoclonal search or not, but they did mention that in that paper So going back into the guidelines that was done by asnak and also I took some from up to date But you guys saw that lines um on all of the presentation So first of all, do you have any clinical features of amyloidosis? If the answer is yes, you have to exclude monoclonal antibody by blood and urine And if it's yes, you have to understand it You cannot go through the attr pathway the traditional images now You have to go by hematology referral biopsy because you can actually have either attr and lichen as you saw in the study And you have to go into a different path If the answer is no now, you can actually perform pyp bone skin y pyp fda approval here We cannot bill for the rest of them And if there is basically a grade 2 a grade 3 now, you know, it's highly specific for a ttr amyloidosis If it's zero you're basically going into different approach. Maybe it's early. Maybe it's not amyloidosis But then if it's grade one, it's equivocal and biopsy would be needed anyway So going into the I won't go into all the protocols, but this is for you to see if you have an institution that has speck ct This is what we recommend and I'll explain why So the finding would be um either by semi quantitation as you can see here negative will have absolutely no optic grade one will be Optic that is slightly there less than the ribs to equal to the ribs tree above the ribs and actually decrease in the bone itself So the optic is predominantly in the heart And then you have the quantitation which you do the circle There is no really mentioning of the size that you want, but you want to get a good size around the heart Copy paste it to the other side of the technologies are doing that for us And then you want to make sure it doesn't sit on the sternum obviously because you're going to have false positive areas So three options one not suggestive when the score is zero or less than 1.5 And then you have strongly suggesting when it's two tree and above 1.5 Anything in between that is equivocal as an imager. I don't like to give you equivocal data I will try to do everything I can to say yes. No, and if I say I don't know I'll tell you why So let's go over some cases. This is a no-brainer across the street. You see gray tree. You don't even need the quantitation So this is another case and you can actually see the optic You can see where is the most deposit of the of essentially the calcium. That's what we see here And there, you know, there is probably a ttr This is an interesting case because this is a grade zero may be grade one and You know, there is a little bit of uptick there that someone can come and say, you know I don't know actually to exclude or not, but When you look at a region of how you have 1.1 said Sorry, that's sort of fluctuating that being said Now it goes into the equivocal right if you look at as snack It's like what do you do with that? Are they gonna are you guys going to take him for a biopsy according to the recommendations? So here you go. There is a speck. There is still some uptake there, right? But there is another problem. How do you exclude? So this is where the speck ct is extremely important because when you fuse them together You just see that this is in fact blood pool uptake those people May have More stasis in their blood are going to take a long time to completely excrete the tracer The uptake isn't the blood pool. It's not along the myocardium and therefore This should not be called equivocal. It should come and say in the report Not suggestive of amyloid of cardiac amyloidosis at tr amyloidosis another grade one and another example of 1.1 and another Essentially, you can see specked only that there is uptake predominantly in the blood pool But obviously your confidence is increasing when you fuse it to a ct image And for those that understand you can see that I really blacked out that image to be able to show the blood pool because look at the ribs I look at the spine how intense it is So I just try to show it But that in a non-expert eyes may go into the equivocal and that may actually send you to a different work up protocol So um another thing this is actually minimally positive So this is interesting case that I just came across not too long ago If you look at that you can definitely say grade two. It's there. There is uptake. You can't argue with that but then when you look at the Uptake and the ratio it's 1.4. It doesn't reach the threshold Is that one of the false negative that that study showed maybe But the problem is that if you look at the uptake on the upper picture you have there You see that it's predominantly in the blood pool But then when you look at other cross-section, you see that there is some uptake in the lateral wall in the basal aspect And then you don't really know what to do with that because according to the recommendation This is highly suggestive according to quantitation It's a so-so and also the spec ct doesn't show much of uptake where it's supposed to be and therefore this would have to go into the other way of Of work up because this is not as specific and that will be on the discrete of the referring physician So the challenges we know that we have again and again shortage of pyp. It's hard to get it We don't have enough kits and we need to sort of fight for it And then I always get the question Can I use the outer bone scan and the answer for that question is probably not because data is not supporting it Now if it would be positive, it's probably very positive, but if it's negative, it's probably not sensitive Another thing as mentioned it again and again, there is lack of knowledge among physician We don't get enough of these compared to what we see So and if we get them I have no clinical history to know what I'm looking at because nobody told me what happened so far So I'll know if I'm looking at the correct workflow of what I see because positive bone scan can also be shown sometimes on light-chain amyloidosis as you could see great And then as I said outreach is extremely important So I don't have time to speak and I really gonna give you a tip of the iceberg but we do have Amyloidosis beta sheet proteins that are specific for those proteins on the pet ct side Compared to the bone scan and it's mainly for TTR because we are tracing the calcium extra solar calcium deposit here We have a specific tracer that goes into this beta amyloid. So those are the three Approved tracers that you can see and When you look at the data, this is an example of a non FD approved But this is the c11 Pittsburgh B compound that you can actually see that there is correlation between mortality prognosis and the increased uptake the quantitation the suv max of the pet so Had been said This is very promising and that's probably holds true for other tracers. This is the Tracer that you all familiar with and you can see that light-chain it will show uptake and ATTR and Non-cardiac negative group will show wash out And it seems to be that the future goes into combination of both to predict some AL and delineated from ATTR Not very cheap method though not cheap at all with that. I will say thank you very And I would be happy to join the panel later. Thank you So next I welcome back our speakers back to the front so we can do a panel discussion and answer some questions And so the way we're going to do this is we're going to alternate between questions from the live audience and questions from the chat Okay, and I have michael's going around if you have questions just raise your hand so you can see you and Go to you questions Okay, so far as far as I can see we actually just have one question from The live chat and this is from Sanjay Shankar and I'm sorry if I I hope I'm Saying the question correctly question is how could you figure out the vague non not so clear cut screening test? like mg us When you do the light-chain assay Sorry, no worries. So how can you figure out the vague not so clear cut screening test? The example they gave is the monoclonal gamopathy of unclear significance when you do the light-chain assay So we are coming actually on the second phase for that We only supposed to receive patients where they have negative negative object We don't even supposed to get To our uh, to our nuclear medicine practice anyone that has any positive So this is the first step of the guidelines and I believe the data shows that Because there is overlapping between ttr and al predominantly the al but you have some sub-population that will have the ttr That that will definitely going to decrease the sensitivity but the pyp goal and that is something that I don't think is is is well Spoken the pyp goal Is to skip essentially the biopsy you don't need the biopsy if you are going through the criteria dimension everything else that That is outside of those three criteria negative monoclonal basically positive Gray to gray tree and now we adding to that the quantitation Should go through a different chain of of work up. So This is much before us and that would be probably discussed when he He won't give the talk and then we can discuss the monoclonal Yeah, I think that as a clinical cardiologist when you have the suspicion of Monoclonal hematopathy You're leading automatically down the hematology side and then the question there is Really working with hematology where they're comfortable navigating that Gamma and saying yes. No And do we have enough information here that We're going to do anything now by definition if it's muggas You're generally going to be watching that patient. Now that does not exclude ATTR So you still may need to have an evaluation in that regard because you can have as we've already seen with our presenters that you can have coexistent problems and coexistent pathology So then you really have to go back and say look everything fits for amyloid Muggas may not explain it and I'll defer again to hematology for the final word on that one in the afternoon But you still have to pay attention to that and this still could be ATTR and again approach it as I don't yet have my answer and we're really not off the hook if you got You know an infiltrated cardiomyopathy appearance on echo You got restricted filling patterns. You've got you know a pericardial infusion. You've got all of those other things You owe it to your patient to pay more attention and not just say well, it's muggas We're okay. We'll just take care of it from there Yeah, I think I totally agree One does not exclude the other I think they can be present You know concomitantly. So I think we just need to be aware of that. So yeah, good Yeah, thank you. Good reminder for this for the person who asked this question Sanjay Sanjar. Would you have Speaker on work up of monoclonal hemopathy leader in the next panel. So stay tuned I would like to add one more thing to that And we as we saw in one of the cases here even someone that not not related to the magas that comes with a negative complete negative work up and then Bone scan was negative again It's not off the hook because it may be so early that we just don't know that it's there or the deposit They didn't even start so again I I love, you know, I used to call it the new zebra because the neuro I'm coming from the oncology as well So the neuro endocrine I like the I like now the elephant in the room Because it doesn't if if there are too many clinical areas It doesn't mean that at some point that bone scan will become positive So again, it's all about the amount of damage that was done to the myocardium for the calcium to Aggregate enough to attract the pyp. So that's sort of the mechanism of action. Do we have any questions from our comments from the amyloid Carpal tunnel, how is it related to like does the amyloid plague deposits in the carpal tunnel or So the amyloid can be a deficit in so many different organs, right? So When somebody has say a hypothyroid and then they have carpal tunnel syndrome You want to attribute that carpal tunnel? Perhaps it's associated with Hypothyroidism and now your carpal tunnel and you also have somebody who has Hort failure with preserve ejection traction And they are hospitalized and then you start asking the question Oh, is there something else that I'm missing out here. Is the deposition, you know inside The nerve neuro vascular bundle and the nerve trappings Around the bones for the carpal tunnel where the median nerve is going through whether there is deposition of amyloid in those areas And whether that is the cause of the hot failure as well Are they related? So I think you need to be just open-minded about thinking that is that this is carpal tunnel Can be isolated and may not be related to anything else at all even the absence of you know, hypothyroid or You know any other you know conditions that can cause carpal tunnel syndrome But when you have confluence of something else, suddenly, you know, the light bulb goes on and you ask the question Oh, could this be could this be is the question that you need to be so that's why we are here because early detection because it is you know clear cut evidence that you start them on therapy where Julie Rosenthal will talk about That there is opportunity to actually quickly You know change the trajectory of the disease and you know The prognosis is actually changed So that's why Thinking about it is is very important Thanks to the panel for a good way to start the morning Eric studley from Mayo Clinic So Chris you said in your talk that you know, you're that epiphany occurs and you you make the diagnosis But but as I go on, you know epiphanies get farther and farther apart and so You know, perhaps the imaging folks could give us an idea of how do we Push the report or the information out From the lab to the clinician because like I said, you know, we go through our busy days and we We pray for an epiphany but often Often it's just patient after patient after patient So tell me a little more about about how how you guys would institute a mechanism to to spark that Yeah, great Eric. Great to see you. Thank you for being here. Great question, right? So The minute you you start thinking about it and then you say, okay, I want to do some more testing and then You already have the echo and that's where some of the red flags are coming up in your mind And then now you do the PYP because in your system the You know in our system the radiologist We actually put the whole protocol together for them And and so we are one on one Directly my nurse practitioner Directly is constantly asking when is the PYP scan when is it done and right on that day that it is done You know, can we quickly connect with that radiologist to give me a call back Give her a call back or whichever it is and then now you have the results quickly I totally agree with you that we need to translate that information quickly To you know, all of the folks that are involved with that patient's care including pcp And then the therapeutic strategy needs to be initiated if it is positive, right? So even if it's negative we got to be asking the question of it's negative You know, we need to be thinking something else is going on if the patient truly has is symptomatic So we can't just say oh, it's negatives. It's not I'm allowed you know, I'm out of the picture I'm not going to do anything more because the patient is still having symptoms and struggling So again patients first to your point. Yeah, we need to be a little bit more proactive clearly So Eric, how about this? How about the echo reports have the the risk or on them? So we had it calculated and then the clinician you say well, if they have hypertension Please add one point to this score and this is the sensitivity and specificity associated with this score This was done with the suggesting beta blockers in patients. So I had a low ejection fraction that was found to increase beta blocker prescription rate So I don't know if we could do that as kind of a clinical decision support. What do you think? Well, I think all of this starts actually with our sonographers So really what it comes down to is that you really do need to have a very solid echo lab And that begins with your sonographers first and foremost And maintaining very high quality standards and without that we're lost Because again garbage in garbage out if your baseline data that comes into The care of that patient is not accurate. We go down lots of different pathways Measurement issues with regard to just simple septal thickness posterior wall thickness. Do we actually define Concentric LVH well that that's critical and it's a stupid simple thing that we've been talking about since You know since we started doing M mode for that matter Okay So with that being said having accuracy and fidelity in that measurement is critically important Along with that having the ability to do Appropriate diastology and making sure that those measurements that we have are accurate And that we really can define is this a restrictive pattern in any way shape or form Those things are critical now a trivial or small pericardial effusion. Yes being mindful and not just blowing it off Those are simple things that we can do that we need to do now as far as the reporting aspect is concerned We get into trouble And where we get into trouble is that a lot of our screening tools and we talk about the risk scores If you're 80 years old with any LVH your high risk for amyloid period by echo criteria And that's not incredibly specific. It may be sensitive as all get out But our specificity there really tends to fall off so we do need to be mindful of that because I get into my world of oh gee was everybody can have amyloid And you start getting into the structural realm and you start talking about tabber patients Again, we know that they have a high prevalence. Now the question is what are we going to do about it? Okay, so you talk about tabber patients. They have LVH They have at least some degree of diastolic dysfunction They've got conduction problems and conduction problems occur Independently of anything else you talk about a right bundle. We worry about that all the time. What do we do about it? We get EP involved We want them to put a pacemaker in before we put a tavern so that we don't have to keep them any longer That tends to be the mindset now when we talk about amyloid Let's go back a little bit when we got into doing structural heart And i'll talk about my other world just a tiny bit here We ended up getting into a multidisciplinary multispecialty beast Now we have to have that same model for amyloid on the structural side. We have Interventionless we have cardiac surgeons. We have imagers. We have radiology and we have anesthesia So for amyloid, we still have largely the same team, but really we don't have anesthesia in this one But we have hematology. So we have to build a very similar multi specialty team This has to be something that is actually taken into account for all of our systems and not just Well, you're at Mayo Clinic. So you get to do this and that's great But it has to be everywhere else because mayo can't take care of everybody You know and our patients are going to multiple areas Oh his bandwidth he's got more business than he wants Trust me But that being said, we have to have these multidisciplinary Multispecialty teams as a part of our regular conversation And being able to take care of patients that way Like I said structural heart. We've done that and we do a fair job We're certainly not there, but at least we have models now, which we didn't have a decade ago So I think this is very hopeful for all of us And I would like to add one thing so I'll put the head of the co-chair of the outreach of the Outreach committee at the society of nuclear medicine as a sort of what we do As the imager is one of the biggest problems and it's not, you know, not only for cardiac amyloidosis Is everything we do we come up with so many new tracers and how do we Tell you guys how to correctly use it And I think your question is really looking at sort of the entire picture because if everyone here Has something that is very good at what it does But how do we collect that so One of the things of the society of nuclear medicine you can all just click 80 to your anyloidosis You'll find being it that's for patients So we also got an educational grant from Pfizer to be able to do something like that Those kind of events are the one that going to bring us into a full practice because yes Maya even if they wanted to like take care of everybody they can't because of also region areas right different population different geographic So if we take from the cardiology world what we do for cardiac circleidosis, there are clinics for that so Maybe less of prevalence with amyloid again, because we I don't think we really know the extent of that disease at this point, but Getting in each hospital help Administrators and that's how we do it from the society help administrator. We teach That position and it's not you know It's not doesn't need to be only oncology because of only cardiology. I apologize They go to see their pcp and that's what you said they do not make the connection I always like to tell the story of a girl that had headaches and then They gave her ibuprofen and then she didn't see anything so they gave her glasses and then she lost your period But nobody sent her to a neurologist to look at the p2 31 So that's exactly the same concept. So we have to To educate the primary physician because it's over the line That we'll see them first and then in each hospital Even we will see one person a week. We can still call it amyloid clinic And that would attract people because they go to the place where the coffee machine is pretty So if they see amyloid clinic They don't care what's going on inside and that's the key of outreach and that's what we do Making sure the patient aware Where is it where it's searchable and it's not out there for amyloid? So that's sort of my advice from the upper side of it Hi matt moorer from columbia. So um, I wanted to just follow up on eric's You know excellent comment, which he always has um in at our center I'm one of our junior faculty discovered that at the end of an echo report when Individuals who are reading the echo actually write suspect amyloid The diagnosis is five to seven times more commonly made by providers than um When I guess it's not written. So The other thing I just wanted to applaud you guys have been at, you know, hundreds of amyloid programs But I think this is very forward-looking the rationale here is very clear The drugs that we have to treat amyloid prevent new deposits We're not sure they extract They're markedly more effective when given earlier and You know, there's no doubt that what we want to do is try to identify people as early as possible Just to highlight one other thing with colleagues at the Cleveland clinic recently is that 83 percent of patients with wild type amyloid have an orthopedic manifestation. So it's nearly universal So everyone in clinic needs to ask when they're seeing anyone who's elderly with the phenotypes We talked about about carpal tunnel syndrome lumbar spinal stenosis and any joint replacement hip knee or shoulder collectively like I said 83 percent of patients are going to have one of those findings and heightened suspicion is the key If you don't put amyloid on your differential, you're never going to make the diagnosis I think that's an excellent point and the one thing that I failed to mention in again echo reporting Is with structured reporting having the ability to say You know features consistent with infiltrative cardiomyopathy slash amyloid and that is a common Summary statement that we have and we use We've not tracked that as far as outcomes, but it is something that we routinely do The biggest challenge that you get I think in community practice Is that for the most part you don't have a dedicated group of echocardiographers that are actually reading So this is an all-comers event So whether you're an interventionalist or non-invasive or an echo guy You're still reading your own echoes. And so it does create a great deal of heterogeneity particularly in community practices And I don't know that we're going to get away from that except for ongoing educational events Getting people to at least go to grant rounds conferences like this and then hopefully Maintaining some degree of heightened awareness, but it is it's a major challenge because You know echoes are still a big part of the general cardiologists livelihood So we're not changing that any time too soon Absolutely great point Matt And the other thing that many times happens in the echo Is that we're diagnosed hypertrophic cardiomyopathy and mistakenly and So when we see for the especially for the echo technicians who are all in the audience When you see something that suspicious It looks like LVH. Maybe that is asymmetric septal hypertrophy a little bit more And you you assume though, maybe there is a Hooker maybe It's just LVH But make sure that you do valsalva on every one of those patients to make sure that is it truly Hypertrophy is there a gradient that significantly increases with valsalva? And if it is and then question is oh, could this be amyloid? This should be always thinking about that concept I come from the world of geriatrics and cardiology as well as medical education And I agree that the vast majority of these patients are seen on the primary care level But you have a captive audience who doesn't have time necessarily to go to grand rounds of that But in the state of arizona to renew your license you're required to take a certain a quiz every two years On basically the opioid crisis in this in this country And that's critical that you take that and pass that before you get re-licensed Why don't we have an initiative to have at least some basic training about amyloid because I think the problem is huge And having spent the last 15 years in medical education getting these people At the fellowship level in geriatrics and the cardiologists and geriatricians myself They don't know jack about Amyloid, I mean it's like oh, that's really weird. Thank you dr. Segal, you know But I think that that's a golden opportunity They have to do this to recertify get their license again And even if it's only if you don't make it the re-licensure Depending on this at least have them respond to a cma program a quiz And then you'll have an idea of how big the problem of recognition at the level where most patients are Looking at it from a higher So we're thank you so much for our store speakers and presenters. We appreciate you. We are now during our coffee break Please come back 1010 I'm sorry So just before the break, I just wanted to kind of update you about something very important This event is actually endorsed by the american college of cardiology And we are truly humbled and and really honored to have had that Opportunity and April and the team have really Worked hard on getting that together in the ACC Arizona chapter Especially with liana college. I want to thank her who's been their executive director for for a number of years And she made it happen. And so we are we have acc endorsements So I just want to kind of be dr. Sue will pursue is a current governor We call them governor of Arizona chapter for acc. There are 60 governors in the country and we all are part of the The steering committee of the executive board actually of acc at the national level when you become a governor And I was privileged to and humbled to have been the governor for acc From 19 2009 through 2013. I can't believe it's almost 10 years ago. I finished my tenure I can't believe that but it was such an incredible experience and will pursue who's a electrophysiologist here at banner He's not able to come today and he was going to say a few words about acc And if they don't can can I talk about it because there's one of the previous governor? And I just want to just briefly tell you about their purpose And what they do so to contribute The the purpose is to contribute to the prevention of cardiovascular disease and to ensure optimal Quality of care for individuals with such diseases in carrying out this purpose So the chapter functions in consultation with the leadership of the college at the national level as a source of advice To local and state government and professional organizations concerning issues related to current after The chapter in the interest of patients physicians and the public In general maintains a high level of social consciousness And involvement with all of the social economic factors You heard the term de and i the diversity equity and inclusiveness is the buzzword It's going all over the place with every society really picking up that tab And also giving access to the highest possible quality of cardiovascular health care So they have core values of patient centered centeredness team or collaboration Again is very very apropos to our discussion with amyloidosis the teamwork and collaboration With all of the multi morbid modality that we see with multiple specialities here And of course the professional excellence They do it through conferences and publications and newsletters and And social media presence in twitter facebook lots of resources and the conversations in cardiology Quality outcomes a do door to balloon gap h2h Images in cardiology and also the large registries, right? So one of the largest registries is going on. It's called the pinnacle registry And i'm part of pinnacle india on the steering committee, which is also part of the Exemplation of the pinnacle in the u.s. And and and they got awarded for the FIT fellowship fellows in training for the local chapter and also for the the best women in cardiology For a chapter in in the country. So kudos to all of them. Thank you to ACC for endorsing and again, thank you all for coming and any questions you have about ecc this Reach out to me and Thanks to lianna college who's also done some phenomenal work again. Thanks for coming Let's have a break and then we'll meet up and regroup again. Thank you You Okay, good. Good morning everyone. We're gonna go ahead and get started with our second session So go ahead and grab your seats So, thank you everyone for a great first session. I just wanted to briefly introduce myself and my co-moderator here I'm amber and rottie. I'm one of the heart failure specialists at bannon university and university of arizona And matt more from a columbia university pleasure to be with you all So we have a great second session for you guys. We'd like to bring up our first speaker Sonia Zabrowski from the male clinic will be talking about the role of genetic testing I know this can be the bane of our existence in cardiac amyloid diagnosis Let alone just all of cardiomyopathy. So really excited for her great talk. Thank you for your attention Hopefully you can all hear me. Okay. Thank you for that introduction amber. Um, as she mentioned, I'm a genetic counselor I work at Mayo clinic and I actually serve our adult general genetics population So I see lots of patients with wide varieties of indications, but I'm particularly fond of cardiac genetics So today I'll be discussing the role of genetic testing in cardiac amyloidosis So no conflicts of interest to disclose breeze through that Um, so given that my focus areas in genetics Uh, it's fitting that the majority of this discussion will focus on identifying hereditary or variant type trans thyrotin amyloidosis Um, so thinking about the types of amyloidosis most commonly associated with cardiac manifestations We've already touched on al and attr In the attr cases as we've also discussed can be wild type or hereditary And genetic testing can help differentiate between the two Which can then help us better understand implications for the patient and their family members So genetic testing for hereditary ttr Amyloidosis involves analysis of the ttr gene And this gene is located on chromosome 18 q12.1 and encodes the trans thyrotin protein Which again as discussed previously is one of the three pre-albumins So I won't talk too much about this since we've already gone over most of it But pathogenic variants also known as mutations in this gene are associated with amyloid deposition Predominantly affecting the peripheral nerves or the heart Though there are a small percentage of gene mutations considered to be non amyloidogenic So ttr genetic variants are implicated in the etiology of several diseases Including amyloidotic polyneuropathy urethroid hyperthyroxenemia amyloidotic vitreous opacity opacities cardiomyopathy and carpal tunnel syndrome as we've discussed previously And from a molecular standpoint pathogenic variants in this gene are nearly always sequence variants rather than deletions or duplications So thinking about the inheritance of hereditary attr These variants are inherited in an autosomal dominant pattern So that means that each child of an individual with hereditary ttr amyloidosis Has a 50 chance to inherit this causative variant And we expect that the affected individual inherited the variant from a parent So we would also anticipate that other first-degree relatives. So siblings parents Also have a 50 chance to share the same amyloidosis causing variant Theoretically, there's a chance that somebody's ttr variant could be de novo or new arising for the first time in themselves But the rate of de novo ttr mutations is currently unknown And we'll continue to dive into the concepts of incomplete penetrance and variable Expressivity as related to this condition But just so we have kind of a framework for what those mean over the next couple of slides Incomplete penetrance really refers to the idea that not all individuals With a specific genotype will manifest a particular Clinical symptoms or characteristics of that While variable expressivity really refers to the variability of signs and symptoms that can occur in different people with the same genetic condition And these things incomplete penetrance variable expressivity are pretty common in the cardiogenetics world And for hereditary ttr amyloidosis, there's been quite a bit of investigation done related to genotype phenotype correlations for specific variants So for example, uh, the valine 50 methionine variant is considered the most widely studied ttr variant And just to touch on nomenclature again Really what this means is that at amino amino acid position 50 there should be a valine and now there's a methionine there And autonomic neuropathy and peripheral neuropathy are most commonly associated with this variant While cardiac involvement is much less common And penetrance appears to vary by age region or ethnic group So just for example in portugal the cumulative disease risk in individuals with this variant is estimated to be At about 91 percent Whereas in individuals in france who are heterozygous for this variant The risk is about 50 percent by age 70 and in sweden the penetrance is much lower Estimated to be at 36 percent by age 70 And in some cases heterozygous do remain completely asymptomatic And then looking at another example, uh, we've also briefly touched on this one previously as well Approximately three to four percent of african americans are estimated to carry the valine 142 isoleucine variant Which may be present in more than five percent of the population in some areas of west africa And most individuals um, who are heterozygous for this variant are expected to develop late onset cardiac amylidosis So over 140 disease causing ttr variants have been identified And this table shows a few additional genetic variants with a breakdown of how these variants have been characterized thus far in terms of prevalence median age of onset at symptom presentation primary ethnicity geographical region cardiac phenotype other manifestations And genotyping doesn't provide us with a crystal ball to perfectly predict disease course or outcome But it can help us anticipate general clinical presentation age of onset organ involvement and potential prognosis Based on what have been generally seen in individuals with these specific variants And we do know that uh, essentially all ttr variants exhibit age dependent penetrance. So risk for symptoms increases with age And research has also been done in individuals who are homozygous for specifically that val 50 met variant And people So people who have two of this variant want an either copy of their ttr gene And this has suggested that homozygous present with a slightly more severe clinical course So higher incidence rate earlier onset than heterozygotes within the same family or people with just one ttr mutation And in these people who are homozygous amyloid deposition was also found to be more widespread Compared to heterozygotes in that study And so another important piece of information to consider when reading a genetic test report or searching for specific ttr variants in the literature Is that the nomenclature of these variants has changed over time So when we look at that val 50 met variant in one paper It might also show up as the val 30 met variant in another paper And really this naming convention Differentiation is just because one includes a 20 amino acid signal peptide in the count of residues Whereas the other doesn't so that accounts for the difference between 30 and 50 But just important to keep in mind as we see these variants pop up in the research And then as previously mentioned, you know, there are many more known ttr variants than just those five So many have been studied to better understand the phenotypes associated with them And and that is available in in the research to find So knowing a patient's genotype and whether their ttr amyloidosis is wild type or hereditary may also have implications in treatment And I am not an expert on the treatment side of things But just to briefly review options may include ttr tetramer stabilizers to address tetramer dissociation In fibril formation or gene silencing therapies, which use Anticent's oligonucleotides or small interfering RNAs to reduce amyloid fibril precursor protein And there are other potential molecular therapies under investigation as well for hereditary ttr amyloidosis That may aim to also either inhibit synthesis or stabilize variant ttr Or to disrupt insoluble insoluble amyloid fibrils So gene editing therapies such as CRISPR-Cas9 technology is one of these methods methods that's currently under investigation So we're probably all familiar with the clinical trials.gov website So I won't talk about that too much But some of the eligibility criteria for these research studies or clinical trials may require a known genetic variant to be present So now that we've kind of touched on why genetic testing can be beneficial It's important to know when it's indicated So ttr genetic testing is certainly recommended for all patients with an established diagnosis of Ttr cardiac amyloidosis regardless of age to differentiate between the wild type and hereditary Attr given the disgust management implications And at this time genetic testing is not indicated for al amyloidosis Another situation that may arise or you know, maybe you've interacted with patients who have done Direct to consumer testing that can be purchased at the store Sometimes patients who do this type of testing and opt in for the medical assessment side of things Maybe identified to carry a common ttr variant so For context these you know tests are commercially available to purchase healthcare provider involvement insurance provider involvement is not necessary And they might screen for the presence of really only three common ttr variants So if a patient is found to carry one of these variants, there's a good chance that it's a true positive But it's still recommended to follow up with confirmatory clinical genetic testing um Now it's also important to be especially wary of patients who might have done direct to consumer testing and they say I have a rare variant in the ttr gene These may pop up when patients elect to Use their data that they've gotten from direct to consumer testing and upload it to a third party interpretation service um These rare variants that pop up from that type of testing have been known to have a significant false positive rate So certainly clinical uh confirmatory testing is really recommended in those cases And on the flip side of that Um, it's also again important to recognize that this testing only really screens for those three common variants So if somebody has a suspicious clinical or family history for hereditary amyloidosis But they say oh, I had negative direct to consumer testing That really doesn't rule out the possibility that this is something hereditary And clinical ttr sequencing would be indicated in that case for a more comprehensive analysis And then another indication for genetic testing would be if somebody has a known family history of a known ttr variant And they want to know what their risk is And in that case, it's really helpful for the patient to obtain records of their affected family members genetic test results So we have reference of what variant we should know to be looking for And it's important to keep in mind that a negative family history Doesn't necessarily rule out the possibility of hereditary ttr amyloidosis There are several reasons why a family history may appear Non-contributory such as the failure to recognize symptoms Early death of a parent or or other relatives before onset of symptoms that really never had a chance to present Or given the variable nature of the condition It's possible that it may not have yet presented itself in a parent or other family members And then once we have identified. Okay, this patient probably needs some genetic testing or is recommended to have genetic testing How do we coordinate that? The testing itself is typically performed using a blood buckle or saliva sample And there are many labs that offer ttr analysis as a genetic testing service So some of these commercial labs who specialize in genetic testing may have convenient insurance billing assistance Where they might be able to conduct a benefit investigation for the patient to provide them with an estimated cost of the testing Before proceeding with testing Or they might provide them with a self-pay option for testing. That's typically around $250 Some of these labs also have policies to not balance bill patients who are insured through Medicare or Medicaid So oftentimes testing might be covered for them Um, additionally, I have on here some Sponsored testing programs as well So these exist to offer no charge genetic testing to patients who meet certain eligibility criteria Like a suspected diagnosis in themselves or a confirmed family history of hereditary amyloidosis So there's often different Eligibility or clinical features that you can go in and say yes, this patient meets this criteria And they might qualify for free testing So these sponsored programs have the goal of providing increased access to genetic testing and counseling for patients And they then might receive de-identified patient data for research and commercial purposes So just a couple of examples of those are the lnylam act program through in vitae laboratory As well as the hatt tr compass genetic testing program through ambre genetics So if you need assistance coordinating genetic testing genetic counselors are here to help In general, we can assist with performing risk assessments Providing genetics educations for patients as well as their family members Facilitating decision-making and coordinating that genetic testing as well Among other things that we can assist with so if you have genetics questions ask us And where do we find genetic counselors or hospital or clinic may have genetic counselors on staff Who can assist in answering genetics questions or point you in the right direction But also many of these labs offer genetic counseling services So you can call the lab and ask questions about variant interpretation or if you need help understanding a result Or sometimes genetic counseling for positive results is included for patients in the cost of testing Or they might partner with independent telehealth companies that can provide those genetic counseling services for patients And a good resource I always provide to is www.findajuneticcounselor.com that can help you locate local genetic counselors So looking past the affected patient themselves and into their their family and family dynamics When a genetic variant is identified to be the cause of a patient's amyloidosis Their family members might be interested to know, you know, whether they're also at risk for Perpetuary amyloidosis as well So testing of asymptomatic family members requires additional consideration and counseling It's important that they have the opportunity to Meet with a genetics provider to discuss their motivations for genetic testing As well as the benefits and limitations of doing genetic testing at that time So they might have certain expectations Of what testing can tell them and how it might impact their medical management or their family dynamics So it's helpful to have a discussion of family history to understand What their experience has been with the condition and that affected family member or multiple family members And kind of to know what the predicted age of disease onset may be for that family Both in terms of what other family members have shown and what we might know from the research side of things about that particular familial variant So it's been suggested to begin monitoring for symptoms around 10 years earlier than the predicted age of onset And it's also important to consider that predictive testing in asymptomatic minors is considered inappropriate So it's helpful to set expectations with a patient that if they're positive for the variant We typically will not be testing their children if under 18 Something else to think about is psychosocial implications of testing really not everybody is going to react The same way to a positive or negative genetic test result finding out about their risk for one of these For this condition So it can be helpful to prompt the patients to consider know how they would really feel either way Maybe if a negative result they might be really glad or relieved that they're not at risk Or sometimes patients might feel guilty that everybody else in their family is positive or or have undergone this Medical experience and and now they know that that's not going to be the case for them Or on the flip side if a positive test result Maybe they'll be really anxious or stressed about the potential health implications Or they could feel empowered to know their risks and understand their management options And then from an insurance standpoint, it's important to think about how The implications of learning about a genetic test result might impact different insurance Eligibilities so something I talk about with patients is that there's a federal law called gina or the genetic information Non-discrimination act that protects most people from their health insurance and employer Asking about their genetic test results or using that risk information to discriminate against them However other insurance companies like life insurance long-term care disability insurance companies Are legally allowed to ask about genetic test results and use them in their eligibility determination processes So for some patients, this is something they really care about for others something that's not too much on their mind And another reason that individuals might want to know their ttr genetic status is for family planning purposes So when a person is identified to have a ttr pathogenic variant IVF and pre implantation genetic testing might be available to select for embryos that don't carry the variant And there are differences in perspective about prenatal testing for familial ttr variants during pregnancy Given the adult onset and variability of the condition So really discussion of the considerations may be beneficial for reproductive decision making as well So with that I just have some references And thank you so much for your time Thank you, Sonia for that amazing Comprehensive overview. I'm sure we will have many questions for you at the panel discussion We'd like to bring up our next speaker Dr. Muhammad Hussein from the University of Arizona Tucson will be talking about the work of of monoclonal gamapathy Thank you for the introduction and happy to be here So my name is Muhammad. I'm an assistant professor at the University of Arizona Tucson and I will be I'm a hematologist Talking to a lot of cardiologists here today and my discussion is work up for monoclonal gamapathy So these are my disclosures So objective for today's talk is I will be talking how we need to work up for monoclonal gamapathy And then work up for light chain amyloidosis and staging and prognosis of light chain amyloidosis So we'll start with the clinical case This is the case that I saw a couple of months ago an 80 year old man with history of hypertension Who was diagnosed with heart failure with preserved reaction infection EFs 55 to 60 percent Patient had three admissions for heart failure exacerbation and echo showed left ventricular hypertrophy Then hematology and that question was effort to me actually from a community oncologist They had already started the work of they had done the SPAP IFE and free kappa lambda ratio So SPAP showed M spike of 0.7 camp per deciliter Immunofixation serum was positive for IgM lambda monoclonal gamapathy Free kappa light chain was 20 and milligram per liter and free lambda light chain was 51.4 and kappa lambda ratio was 0.4 For this patient. So we started further work up 24 over U.N. protein electrophysicist was done We showed 78 milligram per day total protein and 24 over U.N. immunofixation did not show any monoclonal protein cardiac MRI was done, which showed That it was consistent with cardiac mly doses So we found a bone marrow biopsy on this patient with short 5% CD138 plasma cells and congoxidane was positive for mly deposition So we sent this specimen for mass spectrometry to myoclinic and this confirmed this to be a light chain lambda mly doses And patient was started on treatment with data cyborg based chemotherapy He has been on treatment for last couple of months tolerating treatment Well, and the light chains are improving and heart failure is kind of stable for him for now So, uh, this has been already discussed, but the AL mly doses is on 50 percent of all the amyloid Types, this was a study done by Myoclinic and then the rest are all the different amyloid doses including the TTI mly doses and wild type and Heriotree and also there could be localized amyloid deposition as well But main focus is light chain mly doses and systemic mly doses for today's discussion This is not working. Okay All right, so light chain mly doses is a serious disease. There are around 2000 cases per year diagnosed in us so six to 10 cases per million diagnosed per year and the median age of diagnosis is 64 and 10 percent of these patients could have cab criteria and have concurrent multiple myeloma as well So pathophysiology of light chain mly doses is mainly a bone marrow disorder plasma cell disorder plasma cells which usually make the normal light chains Stimulated by different antigens But in this case they start making the the monoclonal light chains and those monoclonal light chains and can form the amyloid Fibers and those amyloid fibres can then have the systemic deposition in different organs in the body Heart being the most common organ than kidneys and liver The second and third and there could be GI involvement and nervous tissue involvement as well So we only need a small number of plasma cells This to cause the light chain mly doses So only five to 10 percent of the plasma cells are usually enough to cause light chain mly doses And initially patients can have monoclonal gemopathy of undetermined significance and then this can progress to amyloid deposition in these patients and amyloid as we said can cause endocrine damage And then these patients could be diagnosed with amyloid So I wanted to spend a minute on differentiating between multiple myeloma and Light chain amyloid osis so patients could have enol involvement from the from the amyloid osis and they could have predominant protein oia But in patients who have multiple myeloma the inner damage is different than these what we see in patients with Light chain amyloid osis so in patients who have multiple myeloma usually what we see is the cast nephropathy or what we call myeloma kidney While in light chain amyloid osis most of these patients if they have the inner involvement The predominant protein oia is albumin oia and not the light chain. So that's It's one of the differentiating features that we can see and then those patients They might not have the myeloma kidney, but they could have the light chain amyloid osis So it's important to get that differentiation done and that can help you differentiate whether it's amyloid or myeloma there So clinical presentation for most of these patients Cardiac involvement is most common. So patients that can present with Heart failure enol involvement so they can present with nephrotic input in oia, which is most commonly is albumin oia in those patients There could be nervous system involvement and can cause painful neopathy Autonomic dysfunction could also be seen patients could be having hypertension disease spell They could have very orbital purple skin changes and then unexplained edema unexplained soft tissue involvement elevated liver enzymes elevated Force and enlarged liver and in the gi they could have diarrhea and gi bleeding as well Uh, so diagnosis requires pattern recognition. So most of these patients if they have On the echocardiography, they have hypertrophy left ventricular septal hypertrophy and then they Some of those patients who are on anti-hapotensive and now they're becoming intolerant to their anti-hapotensive medications are becoming more hypertensive and then low blood pressures history of carpal tunnel syndrome and For the light chain most of these patients would have heart failure Plus minus nephrotic input in oia if they have Enol involvement as well and they could have macroglossia and paiovital purple I think macroglossia is more specific with with the light chain amyloidosis I haven't seen many patients having macroglossia with tti amyloidosis as well And orthostatic hypertension paifal neopathy and they would have the monoclonal chemotherapy present as well So heart is the most common organ involved in the light chain amyloidosis 57% of the patients have cardiac involvement 44% has have enol involvement and then 22% of the patients have nervous involvement Liver involvement is on 17% gi is on 16% and then other soft tissue involvement could be seen in 5% of the patients So this is the i am wg diagnostic criteria for systemic light chain amyloidosis So patients have to have an amyloid-related systemic syndrome They should have either enol liver heart or gi tract involvement or paifal nervous system involvement positive amyloid straining by a congregate in any tissue fat aspirate bone marrow organ biopsy and evidence that amyloid is light chain related established by direct examination of the amyloid using mass spectrometry base proteomic analysis or immunoelectron microscopy is one of the requirement by international myeloma working group For us to diagnose these patients with light chain amyloidosis And they have to have an evidence of monoclonal plasma cell proliferative disorder In the CMOU in monoclonal protein abdominal free light chain ratio Our clonal plasma cells in the bone marrow must be present So whenever we are suspecting patients to have amyloidosis We need to order these comprehensive hematological workup which involves doing a serum protein electrophysicis serum immunofixation free light chain assay Un 24 our un protein electrophysicis and 24 our un immunofixation I think it's important to do all of these testing because Most of the time patients could have just the free light chain disease sometime the Aspab might be negative, but we might be able to pick the disease on the free light chain assay and sometime patients could have just the Un kidney involvement and they could have free light chains in the urine So it's important to do a 24 our un electrophysicis on these patients to determine whether these patients have nephroticine protein or not So a slide on the interpretation of aspab So this is the aspab interpretation mainly patients who have a monoclonal gemopathy They would have Nephroticine point there Yeah, so patients would have an m spike which is presented like this While the other graphs they can have a more of a monoclonal spike Or a polyclonal spike there So aspab usually tells us whether there is a monoclonal gemopathy or present or not And then we do the immunofixation to tell us what type of Monoclonal gemopathy is present and then we use the anti-seer to determine whether it's idg ida or idm or kappa lambda type So like in this patient this patient has an idg Band here and then a kappa band here. So this is an idg kappa monoclonal gemopathy present on this same immunofixation And then these are the cm free Light-chain ratios So the normal ratio in a patient with a normal kidney function is usually from 0.64 to 1.92 and then if the Rinal function goes down the ratio can go up a little bit up to 2.17 So in patients with edf are less than 30 the free light-chain ratio can be as high from 0.67 to 2.17 So these are the normal values if the free light-chain ratio is either more than 2.1 Or less than 0.6 in a patient with low gfr Then that is considered abnormal and those patients need to have further work up for And the light-chain amyloidosis So confirm confirmation of light-chain amyloidosis always involves getting a bone marrow biopsy with congoir strain Getting an abdominal fat pad biopsy Or aspirate and biopsy of the involved organ if we are not finding the congoir positivity on bone marrow biopsy or biopsy of the abdominal fat pad and then mass spectrometry to confirm the the type of that amyloid fibers So this is just one diagram showing the amyloid deposition in the periart arterial regions here pericapillary and then positive for congoir strain and these are the amyloid fibers that can be seen here So this is one of the diagnostic algorithm which proposed in jack for cardiac amyloidosis So if patient there's a clinical suspicion with typical echo and cardiac findings so the next step that We should be doing in these patients is getting a serum and u-in protein electrophysicis and serum free light-chain Acid on in these patients and if that confirms that their patient has a monoclonal protein present Then we will go down this path of Involving your friendly hematologist in that case and getting the fat pad aspirate and a bone marrow biopsy down If the fat pad aspirate and bone marrow biopsy Show the amyloid deposition Then we should get a mass spectrometry to confirm what type of amyloid is this and then if that is confirmed Then we can treat it accordingly whether it's a ttr or light-chain amyloidosis If the the fat pad and bone marrow are negative in a patients with Monoclonal gemopathy, then if the patient still we have a high suspicion For amyloidosis then those patients we can go to mass spectrometry in those patients and We can also get the cardiac biopsy If there's a cardiac involvement to confirm what type of amyloid is this if the ampotin is negative then the on We can go down this path where we can get the the p y p scan in these patients And if p y p has great two to three uptake on and the the p y p scan that Confirm the ttr amyloidosis and we can get the ttr sequencing Done if if it is negative the p y p scan Then I think if you still have the high suspicion Then we should get the cardiac biopsy In these patients end of myocardial biopsy to confirm the diagnosis of cardiac amyloid deposition A slide on the staging for light-chain amyloidosis it is mainly Depending on the cardiac involvement so patients who have cardiac involvement and they have the antipo BNP of more than 1800 Our troponin T is more than 0.025 and the difference in the free light chain is more than 18 milligram per deciliter So patient who has none of these that that stage zero if one of these Is present that stage two if two are present that stage three and if all three are elevated So that's a stage four disease and The prognosis of these patients depends on the stage and we can see here from stage one to stage four The median overall survival goes down from 94 months to six less than six months in these patients So it's imperative to get these patients diagnosed early before they develop stage four Cardiac failure because those patients when they're diagnosed at the stage four disease then their prognosis is poor and most of these patients are not even eligible for therapy at that time because they are so frail and not even able to tolerate the treatment When they have the stage four amyloidosis So this is just one Slide discussing on how we can target The amyloid in most of these patients. So most of the treatments that we have available available so far Directed against the plasma cells. So the therapy that we are using are mainly the anti plasma cells Directed we don't have any good drugs that can target the amyloid fibers that have already deposited So again coming to the point that if we try to diagnose these patients early We might be able to detect them early and can offer them treatments because once the amyloid gets deposited. It's very difficult to To recover from from that damage There are some newer anti fiber treatments that are in the clinical trials There's one k l 101 that is showing some good progress. So hopefully if that Show some good results, we might have some anti fiber therapy But so far the therapy that we have is directed against the Underlying plasma cells. So they're different components. So there's a chemotherapy drugs immunomodulatory drugs And then there are monoclonal antibodies. So chemotherapy We use Melphlan cyclophosphamide. Then we have proteasome inhibitors Uh, which is what is a map is the most Important drug there that we have immunomodulatory drugs emits Lena little mice and then we have the newest modality of the monoclonal antibodies CD 38 is one of the target on the plasma cells that we can use to Target the plasma cells and their tumor map is one of the drug that has shown a very good efficacy in in these patients So this was the endometa clinical trial published in NEJM in 2021 which studied the vcd or the cyborg combination And they randomized patients to two arms one arm got the cyborg another arm got just the cyborg and But this this trial excluded patients with stage 3b Cardiac disease amyloidosis But we have shown here that the data tumor map addition Improves the outcome in these patients significantly as compared to just the cyborg D So most of the patient the standard of care for the first line is if they're able to tolerate We start them on the combination chemotherapy with data Valkate cyclophosphamide indexer methazone based therapy And with this treatment, uh, there was significant cardic and renal responses and this is Responsed at six months and 12 months and we showed that With the addition of the cyborg D. There was a 42 percent cardic response as compared to 22 percent just with with the cyborg D and the same with At the 12 month the response it even improved to 57 percent in the data cyborg D as compared to 28 percent of the patients in In the cyborg D. So it's important to get those Patients started on the combination of the data cyborg treatment once we diagnose them with light chain amyloidosis So treatment options start with data cyborg D consider stem cell transplant if they're transplant eligible If transplant ineligible then we continue them on the data cyborg until We have able to achieve a very good hematological response or better if they have a lapse to factory disease then And there are some other treatment options available like formalidomide indexer methazone Lidomide carfilzomib and patients who have 1114 translocation consider venatoclax which is Another targeted Treatment that we can use in these patients that has shown some good results in patients who have 1114 translocation So the take home message here is that consider amyloidosis in patients light chain amyloidosis if patients have non ischemic cardiomyopathy and they have lvh on echo findings and we start with the work up with The aspect immunofixation and free light chain ratio if patients have full neuropathy autoimmune dysfunction compartmental syndrome peri orbital perp macroglossia that Phenotype is more consistent with light chain amyloid So we check see them during electrophysicist Immunofixation free light chain ratio and if monoclonal protein is present as abnormal free light chain Present then we need to get hematology involved for bone marrow and biopsy in fact that aspirate Before ordering a pyp scan. I think because the pyp scan sometimes can you give you false positive There's an in those patients. I think it's important to rule out the light chain amyloidosis first before we jump on to the next step Over this I would like to conclude and thank you everyone for your attention Listening for being our friendly hematologist and sharing your expertise on al amyloidosis Next we are going to bring up dr. Brett Goodman from the Mayo Clinic Brent Goodman, excuse me from the Mayo Clinic. We'll be talking about neurological presentations of ATTR I promise to be a friendly neurologist It's a privilege to be here part of the part of the discussion today My task is to focus on TTR and and neurology I have If I could break it down to maybe three take home points Really I would have three take home points number one would be This really does begin with carpal tunnel syndrome and we need to figure out how to identify patients With carpal tunnel who are going to have or have amyloid Second Unfortunately, we need to rely on neurophysiologic testing when evaluating and caring for these patients I'll talk a bit more about that and third As has been mentioned earlier We need to get treatment started as early as possible Neurological improvement or at least stabilization that really relies on early diagnosis. And so Those are my three main main points today With amyloid particularly with TTR This can do about anything to the peripheral nervous system and we've seen that including carpal tunnel Ridiculopathy spinal stenosis neuropathy autonomic neuropathy It truly can do about anything to the autonomic nervous system Important to recognize it may be The first part of the of The body to be involved if you consider the media nerve running through the the carpal tunnel to be a neurological Symptom or sign I would Important to recognize that Once there is significant neurological impairment it may be difficult or impossible To reverse to significantly Reverse Neurological impairment. So we need to get these folks diagnosed quickly early And get them on treatment and then Many of the patients need symptomatic treatment as well The different forms of neurological impairment may provide clues to the different forms of amyloid or perhaps even the different genetic subtype So the different neurological manifestations the most common that we see would be Carpal tunnel which you could consider orthopedic or neurological Lumbar spinal stenosis peripheral neuropathy autonomic neuropathy. These are the most common things that we see Our tools are the the history of course our neurological examination Most of these pay these patients really do require neurophysiologic testing They need nerve conduction studies and DMG To make these differentiations, and I'll talk a little bit about why here in a second I would advocate for autonomic testing We have a busy autonomic lab at Mayo And I've cared for a number of these patients over the years It can be very difficult to to differentiate autonomic impairment in these patients from cardiac impairment and sometimes You know particularly if they're on anti-hypertensives, etc So what's what's medication effect? What's cardiac? What's an odd? What's the result of an autonomic neuropathy autonomic testing can really help with that We do skin punch biopsies and many of these patients and the role of that is to to establish whether a small fiber Neuropathy is present But that skin can also be stained for for amyloid so that can be helpful particularly in the Pre symptomatic or maybe minimally symptomatic patients in whom you're considering whether to start Let's say silence or treatment on Lumbar MRI of course is important in diagnosing Lumbar spinal stenosis, but Remember after a couple of decades nobody has a normal lumbar MRI So that needs to be put together with the the clinical story and then of course genetic testing So as a neurologist we consider these different forms of of of amyloid S has been discussed um, I would Like to highlight though this the study out of out of Mayo Clinic Rochester Some of the differences between what they called at the time. This was a number of years ago familial amyloid versus AL amyloid and you can see here in their retrospective study peripheral neuropathy was much more common at presentation in The familial amyloid patients as opposed to AL amyloid patients. So Important to recognize that and then autonomic neuropathy also much more common During the course of illness familial amyloid, of course, this was pretty largely pre-treatment So these definitely differences clinically between these two forms of amyloid just generally So, um, I find wild type amyloid a challenge Oftentimes the patients are are older. They may have a number of different medical comorbidities Most of the patients or really all of the patients that I see with wild type amyloid on the neurological side of things Have carpal tunnel and spinal stenosis I can't think of a single patient over at least the last Four or five years who have who hasn't had that history. So that's very typical It can be very difficult to differentiate a neuropathy from spinal stenosis. I'll talk about that in a moment and while it's not Clearly established. I do think that these wild type amyloid cases can have Can develop a very mild neuropathy. Although again that can be very difficult to distinguish from lumbar spinal stenosis The if they develop an autonomic neuropathy, it's subclinical meaning they don't have symptoms But they may have some abnormalities on autonomic testing Carpal tunnel uh syndrome This is hugely important for us to recognize and I think we spoke a little bit earlier about Healthcare systems and how we might do a better job diagnosing early earlier in someone's course The important thing I think with carpal tunnel is This proceeds the development of other things by sometimes many years can be five or ten years so um, we really have to ask all right Did you have carpal tunnel in times past? Did you have numbness tingling in your hands? Did you have surgery for carpal tunnel? It may not be concurrent with their current cardiac evaluation that a person is getting worked up for So remember with carpal tunnel. It's numbness tingling in the hands. It may be pain Not everybody has pain and it's often weakness The clue the helpful clue possibly is is that it's bilateral, but it's also typically fairly symmetric The problem is that carpal tunnel is so common And it's often bilateral It's by if we do an emg on somebody who comes in with Carpal tunnel in their right hand their chance of having it in the left is upwards of 80 percent so That bilaterality is helpful But in amyloid it's often symmetric the symptoms are are often the same in both hands but One of the things that we certainly need to be working on is perhaps what cardiology has done and looking at Perhaps some ai techniques for identifying possible clues to carpal tunnel What are the signatures for for amyloid on on emg testing for example? lumbar spinal stenosis also extremely common often Proceeds the development of other neurological issues cardiac issues You know classically this is back in leg pain. That's Present when upright went with with ambulation that gets better if somebody leans forward But not all patients have That complaint they may just complain of numbness in the legs or feet Which can make this very difficult to distinguish from neuropathy so To make this diagnosis we need a We really need lumbar mri and then an emg To try to differentiate between neuropathy and spinal stenosis The other thing that I look for clinically is asymmetry typically in the lower limbs Neuropathy related to amyloid is symmetric. So spinal stenosis Is going to be Any sensory symptoms related to spinal stenosis that are fixed that are present all of the time that aren't positional Are going to be asymmetric. They'll be worse on the right foot worse on the left foot worse Comparing side to side and in the legs So that's those can be clues to differentiating between lumbar spinal stenosis and amyloid So, you know, it is important to make that distinction. Okay. Is this multiple lumbosacral radiculopathies secondary To amyloid or is this a peripheral neuropathy? so important to make that distinction and The amyloid what it does is it it infiltrates the ligamentum flavum So it results in narrowing of the spinal canal I should have mentioned earlier with carpal tunnel the amyloid Infiltrates the flexor retinaculum within the carpal tunnel and that's why people experience these these issues So peripheral neuropathy and amyloid now with amyloid Putting carpal tunnel aside Amyloid involves the small fiber nerves first So these are the nerves that send in pain and temperature information into the body That's um in distinction to the large fiber nerves which send in light touch joint position sense vibration These are the nerves that help us out with balance The small fiber nerves are the nerves that send in pain and temperature information Small fiber nerves are involved first in amyloid So if I have if I'm seeing somebody with burning in the feet They may actually have a normal emg They may have a small fiber neuropathy That's early due to amyloid the only way I would diagnose that is with the skin punch biopsy so Important to recognize that somebody can have a normal emg very early in the course Because they have a small fiber neuropathy so Important to recognize that typically then If the amyloid progresses it will involve the large fiber nerves It will affect sensation more generally and then affect the nerves to the muscles and cause With a weakness in the legs This is typically It'll start in the feet and then ascend The general rule of thumb for our neuropathy is that you expect the hands to be involved Once the sensation gets to the knees In amyloid it would be common to to hear that history of carpal tunnel first Or and their hands may stay numb in spite of having carpal tunnel surgery five to ten years ago But so this is what you're looking for historically With a neuropathy with amyloid Important to do an emg again to distinguish Electrically with emg for us as neurologists to distinguish that from spinal stenosis can sometimes be difficult And again, remember the the epidermal skin punch biopsy may play a very important role increasingly for us As we decide who to start treatment on in my opinion, it should be started on patients Sooner rather than later So I've mentioned difficult sometimes to distinguish between these different clinical syndromes Autonomic neuropathy can be difficult to distinguish From cardiac related impairments. We're looking for a history Of orthostatic intolerance. So basically any symptom that's present to an upright That gets better when somebody sits or lays down Is a potential autonomic symptom. So typically that's postural lightheadedness They may have syncope as a result of orthostatic hypotension or near syncope They may have gastrointestinal dismotility. They may report Heat intolerance So important to do if not formal tilt table or autonomic testing postural vital signs So I would have somebody supine for five minutes Measure their heart rate and blood pressure Then stand them up take immediate heart rate and blood pressure And then you test them at three minutes So immediate and then at three minutes three minutes if they have a decrease in blood pressure Without any significant change in heart rate Then that's typically compatible with neurogenic orthostatic hypotension Important to do that Sometimes it can be difficult to differentiate between those who have who are on anti-hypertensive medications Most of the time patients with orthostatic hypotension will have a drop in both systolic and diastolic blood pressure With standing so that can be helpful But ideally these patients really I would encourage formal autonomic testing because sometimes Quite often we will pick up Things that you might not have necessarily expected based upon your history And I would also say that You know these autonomic symptoms the orthostatic intolerance They don't correlate super well with what we find on autonomic testing So I would advocate for autonomic testing particularly if you're wondering All right, what systems are involved with this with this disorder? And then also of course think about GI motility testing and those who have who may have symptoms of Abdominal bloating early satiety, which is feeling like you fill it more quickly than you ought to When you're eating a meal Many of these patients have they've made develop a horrible diarrhea Which may be due to amyloid infiltration of the GI system or small intestinal bacterial overgrowth or result from overflow from constipation So um This is a very significant problem if it develops it can be very difficult to treat as a neurologist if I hear a history of peripheral neuropathy Plus orthostatic hypotension and they don't have diabetes I'm doing genetic screening for amyloid for ttr amyloid after doing Serum minifixation working up al amyloid So and then as a neurologist if I have somebody with an Antecedent history of carpal tunnel syndrome and neuropathy and I don't find some other cause of neuropathy I'm doing genetic screening for ttr amyloid. The stakes are high. We have to make this diagnosis And ideally we have to make this diagnosis early So this was I just wanted to show this case. We just had this come through one of our autonomic labs just a few weeks ago and I think it emphasizes What I'm suggesting which is the benefits or importance of early treatment This was a is a 44 year old female. She was diagnosed with ttr amyloid her dad had died after a liver transplant done for amyloid She reported sensory symptoms and also postural lateheadedness, which was present when standing still She had a Actually quite an unremarkable neurological examination Normal strength normal reflexes just very mild sensory loss on her feet And her cardiac Testing was unremarkable. Her EMG was kind of borderline abnormal her autonomic testing, which I'll show in a second was abnormal She was started on ptes around infusions due to the abnormal autonomic testing and the early signs of neuropathy This probably hopefully this comes across. Okay. I included EMG and in In upper left, which was only mildly abnormal um heart stuff Was unremarkable Um, and here's her autonomic testing Up top is uh is sweating and so she had abnormal sweating up top. Those are the If I have a cursor here um anyhow up top is uh abnormal sweating we put capsules on the skin Iant to freeze acetylcholine and make people sweat at four sites Forearm proximal leg distal leg and foot So this is one of the ways we diagnose an autonomic neuropathy And so she had abnormal sweating on the foot which um Would be suggestive of a peripheral neuropathy or an autonomic neuropathy In the middle is cardiovagal testing So we asked people to breathe at six breaths per minute and then measure how much heart rate variability they have We have normal values for that and that was reduced So these are very typical early signs of an autonomic neuropathy and then Her tilt table is down below and you can see that she Supine was 116 over 76 with a heart rate of what is that 51? And then so she drops her pressure a bit with uh with tilt table testing So she was diagnosed with an autonomic neuropathy this in conjunction with her exam and The borderline abnormal emg prompted the initiation of pete saran and So we just recently got her autonomic redid or autonomic testing This is about a year and a half to two years ish and So her heart rate variability has improved her sweating has improved and Her tilt table study it ain't perfect, but I would argue that it's better So I think an important demonstration of The the peripheral nervous system can regenerate if you catch disease early enough And you treat it So I think it's super important and I think this really shows also the value of of doing testing And allowing that to sort of factor into decision-making in some of these Some of these cases So thank you very much appreciate being here So thanks so much for that really fantastic talk. It's my pleasure to introduce dr. Ellen McFail from the Mayo Clinic Who's going to talk to us about pathology And biopsy for those of you who've heard the term mass spectrometry here The Mayo Clinic remains the national treasure and resource for all of us because every time we want to know exactly what the precursor protein is We send tissue to them and dr. McFail is always very helpful in sorting that out. So we're all very grateful Thank you for that really nice introduction. Can you all hear me? Okay Yep, okay. Well, I'm very very pleased to be here at this really wonderful and comprehensive Meeting and so I come from Rochester, Minnesota. I am a he metapathologist. So I'm not a cardiologist. I'm even a cardiac pathologist But since about nine years. I've been part of the mass spec lab and I've been the mass spec medical lab director since 2017 and so since that time I've seen a lot of cases and I've actually learned quite a bit about the whole amyloid world So I hope this is helpful and we'll go let's get started here So no disclosures Um, so Just as a background amyloid oasis involves basically any organ in the body and there are now 42 different types that have been described if you look at the most recent Description now we used to be at 36 but we're up to 42 and they involve Basically every organ you can imagine But fortunately heart is relatively simple because although we have described this is a We wrote a paper about two years ago. We went and looked at our whole mass spec experience at that point Which was about 16,000 cases and then we looked at each type separately So this description here you can see is the heart And you can see that although we had nine different types at that point in fact, we're up to 10 now 98 of them were either ttr or al so in some ways heart is really really easy Because basically that's the question. There are other types The next most common type is a and f which is a localized disease and that only involves atrium So you really don't have to worry about that either. So basically 99 of cases will be ttr or al And it's also important to remember that aside from a and f these are all systemic diseases So they all the patient may not have symptoms in certain organs. Those organs may be involved. So for instance ttr patients may have prostate involvement may have gall bladder involvement may have You know involvement of basically any other organ. It just may not be symptomatic But that's a place where you could possibly go and look to make the diagnosis And then I think it's already been mentioned cardiac involvement is the single most important prognostic marker across all amyloid types So although other organs may be involved and may have some symptoms The heart is really where the money is for prognosis and outcome Okay, so a couple points I'm going to make today This may not be maybe controversial. We'll see if this brings up questions, but For my analysis most patients should not meet a heart biopsy So we'll start out With using the numbers from the paper that we wrote in 2020 Now I think ttr patients are actually a lot more common than this But because they come to a diagnosis later because they're older because the disease is more progressive and indolent They tend there tends to be subclinical disease They don't come to attention are probably under diagnosed more than al is under diagnosed But we'll use these numbers just for argument's sake. So about two-thirds or ttr one-third or al For the ttr patients about through-corrosion will not have an m protein Again, the numbers vary in different studies. It could be higher. It could be lower But we'll use 75 percent as an estimate and for those patients as we already heard the Cintigraphy scanning should be diagnostic of ttr and there should be no need for any tissue biopsy whatsoever About a quarter of the ttr patients will have an m protein and for them as we've heard Cintigraphy is not indicated And for the al's pretty much all of them should have an m protein and again Cintigraphy is not indicated So we'll go on So for those patients who have ttr And have an m protein Those patients will have a ttr Present in a surrogate site such as fat pad and bone marrow about a quarter of the time And similarly for al for those patients Again, who have an m protein so you can't do pyp scan about 75 percent of those will have an m pro Sorry amyloid present in either the fat pad or the bone marrow and again these surrogate sites are overall quite reliable Not a hundred percent, but overall quite reliable So that only leaves The 75 percent of the ttr patients who have an m protein Plus the 25 percent of al patients who absolutely need a heart biopsy So If you do the math this winds up being about 20 percent of all cardiac amyloid patients Now the numbers are all estimates. So maybe it's 30 percent. Maybe it's 15 percent But it's certainly under 50 percent. So that leaves most patients again should be diagnosed without the need for going to the heart So as I mentioned patients Surrogate sites are often often acceptable as a surrogate for the going to the organ of interest So again An al patients about 75 75 percent of fat aspirates And 70 percent of bone marrows will be positive for al amyloid similarly for ttr About 15 percent of their fat aspirates and 30 percent of their bone marrows will be positive for ttr amyloid And then if those sites don't work there are other sites that have been used with with variable success So lip biopsy is actually a pretty good site for al One paper I was looking at show that about 50 percent of patients who had a negative fat 50 percent of al patients who had a negative fat and bone marrow did have lip biopsy positive for al Again, tensinomium is good for ttr patients However, I would not be convinced that a patient who had ttr in their say carpal tunnel Couldn't possibly have al in their hearts. So I wouldn't use that as a great site for a surrogate I think it's an indicator, but it doesn't prove it And then people do use all sorts of other pre-existing sites such as prostate bladder gall bladder injury. I tracked Whether we should use that that we shouldn't it's hard to say But people often will go back to pre-existing specimens and see if they can make the diagnosis without having to you know Subject the patient to a heart biopsy So the next point is about pathology. So if you do need a biopsy, which is going to be just going to be You know at least half the time need a biopsy of some sort Make sure it's reviewed by an experienced pathologist who can confirm the diagnosis So you think this would be easy, but in fact it's not so again the same problem that Plagues clinicians plagues pathologists is that you have to think of it in the first place Uh, it's not so hard to think of it. If someone tells you that's the question So for instance, if someone tells you this is a heart biopsy. Do they have amyloid? That's not so hard What's hard is when you have a patient who has diarrhea as to gi biopsy Because the differential for diarrhea as you all know is quite broad and although amyloids can certainly present with diarrhea So can a lot of other things So again, you got to think of it and so you need a specialist who Uh is has encountered this and knows how to deal with it The next challenge is the conga red stain. We all talk about that like it's just we do it and that's the end of it And in fact it is the gold standard. It's a cheap stain. It's been around forever It's it's in some ways easy to do, but it's technically challenging So everything has to be perfect the pH has to be perfect. Everything has to be made up quick, uh Freshly The thickness of the tissue has to be correct. Everything has to be correct for this test to work Otherwise you want it with false positive and false negatives And another problem though to come up aware of recently is that we used to think it was 100 specific or amyloid In fact, it's not so the rare diagnosis like fibrillary glenreal nephritis that are conga red positive It's a fibrill fibrillary disease, but it's not amyloid. So again, you need to Make sure someone who is an expert is looking at this And then the next challenge. Okay. Now, you know, it's amyloid What type of amyloid is it and of course as this audience knows the treatment for al and ttr is so Uh dramatically different that you really want to get the answer right so Most pre pre mass spec most typing most methods were antigen antibody based methods So this included immunistic chemistry immunofluorescence And it's called immunogol, which is an em based technique and these are all great techniques for a lot of things But amyloid is not one of them. There are problems with amyloid. That's true I mean, this is our the weeds are our workhorses. I see immunistic chemistry. That's all we do Basically, that's the workhorse for a backbone of our practice in pathology, but not so much for amyloid So there's some problems The first problem Is there's a bias toward expected types? So as I mentioned, there are 40 different known types But nobody out there is doing 40 different antibodies when they come along an amyloid case So unless your case is one of the three common types, this is going to be a problem So you either will miss the type it is or even worse Miss diagnosis as a type one of the common types And then the other problem is the can that chemistry is non-specific Again, this isn't a problem for most areas of pathology But it is for amyloid So we end up with a very high inclusive rate and a lot of cross-reactivity so We think that optimal patient care Requires a better method And so it was actually this problem this very problem that prompted our our institution To develop the mass spec test for amyloid. So this was the first test We launched the world's first clinical test to type amyloid by mass spec based shotgun proteomics back in 2008 and And it was developed to solve this this precise problem And it's now considered the gold standard for amyloid typing now perform worldwide And so we have we absolutely did our IHC for all the amyloid proteins back in 2008 because we realize this works so much better And why it's a great test it directly analyzes the proteins of interest It's unbiased it unambiguously and identifies all amyloid types in a single assay Very very high sensitivity and specificity. So sensitivity is about 98 percent The couple percent we miss is usually because there's not enough amyloid present to do the test And then specific specificity is about 100 percent It uses a paraffin tissue so you can go back to specimens that are 30 years old and you can type the amyloid And it requires very very little tissue. There are a few cases. We can't quite get enough But they're very very rare. So even tiny heart biopsies and tiny kidney biopsies This works fine So just to give you a little background are my sort of simplistic way of thinking about amyloid So there are components of amyloid there are the amyloid signature proteins, which I think of as the straw So again, that's the stuff that's They're ubiquitous proteins In the serum that are soluble and they're just there And so like straw they can kind of just move move freely And then there's a unique amyloid precursor protein. That's the mud. So again, that's soluble And it's on its own Is not a problem, but these are not normal proteins. They're abnormal in some way And when the when these get combined under the right conditions or the wrong conditions You wind up with the immovable brick that is amyloid So here's an example The amyloid signature proteins that we use are apalipoprotein e apalipoprotein a4 and serum amyloid protein So there are actually a couple other proteins that are considered Amyloid signature proteins, but those are the three we use in our lab And when combined with say an abnormal lambda light chain You wind up with al amyloid lambda type Here's another example Same same amyloid signature proteins This time the abnormal protein is an abnormal triton So that trans thyriton Put them together and you wind up with t-tior amyloid So here's an example of a case that we ran I don't want to go through all the the specifics of mass spec in the interest of time But you can see that the image On the left is a blood vessel. This is looking at a conga red under UV light with a fluorescent microscope. So it looks different. It looks kind of bright red So that red material is the amyloid. You can see a very very fine Sort of lavender line within that red That's the line of a laser. So what we do is we take the tissue put it on and um Uncover slip slide and we use a laser Look at the we do a conga red on it and we use a laser to cut out just the amyloid That we can see And that tissue falls into the cap and that tissue gets analyzed So it's a it's a very helpful To eliminate to enrich for the amyloid and eliminate the other material That's actually a key component to this test and why it works so well Then we run the mass spec and we wind up with a personalized profile Which you can see here, which are the numbers We run two samples so you get two columns each one's a different sample Just to make sure we're honest And the numbers are what we call spectral counts, which are a semi quantitative measure of abundance so We can read this the top three here. You can see those are our amyloid signature proteins They have high numbers So we this is a way that we proteally prove to ourselves that this is indeed amyloid So it is and the next most abundant protein Is TTR so this is a TTR amyloid case And yes, there are a few Rare gammas and alphas and lambas and kappas, but that's background serum proteins We can't get rid of them 100% so there's always a few around but the numbers are very very low And we know that's just background And in addition this test is kind of even better because we beyond just doing our usual search To identify say the amyloid type say TTR. We can then use the same use a different database, which is a curated mutation profile and look at the same information Run the search and we can identify the mutation So we can we do this in every case if you send us the case we do this automatically And it's not 100% but it's probably above 95% that we can identify the mutation And in some ways is even better because it's disease tissue So you could have an asymptomatic patient a carrier who doesn't doesn't actually have Disease yet but have to carry the gene Well here we can show here that it is amyloid and it also carries the abnormal protein Um, so here's an example of a case just to show you the problems that we can face sometimes So this is a 74 year old man Had a heart biopsy had amyloid no problem It's typed and I can read this this was done somewhere else actually a very very good institution They use amylo fluorescence, which is actually probably better than ihc And they came with a diagnosis of um al capa And then 31 months later the very same heart biopsy so very very same specimen came to us and They're this uh signature protein. So it's no we know it's amyloid And it was ttr So You where So the last point I want to make is although I have already told you that syracous sites are really good They're not perfect. And so if the clinical picture doesn't fit right Then you're going to have to go to the end of the organ, which is the heart So I'll give you three the first example are rare amyloid types. So again, these are super rare um 808 4 is probably the most common one that we deal with That's a problem sometimes because I think even that can give a maybe Matt, you know, but it can give a um a false result using PYP scanning, but I think this is anecdotal at this point. So that's a problem, but it's extremely rare um The second problem is discordance. I'll show an example of that So here's the case 73 year old man had a long standing Type 1 diabetes history. He had symptoms that sounded good for systemic amyloid um, he did have an mgus a kappa free Capri light shanes and a kappa mgus He had a fat aspirate, which was positive for amyloid His bilmura had 5 monoclonal kappa plasma cells So at that point the working diagnosis was systemic al amyloidosis quite understandably um So he had his fat aspirate typed And we see the amyloid signature proteins. So they're present. So we know it's amyloid But we found was insulin So this is not al. This is not ttr. This is insulin so um in a insulin amyloid is actually the fifth most common amyloid type that we see It's about 1% of cases. This is not a systemic disease It's a localized disease to where people inject insulin It causes decreased absorption of insulin. It causes masses usually But it's a localized process that basically is a red herring But if you go back to our paper of all our fat pad biopsies, although 60% were al and 30% were ttr a full 10% were insulin So this is not that rare. So it's not un Unheard of that you will encounter this so this happens and basically it's a red herring So our clinicians knew that and they said, yes, this patient still could have cardiac amyloid And so a heart biopsy was done And it turned out to be ttr So In the end this patient had three things. He had the main thing which is cardiac amyloid ttr wild type He had an incidental localized insulin amyloid And he had an incidental mgus So yes, there can be just people can have more than one amyloid type either in different organs or the very same organ And we've written about this other people have written about this. So Is it common? No, does it happen? Yes. So don't be surprised and just keep going if The story doesn't make sense with the surrogate site And the last example, okay, I forgot about this So this is a paper we had written about whether you could use surrogate sites like prostate or bladder or tendon as surrogate for cardiac Amoy because if you think about it who gets cardiac amyloid? Well, it's kind of old guys, right? So the old guys often get prostate biopsies and bladder biopsies So this was kind of an interesting study And so we had 16 cases that had we had a heart biopsy Plus one of these sites and 14 out of 16 would were concordant, which is great But two were not and so it's important that you know about these So the last one, which I think is 29 Was discordant this person had a type of amyloid called seminal gel in which is localized to seminal vesicles and is prostate And this is always localized disease So this one was did not pose a problem because you would know that there's no way that's what was in the heart And the patient had I think al I can't read and read it from here Al in the heart. So that's fine. There's no way that could have been the same thing The other case case 10 was potentially a problem because he had al in his bladder and ttr in his heart So al can be in addition to being a systemic disease can be a localized disease And localized disease al in the bladder is a relatively common clinical pathologic entity So again, this is an example where using the surrogate site Didn't work and the clinical picture didn't fit and the clinicians were astute and went to the heart And diagnosed a circuit type there. So this is just to keep in mind that this can happen Usually it doesn't but it can And the last case this is the one that gave me Endless gray hairs. This was a 91 year old guy who had prominent I'm going the whole story because we're out of time here, but he had prominent interstitial amyloid 98 percent of what these big blobs of interstitial amyloid, which is a typical pattern for ttr And so we typed it It was interstitial agrit and again, it was ttr But the patient didn't behave like ttr. He was treated for ttr and he basically fell off a cliff clinically And so we went back And sure enough if you really hunt hard enough you could find rare vessels that had amyloid That look different. The other interesting thing was this patient had a fat aspirate Which is positive for al amyloid which also posed a big problem because we think that's that Fat aspirates is a perfect surrogate. So how could he have a different type in his heart? So I went back to the heart and we found these rare vessels that had amyloid And we we dissected those out separately and they were so rare that we could only come with a single cap But sure enough we ran it and it was lambda So this patient I don't know if you probably can't see this very well because the numbers are small so small But there was not a speck of ttr in those vessels And similarly there was basically not a speck of al In the interstitial areas. So they were two entirely different amyloid types two different Antitomic compartments in the same heart, but even though 95 plus percent of it was ttr He was behaving like al So we did get treated for al and he improved So again that the amount of involvement of the tissue is not necessarily proportional to what the patient's going to do clinically so This is extraordinarily rare Like this is about the only case ever seen like this But but happen once it can happen again So again, I think the surrogate sites are excellent But if the clinical picture doesn't fit you have to go back to the heart and again Senate to a very good pathologist because these are hard to diagnose So these are my take home messages for one Most patients with cardiac amyloidosis should not need a heart biopsy and about hash at least half should not need a biopsy at all For patients who do need a biopsy surrogate sites like fat aspirin bone marrow are often acceptable If you send them if you need a biopsy Send it to a good pathologist And we recommend typing it by a robust method like mass spec And finally surrogate sites, although very good or not perfect And if the clinical picture doesn't doesn't fit get a heart biopsy So that's it. Thanks for attention Thanks so much. That was outstanding Um, it's my pleasure to introduce the dr. Julie Rosenthal who's going to be speaking to us about emerging therapies and potential obstacles including or navigating prior authorizations Um, I just say parenthetically there are two great things about amyloid as a field one is the patient so lovely and two is Get to watch colleagues like dr. Rosenthal develop really amazing programs all by herself with the help of other colleagues And um, she's become one of the national experts in this arena. So pleasure Thank you matt And thank you everyone for allowing me the privilege to be here with you today It's truly an honor to be at our inaugural asu cardiac amyloidosis symposium today Over the next 20 minutes. I hope to provide you a tour de force of therapies for both ttr and al amyloid These are my disclosures Hopefully what you will appreciate by the end of this morning Is that there's truly been an explosion in the development of therapies for individuals living with amyloidosis We have multiple strategies and no longer do these include only Palliative and pastoral care, but we actually have therapies that will reduce overall morbidity and mortality for our patients living with amyloid So how did we get here? It was almost 150 years ago that dr. Verkow first described this starchy protein. Well called amyloid But only 30 years ago. Did we actually have our first intervention for hereditary polyneuropathy amyloidosis patients specifically with liver transplant And then it was almost 30 years ago that our colleague dr. Kelly at Scripps really described the kinetics that led To understanding how amyloid fibrils of ttr background form Which then launched the work into tofaminis, which ultimately led to the approval Of our first stabilizer in 2019 But silencer therapies hit the market in 2018 and we now have three silencer therapies available for our hereditary Polyneuropathy patients and most recently approximately a year ago or two years this month We had the fd approval for our very first al amyloid drug daratunamab everything else prior to that had been used off label for al amyloid So this is an overview of this morning. We're going to start with Highlighting some therapies for ttr amyloidosis knowing. This is a cardiac symposium. I really just focus our attention today on Tofaminis, but I want to highlight there are several other therapies available Then we'll talk about some plasma cell therapy and some other therapies for our advanced patients So to set the stage, I'd like to begin with a case. We begin with a patient. I share with dr. Goodman He's a 65 year old gentleman with hereditary ttr amyloid 380 ala and he like most 380 alas had a mixed phenotype including both cardiac and neuropathic Phenomenon he was quite advanced when I met him several years ago And his advanced stage was defined by his cardiac involvement as this is the driver of morbid immortality in patients living with amyloid You can see that by his elevated cardiac biomarkers We saw earlier from our colleague dr. Burke some classic features of individuals with amyloid on echo So this is a male apical 4 Hopefully you can all appreciate the bi-ventricular thickening here in both the lv and the rv As well as some bi-atrial enlargement and interatrial septal thickening And on the right you see the classic apical Sparing strain pattern otherwise known as the cherry on top Here is his technesium pyrophosphate scan. You can see here that the tracer lights up Greater than or equal to the bone. So he was a spect grade three consistent with his diagnosis of ttr amyloid So in this setting, what would you do? How many of you would start him on a silencer? Stabilizer maybe enroll in a clinical trial start combo therapy revert advanced therapies How many of you have no idea what i'm talking about? Well, hopefully by the end of the morning You'll feel a little more comfortable Again, I want to set the stage really on stabilizers You've already seen this diagram already this morning in different iterations But I just want to highlight the formation of ttr amyloid again It all begins in the liver the liver makes this tetrameric protein called ttr or transthyretin It's this critical unfolding step of that tetramer that leads the development of amyloid fibrils Which is an ultimately deposit anywhere from head to toe leading to a multi system dysfunction So we have three main pathways to prevent and delay the progression of individuals living with ttr amyloidosis We can start at the liver with silencer therapies again These include patiziran anotiracin butiziran We can actually target this circulating ttr ketrimer itself with stabilizer therapy We'll focus today on tofamidus and perhaps the holy grail will come with actually extraction or removal of fibrils This is otherwise known as degrader There's a lot of work going on right now in the monoclonal antibody arena both for ttr and al amyloid But again, I want to highlight tofamidus today As this is our only approved therapy for individuals living with cardiomyopathy and ttr amyloidosis Again a stabilizer there is to prevent that critical unfolding step So we lead to an increased concentration of serum ttr and subsequently a decrease in deposition For those of you not familiar with tofamidus It really made this stage a couple years ago. Thanks to our champions of amyloid dr. Mauer who's here today and Dr. Epizzi who our community recently lost? Do their work and colleagues for the htr act? Study this was a randomized control trial looking at different doses of tofamidus a high dose low dose and comparing to placebo And overall we saw a significant reduction in mortality You can see separation of curves here at about a year and a half In individuals taking tofamidus compared to those not We saw overall 30 reduction in all-cause mortality The number needed to treat prevent one death at two and a half years is about seven and a half patients And four patients prevent hospitalization at one year Not only does this stabilizer demonstrate a reduction in mortality, but we saw a reduction to overall morbidity You can see there's a significant separation of curves at six months in terms of the decline of a six minute walk So individuals on tofamidus seem to walk longer and stronger at around six months and over time compared to those not on stabilizer Not only do you see improved morbidity from a functional standpoint, but also quality of life Most of the people in the room are familiar with kccq You can see that the decline in kccq scores is less steep than the decline in individuals not receiving drug We once again saw a significant improvement at about six months This was recently presented at isa by my colleague Dr. Martha grogan looking at the long-term extension data from the attr trial on the top You can see individuals who are initiated on tofamidus from the very beginning This is the yellow line as you can see the gray is the placebo But at 30 months individuals in the trial were allowed to cross over and ultimately Allowed to receive stabilizer therapy And hopefully what you can see on the gray curve is that the rate of decline in the Individuals who were once on placebo and converted drug has slowed down And then the decline in the individuals on tofamidus doesn't really seem to be declining anymore It's almost like they've reached a steady state now over a five-year follow-up once again Highlining that their quality of life contains to be better In addition to reduction morbidity mortality We've heard already from my colleagues this morning that timing does matter We know that trying to pick up people earlier in disease Tend to have better outcomes in terms of morbidity as well as mortality with hospitalizations And survival so individuals who are start on treatment later in their stage of amyloid tend to do less Well compared to individuals who start earlier in their journey Also, we know that regardless of dose individuals receiving some form of tofamidus do better than those not receiving tofamidus at all But does dose matter? More recently our colleagues published that yes dose does matter You can see here on the forest plot that dose mattered not only in the initial trial But also in the long-term extension trial those receiving higher dose tofamidus 80 milligrams compared to low dose tofamidus at 20 did better So knowing that we do have multiple therapies, how do we choose? Specific therapy for individual living with teacher amyloid is it based on the organ based on how the drug is administered the cost of the drug Or is it a combination of factors? Obviously this morning I did not go through all the drugs But as I highlighted hopefully for you in that timeline we now have four Approved drugs by the FDA for amyloid but this table that was adopted from dr. Kittleson and colleagues highlights that we have three FDA approved silencers specifically for hereditary pulmonary neuropathy patients We have one stabilizer Approved for our cardiomyopathy patients both hereditary and wild type that is tofamidus And then we have de flunazol, which I think some of us in the community continue to use off label Really because of cost as you can see on the far right hand side here The cost of these drugs is extraordinary as dr. Post alluded to and while there are financial assistance programs available for our patients I think we as a community need to do better and need to do more So getting back to our case of this gentleman I met we initially met in 2017 remember in 2017 Aside from liver transplant for hereditary pulmonary neuropathy patients. There really wasn't any therapies around in 2018 He was initiated on the first drug available, which was a silencer petezeran And over the course of those four years. He actually did much better. He Got off of walking with a walker his heart failure improved clinically. He was doing much better Interestingly in 2021 he develops an intermittent hematuria for this He underwent a renal biopsy that raised question of malignancy And ultimately he underwent an effrectomy and all the nephrectomy showed was oodles and oodles of amyloid So I think that there's still have a lot to learn about how ttr proteins can affect the kidney This gentleman did not have any proteinuria And currently he um continues to be with us, but is living with some progressive heart failure The importance of this case I want to highlight I had to believe it was dr. Vijay who talked to us this morning Meant in survival for an individual with hereditary ttr amyloid used to be about two and a half years Three and a half for wild type, but currently with the advent of all of these therapies We're changing the natural course for these patients and their families So this is a nice summary adopted from dr. Ruber and colleague really just to highlight that we do have options for our patients This doesn't even highlight what's to come Apollo b was recently presented at isa and hfsa and I believe is in progress with the fda So potentially petezeran might be available for our wild type cardiomyopathy patients But for now it's to famine us as well as off-labeled diffusional Again for hereditary patients specifically those with mixed phenotype I think we should consider silencer versus stabilizer the data Has yet to really be presented. You know should we do combination therapy is silencer superior to stabilizer or vice versa I think more to come on that front So switching gears to al amyloid osis and anti plasma cell therapy Like to just start with another case and I think this case highlights a few stereotypes one amyloid is not just a disease for men This is a young woman of jamaican descent Who presented for her third opinion re heart failure and was actually found to have light chain amyloidosis She presented in quite an advanced case. She was stage four with clearly symptoms of failure to thrive She had actually undergone a pericardial window to recurrent pericardial effusions more than a year prior to meeting me She was having recurrent pleural effusions necessitating multiple thoracentesis You heard earlier from my colleague a little bit about mayo staging and whether you use mayo staging for ttr amyloid or al amyloid Once again, it's the cardiovascular pathology. Um that really highlights the morbidity of these patients So here is that al staging curve again And I think one of the thing that I would just highlight in addition is these curves remain quite steep Overall mortality for an individual with stage four amyloid untreated is less than 50 and that's highlighted by The sort of brown curve there Thank you But um these curves like I tried to show you with the ttr case are really changing most of this data stems from Old treatments old chemotherapy based treatments for individuals al amyloid such as the melphalan Prednisone therapies that most of us when we were in training um were most exposed to Cyber D really didn't hit the scene until 2012 But now we have a lot of things in our arsenal and I apologize This is supposed to be not there Um, but basically we have a lot of different agents whether it's melphalan and prednisone But cyber D has really been the standard of care up until more recently with the undramino tile leading to cyber D Dera tuna ma'am This has truly been a game changer And I think more things to come with novel therapies and perhaps targeting cytogenetics to tailor therapy for our patients But and ram and I just want to highlight this was Published just over two years ago and now that led to a game changer for our patients living with al amyloidosis Dera tuna ma'am is a monoclonal antibody targeting the plasma cells and what this trial looked at was a randomized controlled trial Comparing our control group, which was standard of care cyber D Cyclofosamide rotizumab dexamethasone versus the cyber D plus deratuna ma'am What hopefully you can see is that there is a significant risk Reduction in individuals with the cyber D. Dera compared to the control group more than 50% of these patients were able to achieve Complete remission compared to just under 20 receiving our prior standard of care cyber D So getting back to our young lady. She actually started cyber D. Dera prior to the FDA approval We were using off-label Dera back in this time period in august of 2020 It took her two months to normalize her free lighting ratio and at that time she was actually in complete remission This was actually shown in andromeda, which she would have been excluded from because she was in may of stage four So they excluded the the sickest of the sick patients This demonstrates that you can use this regimen in quite sick patients And I recently saw this young woman last month and thankfully she remains in complete remission She is now on surveillance monitoring and just to highlight how much remodeling can change I think you saw a nice example from dr. Goodman When you're thinking about remodeling from an autonomic reflux study and so forth We definitely can see some cardiac remodeling this young lady was requiring 200 milligrams of torsemide daily With intermittent boosters to control her volume status. She was initially getting multiple thoracin tc's Now she has not had a recurrent plural effusion in almost two years And when I saw her in clinic last a few weeks ago, I decreased her torsemide to as needed only She is back to living life But what about patients who are really this advanced patient who I think have missed the boat when it comes to potential turnaround with chemotherapy or stabilizer or silencers You know, we can think about transplant Autologous stem cell transplant is still used for certain individuals living with ale amyloidosis But I think our program is steering more and more away because we are finding that therapies are working for our patients Knowing that I'm a cardiologist and this is a cardiac amyloid symposium I just want to highlight The role of heart transplantation and I'll save stem cell transplant for another time But people back in the day used to think that we could not transplant our individuals living with amyloid And this comes from old data out of male clinic actually showing that individuals with amyloid tended to do worse A more modern cohort looking at our united network of organ sharing data from 2008 to 2013 Demonstrated in fact that individuals with amyloid Can have just as good outcomes as individuals not with amyloid The difficulty with unos data reporting system is it doesn't differentiate between those with ale amyloid Which you have seen perhaps have a greater morbid immortality compared to those with ttr amyloid in some respect And so it's kind of among us as amyloid centers of excellence to kind of look at the data a little bit more granularly Our colleagues at columbia as well as other centers like stanford and cedars have demonstrated while numbers are small Um that these patients whether they have ale amyloid or ttr amyloid can have just as good outcomes as those Not living with amyloid And I think this stems from us understanding as a community Who these patients are what their comorbidities are and making sure patient selection prior to transplant is good And I think what's really interesting now these cohorts that i'm highlighting here This is prior the era of actual stabilizer therapy or silence or therapy So I think there's going to be a lot more to come in the future in terms of how we're managing them And just to show you that um You know since we've all been in the room kind of looking at data points and graphs These are the people we're talking about these are the people who hopefully were impacting their lives As well as their family's lives. I actually just saw this gentleman for his four-year annual follow-up He just finished a 5k back in north dakota. This was actually a patient sent to me from dr. Grogan So this was his one-year heart transplant anniversary But now he's still out there living life and next to him is kathy kathy. We meant after basically one cycle of chemotherapy with cyborg idara on a balloon pump and ultimately we transplanted her and she is going to have her Two-year anniversary this march. She is actually only on surveillance She is not required to stem cell transplant or recurrent chemotherapy And I think that's a question that um myself and colleagues are charging our hematology colleagues You know, how much how long do we need to continue these people on therapy versus just maintenance? So with that what's to come you've already heard from my colleagues dr. Post Sonya sobrowski and others there are so many clinical trials available I would encourage you to go to clinical trials.gov today last night I typed in two keywords treatment and amyloid and more than 500 hits came up alone Cardio transform for any of you in the community who are still enrolling. Um, we're still caring for patients This clinical trial is still enrolling. He lives be hopefully we'll have data come out in a couple more years This is looking at bootes around silencer therapy. It's a depot injection Acoramidus waiting for the results. Hopefully the next year or two. Maybe sooner two years No, no, no June June. Okay. Excellent. Um, what about gene suppression therapy? This is really going to be potentially it'd be a game changer You perhaps have seen a couple years ago with new england journal published a case in our hereditary polyneuropathy patients Seven patients showing one dose wonder. Um, they can really change your entire genetic makeup Phase two clinical trials are ongoing and phase three Are in the works But this really could be a game changer for not only our patients living with teacher amyloid But perhaps other diseases And then a lot of um monoclonal antibody trials are going on right now These are two active trials for individuals with al amyloid and what's nice about these trials is they're including Are really sick cardiac patients a firm al is looking at these mayo stage four patients who otherwise would have been excluded From clinical trial. Um kill 101 is looking at a different staging system. But again Sick or heart patients with mayo stage 3a and 3b So I think lots to come and encourage you And with that I will just close with this image by monay This was the actual painting that launched the movement of impressionism for any um impressionist lovers in the audience This is called la soleil avan or the sunrise really. I just think amyloid targeted therapeutics They're finally here, but there's a lot more to come and I think tailored therapy is certainly on the horizon with gene suppression Maybe looking at cytogenetics and thinking about those who might respond to venetoclax if they're not responding to the cyber de dera And other things So with that I could not be here without my amazing team So I want to thank them as well as all of you for being here. Thank you That was fantastic. Please please don't go away if the speakers could all come up. We'll Begin a little lease panel discussion. Um Suddenly if there are questions from the audience, please raise your hand and we'll get your microphone. So it looks like there's some In the background there. Okay Actually, we'll just start. Um, maybe one question for sonia. So, um, you mentioned this 23 and me genetic testing. So you have a 25 year old who is looking for god knows what but they have a val 122 ILE variant and they show up in your office. Um, no symptoms. So what are you telling them? Yeah, that's a great question and I've actually run into this somewhat recently. Um, so You know, essentially the first thing is I asked them what research they've done on their own Because it's really helpful to have an understanding of where they're coming from and you know What their impressions of are what they've read online or maybe what they've even read from their own genetic test report but The the first thing I tell them is That variant in particular. This is probably a true positive So I I kind of treat the session as if you know, we've already got a positive result But that there is some chance that maybe it's not so we do proceed with a clinical confirmatory testing As I had mentioned before But we we are talking about, you know that that increased risk for the cardiac amylidosis In particular, we talk a little bit about amylidosis in general Implications for family members, you know, like I said really kind of treating it like a positive test report at that point But that we'll have further discussion once the clinical results come back and and usually at that point It's a phone call to confirm That that the results did come back positive And at that point I also talk about our awesome Multidisciplinary clinic and and the providers that we have here I know we just heard from Dr. Rosenthal and Dr. Goodman and and they are really great And so I talk about the support that we have on our team and that there There is support from other clinical standpoints And and the genetic implications of that as well just in terms of What are we thinking about for family planning and and other family members because this oftentimes is a surprise, you know They many times don't even know that this is something in the family or had never heard of this before So there's a lot that we cover in one of those genetic counseling sessions, but It is something that comes up and you know, I Whenever patients ask me about 23 in me testing or direct to consumer testing in general should they do it? Should they not really it's a personal decision and it's up to them But I tell them, you know, there are things that we might find out about that you're not expecting to find out about So certainly worth doing your research ahead of time And considering both what it might need for yourself as well as your family members when you get those results back And maybe I just asked Julie So what do you say clinically to this person who's now been referred to you and their 20s or 30s with v122i for them? I mean And they're asymptomatic Yeah, this is definitely a struggle and I think something myself and colleagues talk about often But just try to reassure them and also just encourage them to follow back You know, typically I've been recommending five years We unfortunately don't have guidelines for this and so I base this office some data from hcm patients and their families in terms of screening But try to provide them some education. We have a great team of nurse coordinators So try to provide them that education of signs and symptoms to look for at the same time as sonia alluded to Sometimes that stigma I think have really mentally affect patients So then they think they have a neuropathy when they don't have a neuropathy or they're worried they have chest pain and there is no chest pain So you do want to be cautious and understand your audience and I think asking them You know what they understand what they know and how they feel but try to provide reassurance and Just bring them back to kind of hold their hand a little some respect Yeah, I just agree. I mean this is a disease that we heard as an age dependent penetrant So we don't see v122i penetrating usually before the age of 50 the opportunity may be that Love ones who are older in their family may actually have a clinical phenotype and maybe those are the individuals So I always encourage older adults who have the disease to get their Not their kids tested but rather their siblings tested question So I work as a hospitalist and I see a ton of heart failure patients You know and usually cardiologists are involved when there is low ejection fraction but then They kind of turf off a lot of diastolic heart failures and you know, a lot of echoes are Not actually read by Experienced cardiologists if I may or it's in the substance and not in the conclusion and a lot of times these are missed So there are a lot of barriers to diagnosing early And also our hospitalized patients have that revolving door mechanism where they keep coming going coming going And a lot of them are 80 plus or 75 plus and now the cost versus benefit as well as What is the you know when you say the biomarkers and you're saying Two out of three makes it stage three or stage four in your life expectancy is 40 months to six months Here you're dealing with our patients already have Multiple medical problems chronic kidney disease their tropes are elevated BNPs high to start with So when you say 40 improvement with treatment, I want to know in years Am I prolonging life or delaying death or I'm actually benefiting this patient? What is a number of life? In years that you can give with treatment and without treatment so I can approach my patient in a positive way I think that's an outstanding question and something that each of us are faced with quite routinely And I think you highlighted that question about the multiple morbidities, right? I think it's if you look at the patient and they can't get out of bed on their own Is this really the patient I want to offer an endomyocardial biopsy to and start thinking about Chemotherapy or is the right thing to do to offer palliative care? So I think you have to treat each patient as individual I don't think we're in necessarily the exact place to judge, you know, what is their life worth to them But looking at the whole picture are my therapies and the treatment's going to ultimately cause harm Or as you said, are they going to cause benefit? But I think that the important thing to know is that this decision does not have to be made on your solar You heard today from a number of colleagues in different subspecialties Amelidosis can affect many things So this can be a team decision and approach to how to help you counsel your patient or also just help counsel the patient and their family But sometimes in my patients who are quite advanced in age 90 plus 85 plus with multiple comorbidities Even if they have TTR amelidosis if I feel they have class 4 heart failure stage D And I don't think they're going to be living more than a year I'm not going to be offering these patients a stabilizer therapy. That's a quarter of a million dollars a year because I'm not sure It's going to provide that benefit We saw even from the ATR ATR trial while there is some initial benefit early on from symptoms It doesn't happen overnight this takes several months and you're not seeing more brutality benefit for more than a year and a half So while things might change For now, I think you just need to continue to approach each patient on individual basis and reach out to your colleagues Who can help provide you some guidance If I can add a little bit to that So I think that's that's a great question. And I as a hematologist I saw see a lot of those patients who have like straight three or straight four And by at your heart failure and they are diagnosed with lighted amelidosis And then are they eligible for treatment and will the treatment improve the their Quality of life and will it prolong the the the life expectancy? So Just to give you an example. I had I saw a patient Like she was in the 60s late 60s and she was diagnosed with state for heart failure at another hospital and then The hospitalist saw the patient cardiologist saw the patient they diagnosed and then she was sent to hospice So she was in hospice for at least like two three months and then She came to see one of our cardiologists Who specializes in Amelidosis and they started the work up and finally diagnosed her with Lights in amelidosis. So then she came to discuss Her options with me and I I had the Discussion with her. Yes, the outcomes of prognosis is not good because you already have state for heart failure But we can at least give a trial of the treatment and see if that improves your quality of life And we started on a single agent to mummab initially to begin with because she was Wheelchair bound and she was not even able to walk on her own And after first couple of months of treatment her symptoms started to improve And now she is able to do her activity. She is able to walk at least She's now six months into the treatment and she's out of the hospice and she's doing really well So some of these patients can be very sick when we start the treatment and experienced positions when we start the treatment and we start Gently and see how they tolerate and if they tolerate it, okay That can help improve their quality of life and also can improve the longevity I don't know whether it's going to be One year two years three years that she's going to live but at least she will have some quality of life and Most of the treatments that we offer these days, especially in the Hematology world and not cytotoxic chemotherapies and most of these treatments are very well tolerated But we have to start gently and build it up slowly and we can improve the quality of life in these patients All right, just to add that I think you're in a unique position as a hospitalist There's data from a national health system in the in the uk in which patients with ttr amyloid Are hospitalized in the last three years of their life 17 times So you talk about the revolving door if you can make this diagnosis You can institute therapy We may be able to as dr. Rosenblum was mentioning prevent some readmissions So, um, you know, that's what we're hoping for other questions in the back Yeah, um, how different is amyloidosis and amyloid plague formation in patients with Alzheimer's So the amyloid type in the brain the for the amyloid amyloid, uh, sorry Alzheimer's patients is a different amyloid type called a beta Uh, so that's a specific amyloid type there, but maybe 16 different amyloid types seen in the brain, but some of those are very very rare So the most common one is a beta and that's the Alzheimer's amyloid Is that the question answer the question? sometimes there can be some confusion particularly with family members who may read about and they have amyloid diagnosed by us say ttr or wild type Or variants And then they may may read about amyloid associated with Alzheimer's, but There really isn't any association and usually it's just a matter of of reassurance but it does get to the To the point that we've been discussing which is these older patients do have multiple comorbidities And so we we do struggle with this and some of the patients who they may For example in neurology, they may come in with a little bit of neuropathy But they may have a lot of dementia for example. That's unrelated So a number of the patients may have other comorbidities which need to be factored into treatment decisions So on So there is the idea There may be amyloid opaths so people who have Amyloid of different types in different parts of their bodies there has some evidence maybe that there is a link between Alzheimer's and amyloid elsewhere But it's kind of tenuous and I think there needs to be a lot more research But that idea is at least floating around out there I would just add that my clinical experience of the overlap is pretty minimal. I'm surprised You know like the average age of these patients is 75 or 80 and most of them are quite erudite and The coexistence of the two at least in my clinical practice haven't seen really a thousand patients with TTR Is much smaller than I would anticipate the other thing I would also submit is I think The cardiac amyloid world has done a much better job of actually taking care of this disease You hear what's coming out of FDA approvals for Alzheimer's disease and it you know is associated with pretty high costs and not much You know necessary clinical benefit But the same argument is being held which is if we can move upstream and identify people earlier In Alzheimer's disease. These therapies might be more beneficial in some regards So I think across all Alzheimer's all amyloid diseases early diagnosis is really critical You know a great Conversation great talks. Oh my god. I'm learning so much already from each of you. It's fantastic So in my reading Therapy Julie or Matt or anyone I think you probably did mention maybe I forgot I missed it Doxycycline plus Toro or psodeoxycholic acid What if it is the data that's one secondly from a patient perspective and you know regular every day After you've seen your patients. We thought of these hot failure or whatever their question. What should I eat? What should I take? You know and you know how much excess those of the most common questions almost on a daily basis with every patient and then some What is that some question What about green tea doctor Rosenthal? What about turmeric? Will it prevent Alzheimer's will it prevent amyloid doses? Is there any data or is there a therapeutic strategy that maybe You know, there is some evidence there. What are your thoughts on that? One question. I think prior to 2018 most of us in the room who are practicing Amyloid physicians. These are the tools that we could reach for in addition to palliative care Um, we were reaching for these things like Tadka and doxycycline and green tea I found doxycycline the state of arizona quite challenging due to photosensitivity seeing lots of sunburns and our patients or gi intolerance That being said, I think the data is quite minimal and There's some data into manual models But we haven't seen on a large scale in human models overall morbidian mortality benefit and due to potential side effects and drug interactions I'm no longer using these in my practice. The clinical trials did exclude patients from taking specifically the green tea I do not know about turmeric, but um, maybe matt can comment on that in the hdr But I know doxy and green tea were excluded from some of the clinical trials. So those are not agents I'm using there was actually some data recently published for our al amyloid patients I think people are now steering away from doxycycline even in al amyloid Which used to be standard of care in that first year. We're giving doxy with the cyborg So I think the community is going more away from those More herbal or other types of agents for treatment of amyloid To answer your second question in terms of what do we educate our patients regarding diet? I think that's a whole one hour lecture in terms of the supportive care from a heart failure standpoint Right for individuals amyloid. We talked this morning or I talked this morning about disease targeted therapy But what about how we treat our patients just from a neuropathy standpoint or heart failure standpoint? Those are whole lectures in themselves from a dietary standpoint. Most of these patients I find are quite Cacetic malnourished due to malabsorption or just poor cardiac output and difficulty absorbing So they get that early satiety feeling So I typically put my patients on a seafood diet. I've coined this term from Eric Steadley Not that they need to eat seafood but meaning they they see food they eat food You know, there's a lot of controversy for those that you attended the ACC Arizona I was a part of a debate with a colleague from Tucson, you know salt restriction versus no salt restriction I do not salt restrict in my practice. I think there is great data out there for salt restriction in the hypertensive heart disease world I think um, dr Maher recently had a paper out in jack with some additional colleagues, you know On what is the optimal diet? And I think trying to tailor to your patient is probably the most important thing and for these patients quality of life Should be at the top of our list. They're suffering in so many ways So for me and for many people food can bring pleasure So I let them eat whatever they want to eat and just might mean some extra torsemide or lacyx or bumex not to provide To any one department. So just let them enjoy Dr. Maher Ellen, I wanted to ask one question before we break for lunch so If we have a 30 likelihood of detecting the monoclonal protein With fat or bone marrow in ttr, but we have a 70 or higher percent in al Should we be preferentially considering cardiac biopsy in patients with suspected attr? And the reason i'm asking this question is It takes time in some institutions to organize a bone marrow biopsy and a fat pet biopsy And by the time you get all that back and it's negative you have a 70 chance Now you're going into potentially cardiac biopsy or you could just preemptively treat them for attr So i'm just sort of wondering. I feel confused as a practitioner What type of biopsies we should be ordering when? That's a great question And in fact, I had put out this conversation with one of our our cardiac amyloid guys Is that mayo rochester a couple days ago? But I think when there's an m protein, you don't know which one it's going to be at that point It could be either one so um That's why we next go to the fat and the bone marrow at that point I suppose if you're really strongly pushing for treat as fast as possible The ideal site is the heart. So I don't think it's ever wrong to go to the heart first but um because at the point With the m protein, you really don't know which way it's going to go If it's al then you have an 80 chance of making the diagnosis with something a lot simpler like a fat or a bone marrow So it's an excellent question. I don't think it's ever wrong to go to the site of interest first Is it okay to treat without having the protein because if you have a negative biopsy then you're empirically treating for attr Is it okay to stop, you know there and say well, we didn't find it in the bone or fat? I'm not sure the clinical But I would be very cautious about trying to treat me without being sure what the precursor protein is I mean, look, these are two Very different diseases if you see enough patients al is a medical emergency So if you get light chains back and they're abnormal These patients usually look very sick and this is something in which you need to move quickly I mean In the days and we started to try to do transplants on patients with al amyloid the median time to death was 56 days Now these are really advanced al patients as we saw and occurs So, you know, you measure light chains and it's abnormal You need to have a clock in your head as martha grogan would say and you need to get that person in And move as quickly as you can whether it's a fat pair first and if it's negative then our biopsy You know ttr is a very indolent disease The other thing just epidemiologically is that you know ttr is the tail that's going to wag the dog Right. It is going to be as we heard. I bet 95 percent of all cardiac amyloid We've seen the future just given the epidemiology who's getting you know amyloid and aging so If you do this enough you get a real good flavor for what people have but I just say You know if you think they have al call all your friends call them quickly your hematologists get consults And do not dawl, right? I would just echo the following. I think if we walk away from anything doctor saying Highlighted in this morning's talk is al amyloid is a heme emergency. So from a cardiologist perspective I hope that each of you think of this as a STEMI time is light change Just like time is myocardium and I would never want to treat these patients blindly You heard from dr. McFall this morning 25 to 40 percent of individuals with ttr amyloid are going to have some kind of mguss And just because they have an mguss they might have al amyloid. They can have wallenstroms They can have ttr. So I had a patient who I for sure thought had al amyloid Fat pad was negative. He went for a bone marrow and turns out he had wallenstroms But didn't fit his cardiac picture. So ultimately he got a cardiac biopsy and turns out he has ttr amyloid So his wallenstroms is now remission and he's on to famine is interestingly his ejection fraction remodeled went from 20 To 65. So I'm thinking this was some light chain circulating toxicity I don't know But I think that we have potential to cause more harm than good if we're treating an mguss blindly I think many of us on this stage in this audience have seen individuals being treated with chemotherapy for ttr amyloid because they had that background of mguss. So really Thanks to our colleague Dr. Dahlgren and colleagues at Mayo in 2009. We developed this technology you heard about this morning with mass spec so I think tissues issue and To stress to each of you in the room, you know, where do I go? You go wherever you can get the fastest Result like who can help you the quickest as dr. Maurer said you call all your friends Fat pad yield is somewhat low for ttr amyloid, but that doesn't mean they don't have ttr And the biopsy of the bone marrow too might not show ttr or al amyloid So you ultimately do have to go to the organ that is problematic. And I think in this day and age Cardiac biopsy is relatively safe. There is about a 1 to 5 percent risk of perforation, but in experienced hands This can be done and should be done All right, that's wonderful. I think we should break for lunch. We'll be back at 12 45 for our keynote address Good afternoon everybody Thank you again for coming out to this inaugural asu cardiac amyloidosis update I think it's really a testament to all of you as well as the individuals who organize this event Dr. Chris vj. Dr. Sandesh chev and jenice guzman for putting on such a spectacular event I have distinct honor and privilege of presenting our keynote speaker Who I believe really does not need any introduction, but here is dr. Matt mower For those of you who have paid attention this morning You would see that there's not an amyloid project that dr. Mower hasn't touched Over the last several decades and it's really a pleasure and honor to share this stage with him today Be someone that I look up to as i'm sure many of you in the audience do so with that Dr. Mower So it's really great to be with everyone and um 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 repetsi Who was the co-chair of the attr act study with me who unfortunately passed away suddenly he was A lovely man very curious real master of medicine credited with a paper in 2005 and jack using dbd Centigraphy And if those you knew him he had what we call repetsiasm these ways of kind of making associations that were Kind of unbelievable. So a great loss for the community. There he is presenting the attr act data at the ec 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 End of myocardial biopsy to one that you can diagnose with centigraphy and 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 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 you know multiple admissions We heard from one of our hospitals earlier Later on he had a phenotype with a pretty low blood pressure orthostatic. You can see he had an increased wall thickness No aortic stenosis even at rvh And someone had done um light chains on him and they were abnormal These are in milligrams per deciliters lamb 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, but uh, you know 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 a fib that became a persistent after A few paroxysmal bouts and he had a cast to evaluate for coronary disease didn't have much But he had an elevated lvedp No one seemed to notice that they gave a mace 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 plural effusion that they tapped thinking it might be malignant And two years later now he's in persistent a fib his ef is declined And he gets crazily an avian odoblation and a bivy pacemaker and So this was a guy seen by one of my bosses milt 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 you can't see it's got the atrial fibrillation Diffused low voltage not only in the limb leads, but precordial And uh, pseudo infarct pattern with poor precordial our way of progression And this was his echo cardiogram At the time we were seeing him. So he's got, you know wall thickness like 25 millimeters He's got no lv chamber capacitance His endiastolic volume is like non existent his atrium or like twice the size of his ventricle And this was years ago. So we didn't have p yp. We're talking, you know, 2000 and two or three So we did a right heart cathina 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 um, we did an endo myocardial 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 bipolar eyes the 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 um, this is two cases that I wish I could tell you are rare, but they're not and these are data from isabel usada Who runs the amyloid research consortium and she surveyed patients and is what they said I had to wait a long time. I had to see lots of doctors and unfortunately the Provider that's in misses the diagnosis most often is a cardiologist who basically say These patients often have hypertrophic cardiomyopathy. Um so, um We've heard this morning, but just to remind you amyloid is um, uh, 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 and various organs in vivo But as I like to jokingly say but probably not untrue cardiologists are not the brightest folks In the don't know nobody's tools in the tool So we don't 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 a cardiac amyloid or age related um And again the key here is to make sure you distinguish these two disorders because they differ not only in the biology The precursor protein, but in their outcomes the prognosis the genetics and most importantly how we treat them Uh, so just to highlight um a l is a disorder of the plasma cell it affects people of all ages But I just uh 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 um Hearts 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 um with advanced disease All the way to the right is wild type ttr 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 silence or 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 um 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 amyloids. 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 in certain conclusions one of which was Not he said this was fallacious and I mean do but more often the diagnosis was correct from someone from harvard But he attributed that just because they knew about the case and they heard it in the hallway But it's kind of embarrassing to do one of these cases in the england journal 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. So you walk 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 Um, uh, 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, um, this is the impression of most providers are looking for a needle in a haystack And these are the data we heard today, right? 16 percent of patients undergoing a taver of amyloid 13 percent of patients with heart failure to preserve df and an increased wall thickness 6 percent of heft-peft patients in the community 5 percent 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 was one or two percent 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, uh, the famine has got approved under the fda designation of a rare disease So these are the data Don't want to rush too quickly. So this is al amyloid. It's a disease that affects one person in a hundred thousand Or 10 per million. So you can do the math. They're about three to five thousand new cases in the u.s Even if they all live 10 years, which they don't, um, 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 percent of african americans carry a variant depending upon if they live to be the age of 60 There's estimates that there are 25 000 120 000 african americans who have a variant ttr And that's not included in the other mutations. We heard about so I would say not so rare And a wild type disease is just gonna, you know, 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 a patient has amyloid. Who says the red ekg just raise your hand No one put their hand up at 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 has 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 formulate 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 balonia They took a thousand patients and they quickly a third of them had hcm a third had hypertensive heart disease The 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 or basically amyloid So this is a very simple way and as you can see Low voltage not very sensitive but specific increase wall thickness very sensitive But not specific could be anything but the two together 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 pads negative You can't stop there. You need to go on because the sensitivity While we talk about it being 70 or 80 percent is nowhere near good enough for a life-threatening disease And so fat pad biopsy negative. You think something's going on got to 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 prayer prepared clinician So we talked about this but this is a disease of heff path usually without and it's later stages hypertension typically with in men You can see pressure volume loops to the right upper right for those of you who don't remember This is how we study physiology, but we are increasing You know the edp vr 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 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-hypertensives They're getting on less and less medications. Um, these are patients who always have an elevated jvp and right heart failure As I said, I'll show you some data. They don't like ACE inhibitors or beta blockers Um, if you're looking for a big tongue and uh, periorbital purpura shown here for ttr You're never going to find it doesn't exist. It exists in al amyloid But for ttr as we heard there are lots of um, 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 pop-eye sign So you can look like dr. House with the residents if someone has a biceps tendon rupture and uh, their biceps You know 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. I mean you could you should do it and you will do it, but you could look pretty Um, uh, erudite on rounds And 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, um, uh, these are the still frame uh 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 atrial septum. They have valvular thickening their atrium get big early on They have diastolic dysfunction, but if you miss the boat like in our patient, they'll end up with a low ejection fraction Um, uh, so that's uh, clearly a late phase phenomenon. We heard about pericardial effusions Um mri's are very useful. This is what I used to call the peak in the squeak test You know 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 ah And they referred them off to the amyloid center in part because they were You know unsure what to do and also a little embarrassed that they didn't kind of sort it out sooner So this is 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 leads to the apical sparing So um lots of clinical clues, right? And you should really understand the non biopsy 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 um Again end of myocardial biopsy is not a bad test It's really hard to do the worst thing and an end of myocardial 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 Syntigraphy member claudio publishes paper in 2005 using dbd. We wanted to use dbd. It's not available in the us It's actually not true. That's the only isotope is pyp. We learned during the You know 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. Um mdp is not fine and doesn't work. So don't use mdp Um, and this is how these scans are graded, right? Uh, zero is no uptake. We heard one is uptake Less than the heart twos and threes 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 non-invasively with a pyp or hmdp scan if they have a phenotype that's consistent with amyloid Right, don't scan someone whose ef is 10 with an eight 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 they 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 to biopsy and you have to have Grade two uptake, but you need a spec scan So we try to highlight some of these errors in a paper in jack Mazhana led to charge here With amartha grogan and others but you can see in the upper right as a patient's got a floridly positive pyp scan Right it's in the myocardium, but 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 percent right so doctors are ordering pyp and not ordering the monoclonal proteins Second one is I just highlighted here. Here's a grade two 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 know you will run into some unusual mutations or variants that don't uptake pyp So this is you know 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 you can see the blue is the biopsies It's under 10 percent 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 test do you do in medicine? We're a 30 percent of the time you're making a clinical diagnosis It's not perfect though. So people who had grade two scans when we used Specked as the quote-unquote gold standard 64 of them were blood pool not positive scans right not positive So in the community we're seeing a lot more of this planar imaging people getting on tifamidus and they don't need tifamidus It turns out the overall false positive rate is almost 10 percent. So screening is great But you know you'll see you know 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 you know techniques that are a lot more sensitive In fact, you can have a normal 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 an 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 and the key then is that translates into better survival Not because 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 and for those you 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 defamitus is not available in in the uk because it's too much money. They didn't pay for it And in our data here just to show you the older you are like all things the greater your mortality per year Right if you have variant disease, you tend to do a little bit worse But you can see if you're diagnosed by You know a pyp you have a lower mortality, right? 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 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 mean you have to do one On each day you can just bring them in and do all three on the same day And you're basically make a diagnosis pretty quickly assuming again They don't have monoclonal proteins if they do you have to 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, um, sorry, this is the landmark tifamidus 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 costs too much, but um But this is probably the most important unpublished data from the trial So in the trial there were 37 the 441 people in the trial 37 with nyha class 1 less than 10% right and they had at the point Confidence intervals in this example are why but just look at the point of students They had a 64 percent reduction mortality whereas Those with class 2 at a 39 percent reduction were telling those with class 3 only had a 16 percent So very clear evidence that if you start this drug earlier I mean, where else do you see more than a 50 percent 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 could 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 percent overall had amyloid and 22 percent of men Had amyloid so you could start screening all the patients who are getting a TAVR A becky han a famous echo cardiographer taught me that you can just look at the echo and if the S wave on the echo is less than six Everyone who has amyloid has an S wave less than six in this trial because she helped us read the echoes And you got rid of 50 percent of the patients who didn't need to get screen So this now brings the yield to 44 percent 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 our colleagues fin gustason and others in finland and and you can see here They have a national healthcare system We basically found 1179 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 Heff path is a disorder of older obese individuals, but not amyloid in our experience But you can get one in five men Who has this particular phenomenon? So um Definitely a very high yield. I think and they summarize the data here. You can see this, you know, one in four one in five prevalence in older adult males So we have a screening study that was funded by your government Called scan and p in which we're focusing on minority populations in particular because they have a The variant that we talked about that's common. It's called scan and p with rick ruburg 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 And this is a study we did with a nia funding that led to a grant that were thrilled to be working with Mayo clinic and ellen mcvallon So in uh 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 um 34 35 of patients had amyloid in their spine um When we sent the tissue to the Mayo clinic to figure out Was it 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 and 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 mass spectrometry won't be a critical So 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? And if the data in finland are correct, we're going to find lots of patients who are relatively asymptomatic but have a disease So we're excited. I'm rick ruberg 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 a 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 as amyloid, right? So pyp scanning we saw 90 percent sensitive 100 specific when you exclude monoclonal proteins, but one in two people in the study had amyloid So the pretest 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 percent You will have, you know 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 and so it's going to be really important to use clinical features to increase your pretest probability And to make sure you're doing the scanning test really really really appropriately You need to scan with spec. You need probably scan at three hours to avoid the blood pool at one hour In low pretest probability populations So the second thing I was asked to talk about which i'm gonna, you know, try to run through quickly Is um 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 right? I mean if someone tells you dogmatically that they know exactly how we should be following these patients We don't know that and we really do but this is the most common question, right? We all get which is hey doc, you know, how am I doing? Is this the feminist thing working as the other drugs? So there's a good rationale for screening, right? I mean for following patients, right? 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 bi-v pacing that the government's interested in around the country for patients who have amyloid We have reasons to think of a bi-v pacemaker people who develop atrial fibrillation may need to go in sinus rhythm And then the thing is if we have three or four therapies approved How are we going to switch which one are 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 you're dreaming, right? I mean the pre-certification process will be cuckoo. So let's just talk about some of these And the data 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 a diastolic dysfunction reduce 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 chang It's actually been published in jaha and these are the data on outcomes and 150 ttr patients for beta blockers and ace inhibitors For mortality the answer is no benefit, but richard because he's astute found this You know, I see patients. They weren't feeling while 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 Right, you could imagine and the hazard ratio for deep prescribing the beta blocker is more than 50 percent I saved more than 50. I reduced the chance of dying by more than 50 percent by simply stopping the beta blocker So, you know, 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 Um, uh, I think there's a big role for sgl t2 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 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 Uvalemic might be and protect their kidneys might be an sgl t2 So food for thought and people are interested. Um, these are the data from a patient in my colleague Dr. Nebovian's open label study. This is a 90 year old lady who has an nt probing p of 10,000 over 12 weeks Her nt probing p went down to about 8,000 She basically uh, the red is what would have caused us to stop so for cratine, which was already high Would have went up by 30 up by 30 percent or e gfr We would have doubled in the stopping rule and you can see in this study Her cratine remains stable and she required actually less diuretics and that's what we've observed in this 15 person open label study Um, uh, so far that we usually get rid of the metallo zone if they're on high dose or cut their torso might quite a bit These are data from bret sperry in which he took the top cat trial no one knew in this trial I have peft 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 didn't and aldosterone antagonists had a mortality benefit in patients who had a phenotype That looks like amyloid so we often give them mra's Um second is pacemakers and bradycardia. Um, so this is a new focus of our attention These are data from claudio's group again poor claudio. Um, uh, but these are Three risk factors for developing a pacemaker need a pacemaker an 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 e k g and c and c do they have a wide q r s? And just to highlight if you have all three of those things you have a 40 chance of needing a pacemaker within 12 months So those are people who you know, you should start maybe doing long-term monitoring on and check Um, uh, you know, this would be I think a really good place to think about a bivy pacemaker. Why? Because these patients become pacemaker dependent like the many you put the pacemaker in right and like electrical conduction systems frayed with amyloid they have a stroke volume of you know 45 ml's index is 25 ml's and now you start to rv paste 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 bivy pacemaker trial Which everyone will get a bivy upfront, but for six months we turn it on and turn it off to get the information Oh, so this is the bane of everyone's existence in general cardiology. I call aphid the most overtreated heart rhythm in the world But should we restore normal sinus rhythm? I have no idea This is my approach to aphid for all patients amyloid or not And that is the two by two table of are you really symptomatic or not due to your aphid? 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 amyloids 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 aphid 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 the bottom line is early amyloid patients might stay in sinus rhythm After cardioversion or aphid populations, but patients with advanced amyloid almost never do so. I don't rush to do things Um, 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, uh, you know, these are the Current um across the spectrum of disease we used to famine us But certainly for those who have silent 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 up on each of these the clinical ones So new york art class or recent hospitalization. Are they taking more diuretics or performance based measures? So new york art class Fantastically prognostic you can see there right like the dose of diuretics fagnacically pro prognostic So we use those To modify the mayo and the knack staging system and it turns out they really improve the a you see 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 art 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 Six minute 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 six minute hall walks definitely go down quite a bit over time And as we saw while tifamidus doesn't make the six minute hall walk better. It prevents the decline So I endorse that Um, 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 you After the dollhouse university one to nine and you can pick and this was Evaluated by the group in canada and sir cart failure and you can see there were people here who are not frail in a cfs one to three Pre frail four to six and frail and everything about them was uh much different, but interestingly Turntiles 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 tifamidus We've actually become really interested in this which is called the short physical performance battery in my lab So this is a marker of physical function involves three items It's uh your balance. Can you uh, can you um Can you put your feet together and hold it for 10 seconds? Can you put one foot slightly in front of the older hand 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 delaying kitsman use this as the primary endpoint So these are data just from our center that we are 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 someone was mentioning muscle Loss before but they seem to do much worse and we're measuring it in scan np as well Um 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 a nt pro bmp above or below 3000 and troponin t above 0.05 And the other staging system is the gilmore staging system Which uses the same nt pro bmp cutoff but an egfr renal dysfunction above or below 45 So you can tell someone you know your 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 can see here These are changes in the next stage at six months one year in two years Stage changes people do worse and you can see the hazard ratios here for changes in nt pro bmp So a 10 point change in their nt pro bmp and the weekend call on saturday Oh, so what does it mean it went from a thousand to a thousand ten is it means nothing right, you know But a 500 a thousand or two thousand point change those really have a meaning for patients um If you really want to get into the weeds it turns out uric acid is really high in these patients and it's prognostic independent of their diuretics maybe sglt twos will modify that risk because they lower your uric acid And um, 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 um in patients that we published on um, and then Not finally, but we can always use, you know, all these sophisticated, uh, cardiac testing. So, um, ekg's well, there's lots of afib There's lots of conduction disease and then there's A low lowering voltage over time and these are some of the findings that you could look at and see Um, 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 experience patients risk of afib and the risk of needing a pacemaker So it's just that they're just plotting along in that regard Um, this is what my nurse practitioner won the heart failure society nursing award for we stuck xyle patches on 50 patients Expecting to see lots of heart block. We saw a nuance at afib and 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 eight percent So a yield of about 15% and ugly Hair raising. 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, um, I think there's a useful thing to do and the frequencies probably should be modulated based on how You know severe the phenotype is Um, uh, what can we do to measure amyloid loads? So patients always want to know how much amyloid do I have and where is it 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 a half a million dollars a year we may end up needing to get some tests To figure out are things really better or worse in this regard So, um, 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 changed because this is over 30 months It's less than a millimeter right in in hundreds of patients. 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 you know 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 Um, uh, maybe quantitative bone Syntigraphy is a good idea You know, there are ways using ct to quantitate and these are provocative data from a center showing that This the the p yp 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 p yp scans can become negative right to go from grade three to grade, you know a half So um I'll touch upon that in a minute. These are data from the knack to the left with patisserie Patisserie 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 To famines 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 an individual patient. It could hold some promise These pet imaging agents. I think are really where the money is going to be So this is floor beta pier and then to the right is what we're using a columbia A compound made by jonathan wall It's a small peptide that he's labeled with i124 and it images amyloid all throughout the body In every organ and you can get really fantastic images and then you can quantify How often will we do this? Once every few years is my sense, right? I don't think it's going to be like sarcoid that it's going to melt away in three months, you know 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, right? He's got You know a clear grade three scan and you can see on spec. There's you know the circles there And then we gave him silencer treatment and we were kind of intrigued So we did another pyp scan all my colleagues called me and said, why'd you order another? I was like, I was just curious, you know, I wanted to see what happened is pyp's gone I mean there's no uptake anymore, right? So this is cool, right? And it's about, you know, 30 percent of patients with silencers This is happening too We then brought him in for the pet scan, right? This is his pet scan with the jonathan wall compound his heart's full amyloid still Right, I mean, so we never knew what pyp was even binding to we heard earlier. 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 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 and that is Remember where all doctors just talk to the patient, right? Just ask them how they're feeling And these are the most engaged and 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 kcc cues that were given to patients remotely In an arnie trial paradigm in which they just measured it and guess what the patients when they were feeling worse on their kcc q That predicted their hospitalizations And they got better after them and so I think there are ways that we can really engage patients in a much better way Certainly all of this testing and everything is going to require as you have at your center is a bunch of experts, right? And it's amazing to see all the individuals whose expertise is essential, right? 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 multidisciplinary care So I'll just stop by saying early identification of patients is feasible We don't know what the best strategy is right? 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 Excuse me 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 recording and see because you may teach us all That there'll be you know a better way And certainly we're going to need that in order to optimally take care of people because if we got to choose between therapies We're going to have to have convincing or add a second theory. We have to have convincing data I think we got a lot to learn from implementation scientists. I'm not those folks But they know how to engage patients a lot better You really in our shared mission of optimal monitoring disease And we really got to you know, bring the patients into all of this and they are really fantastic partners So again, thanks for allowing me to come out west. They're really appreciative I 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 pre-symptomatic Family members Just wanted to get your thoughts Yeah, I mean, I think it's really look. I mean we have enough to do but remember those you're pointing out There are lots of allele carriers out there. So, you know, it's you know I jokingly say to the companies in this space are like, who can we find in screen? I'm like just screen the family members. You want you want 50 50 yield? You know, they have a brother or sister. There's a 50 50 chance I think they probably have a phenotype more than certainly cardiologists know. So, you know, I wish we had more bandwidth I mean my sense is that neuropathic findings are occurring much earlier than the cardiac findings They're 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 v122 eye patients in which at the cleven 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 the idos who makes acaromidus So tifamidus is the stabilizer acaromidus is the next generation stabilizer They had planned they 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 difluenacil every single one of them and I usually give them if they're willing to take it difluenacil do I know that that's the right thing? I don't but I mean I watch their parent got forbid die of a miserable disease They watch the parent and they're pretty motivated Now if I wouldn't give difluenacil 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 free flowing thoughts I don't know if that address is 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 Yeah Yeah, yeah, so um, they get anticoagulated if they have atrial fibrillation Irrespective of their chad's vascular, right? So you see a fib they should get anticoagulated Doesn't really matter whether you give a dohac or warfarin in our experience Merging data suggests that Is true often all these patients go on a you know 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 a fib but their strain on their atrium is non-existent Like they are in a fib that is 22 percent of patients with ttr amyloid 22 percent, 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 could 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 a fib with amyloid blacks or whites? Whites by far statistically significant in the general population who has more a fib blacks or whites? Whites there's actually a risk score for a fib and includes race nationally published from many studies but When you develop a fib 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 uh african americans probably have an atrial cardiomyopathy They may be resistant developing a fib and when they develop a fib they're worse off if all this holds out I bet in 10 years Um amyloid may lead the way to a change in general clinical practice. I'm not sure we should be anticoagulating people Just because of a fib 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 you know 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 In amyloid so are we going to develop those criteria that you have listed Eco criteria and the biomarkers as a means of putting something into a screening plan just like I mean We have smokers and we screen them for triplets. I think now time has come But with the aging population we may need to develop new screening You know guidelines Yeah, I completely agree with you I'm just trying to profess to you that I think it should be scientifically based and so You know, there are lots of benefits to the screening, right? 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 and look From a screening perspective everything's been met except cost effectiveness You know if you look at the who criteria, but that's important, right? Are we gonna have too many false positives, right? I mean Part of the impediment all this I don't mean to you know is I've been saying it for a long time is These drugs are way too expensive. I mean like 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 well, 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 I we're planning to pool the finished data our own scan np data Omar Aberdesi'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% You know exactly what you want to do for everybody You know set there may be different approaches as we heard when you're 95, you know My dad's 101. Unfortunately. 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 colleague's like I love you map, but I'm not going to look for if he has amyloid I think she's doing the right thing, you know So Experience Yeah, I was a I was a big naysayer. I have to say I'm 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. I don't know if I made it well is that when the pretest probability is very low When you start screening, right, you're going to look for One patient out of 20 or You know 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 You know one that can really suggest the phenotype in a lot more specific manner So the biggest concern I 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 in three-vessel disease and you know, it was always positive But we've all taken care of women who have like an isolated circulation and the stress test is negative or doesn't reveal things So when your pretest probability declines, it's an old, you know, well proven epidemiological phenomenon screening tests 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 to famine us for six months Spent the three or four grand for the first month a thousand dollars And now they spent 10 grand or five grand whatever out of pocket and you tell them Sorry, you don't have amyloid. They're like, well, why did 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 Yeah, so, um, 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 100, right? So Right 70 divided by 100 is 70 percent injection 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 an endiastolic volume of 50 half a small right small chamber Their stroke volume is now 35 ml Their e f is 35 divided by 50 is still 70 percent. 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 bmp 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? Why was it two because this disease developed so slowly that these people can acclimate in a big way So a lot of messages there, but they need they need a faster heart rate Usually they 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 carvetal 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 heffaff 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 unimportant You know They're almost never fat I mean I see a patient who comes in my office who's referred in with a grade 2 p y p scan That's been planar imaging and their bmi is 35 my antennas are up that this is not Amaloid right and it's just not you know like I can look at them ago I'm pretty sure when we do our p y p here at three hours and we do spec You're gonna not have amyloid and I start talking to them about No, 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 Yeah Eric Last but not least Okay One you mentioned the orthopedic data But the other Interesting thing anecdotally that dr. Rosenthal and I have been talking about and actually dr. Grogan up at Rochester Is that a lot of these ttr folks see to be In their pre-morbid lives Very athletic Yeah, all american football players black diamond skiers You know 60 year old mountain bikers So two questions one do you think that orthopedic issues Somewhat is a relationship to the fact they've led athletic lives If you believe that that observation is sort of 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 uh in london baladi who basically is shown. Well, how does ttr misfold You know and dissociate and certainly if you have a variation in ttr It's it's it basically falls apart a lot easier But um the kinetic stability assays that jeff kelly who invented to famine has developed Don't show that ttr is much less stable and wild type patients than normal controls We published it. No one seems to pay attention to it There's no doubt that if you more if used to feminists, you'll prevent the disease So um one other way you can you know break up ttr is by sheer forces proteolytic enzymes and so forth So one hypothesis is that the organs that it goes into are ones that um 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 if 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 for 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. Um a lot of a lot of Athletes though. I do see that So as 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 sort of tertiary referral amyloid centers versus the um amyloid programs, uh That hopefully will become more widespread as we're showing, you know here in arizona there's interest You know, uh, I'm shocked that in a great way that so many folks from around the valley are here And then you know back to the 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 the roles of those different groups of folks? Yeah, it's a great question. I mean look, um if we're right, there's going to be you know Hundreds of thousands of wild type ttr patient, right? I mean, you know, like I said, um, 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 it I don't have a good answer. It depends upon your local resources It depends upon what their needs are clearly the need a heart transplant They're not going to go, you know, except to 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 IV infusions every three weeks. Can you imagine I have I have 840 people As of last week on Tofaminus I mean, can you imagine if 400 of them wanted to get IV infusions of patisserie and every three weeks? I need like 40 nurses to put the orders and I put nurse 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 what people I think appropriately in your state are discussing Which is this is only going to become a bigger bigger and bigger part of health care 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 Amaloid center, but they don't need day to day Especially in the early in the course of the illness there They basically, you know, take Tofaminus take 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 Um, they certainly um, 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 few months 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 So dr. Vijay has assured me that he'll have the last word today, so I'll be brief First of all, um This uh, this event couldn't couldn't have been possible with all the help we've had Um here at ASU and from our partners our speakers and all of you as attendees I do want to single out, um, april johnson. Um, she's been my right-hand person in organizing this In addition, uh, Stephanie calderone, nicole, hernandez Craig woods and my colleague at IFH As well as the staff here at asu health futures And our live stream team Um And and matt I really want to thank you. I think I can't imagine A better person to come out to really kick off this effort in arizona Um, I have to say I think uh, I think we were really lucky to get you and it's really a pleasure to have you here Um, and in fact, I have to say, um I thought your slide deck was a little long until I heard you start speaking and I've never seen someone go through so much So quickly so effectively so that was amazing I wanted to say that but i'm glad you said it, um, and, um I do disagree with your your statement that cardiologists are not the sharpest tool in the shed But uh, otherwise I agreed a hundred percent with what you said um And you know a couple observations struck me that You know we talk about community and I think this is really a good example of our community coming together We have, um, arizona heart foundation Sonography students here and that was really kind of a bonus. Um, so thank you Um, we have you know practitioners from primary care from geriatrics. We have advanced practice providers We have pharmacists really have so many people that um, I think, uh, you know, I haven't seen in one place and furthermore, we also have great, um a specialist I think I probably learned the most from our pathologists or neurologists or hematologists I think for me as a cardiologist. It was really extremely instructive, but I think I've never Had that As well as our primary care representatives And so, you know in this world of zoom and post-covid it's just it's so it's so refreshing to be, you know, in the room with with people And uh, you know, just a couple housekeeping. We will have everything available online on youtube Uh, see me credit will be available if you fill out the survey Um, so here I'll turn it over to uh, dr. Vijay, you know Sunday's already summarized And really appreciated everybody's input of course input from all the faculty members Is really been phenomenal and all the principals are now hopefully Getting embedded into our dna, right? I mean it's phenomenal to give all the faculty members a bigger class And of course the class for the audience here and also the people who are online that the Authority might as well give them another round of applause because without you it wouldn't be possible You could declare a war and nobody came I don't mean anything, right So so and then thirdly, uh, of course, I want to uh, thank and appreciate what sunday just done it then really Aligned all the all the dots and and cross all the t's and really delivered something phenomenal and and brought this program to provision So give sunday a big a big hand and finally You know, I always believed uh that uh, you know being lighthearted You know Preventing from heart attacks and trolls. So that's been my philosophy and principle all my life So you like harder to joke around and have fun and do this and do that and and I thought that I was Doing pretty good in my practice and engaging patients like matt said that he's a patient's voice Okay, I wrote a book You know about my own patients are my through my life calling invoking your inner therapy that the title of my book I wrote it recently in hot failure And for the league community for everybody and and I thought I was doing a pretty good job And and I had this patient who had diagnosed with amyloid and had uh You know the severe aortic stenosis 84 years old and with vipers died 10 years ago And he had severe aortic stenosis. He had the loud murmur. He's awaiting waiting for a tabber and uh, he thought of hearing and so uh, he'd come to see me and he's waiting and So I see in the ball, you know, I never go to the ball I said no, I want you with me. I'm gonna go something other. Okay. I'm going to go suddenly I see is there a courier guy with the beautiful young brawn and he's on the other side of the mall And he's like waiting it to me And I mean, you know, the doctor the go So then he'll be later. He comes back to see me and he says Look at him and I say you're doing pretty good for yourself. All right. Yeah. Yeah. Yeah, doc. I'm calling your advice Following my advice, you know, I'm like suddenly So what did I say? He said well, you said get a hot mama and be careful And suddenly it occurred to me That between my accent and his hearing it's got lost in translation. Is it get a hot mama and be cheerful? No, no I said you got a hot murmur. Be careful Again, thank you all for coming be lighthearted. Have been have a fantastic