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 as