pirate and biopsy of the involved organ if we are not finding the congoir positivity on bone marrow biopsy or biopsy of the abdominal fat pad and then mass spectrometry to confirm the the type of that amyloid fibers So this is just one diagram showing the amyloid deposition in the periart arterial regions here pericapillary and then positive for congoir strain and these are the amyloid fibers that can be seen here So this is one of the diagnostic algorithm which proposed in jack for cardiac amyloidosis So if patient there's a clinical suspicion with typical echo and cardiac findings so the next step that We should be doing in these patients is getting a serum and u-in protein electrophysicis and serum free light-chain Acid on in these patients and if that confirms that their patient has a monoclonal protein present Then we will go down this path of Involving your friendly hematologist in that case and getting the fat pad aspirate and a bone marrow biopsy down If the fat pad aspirate and bone marrow biopsy Show the amyloid deposition Then we should get a mass spectrometry to confirm what type of amyloid is this and then if that is confirmed Then we can treat it accordingly whether it's a ttr or light-chain amyloidosis If the the fat pad and bone marrow are negative in a patients with Monoclonal gemopathy, then if the patient still we have a high suspicion For amyloidosis then those patients we can go to mass spectrometry in those patients and We can also get the cardiac biopsy If there's a cardiac involvement to confirm what type of amyloid is this if the ampotin is negative then the on We can go down this path where we can get the the p y p scan in these patients And if p y p has great two to three uptake on and the the p y p scan that Confirm the ttr amyloidosis and we can get the ttr sequencing Done if if it is negative the p y p scan Then I think if you still have the high suspicion Then we should get the cardiac biopsy In these patients end of myocardial biopsy to confirm the diagnosis of cardiac amyloid deposition A slide on the staging for light-chain amyloidosis it is mainly Depending on the cardiac involvement so patients who have cardiac involvement and they have the antipo BNP of more than 1800 Our troponin T is more than 0.025 and the difference in the free light chain is more than 18 milligram per deciliter So patient who has none of these that that stage zero if one of these Is present that stage two if two are present that stage three and if all three are elevated So that's a stage four disease and The prognosis of these patients depends on the stage and we can see here from stage one to stage four The median overall survival goes down from 94 months to six less than six months in these patients So it's imperative to get these patients diagnosed early before they develop stage four Cardiac failure because those patients when they're diagnosed at the stage four disease then their prognosis is poor and most of these patients are not even eligible for therapy at that time because they are so frail and not even able to tolerate the treatment When they have the stage four amyloidosis So this is just one Slide discussing on how we can target The amyloid in most of these patients. So most of the treatments that we have available available so far Directed against the plasma cells. So the therapy that we are using are mainly the anti plasma cells Directed we don't have any good drugs that can target the amyloid fibers that have already deposited So again coming to the point that if we try to diagnose these patients early We might be able to detect them early and can offer them treatments because once the amyloid gets deposited. It's very difficult to To recover from from that damage There are some newer anti fiber treatments that are in the clinical trials There's one k l 101 that is showing some good progress. So hopefully if that Show some good results, we might have some anti fiber therapy But so far the therapy that we have is directed against the Underlying plasma cells. So they're different components. So there's a chemotherapy drugs immunomodulatory drugs And then there are monoclonal antibodies. So chemotherapy We use Melphlan cyclophosphamide. Then we have proteasome inhibitors Uh, which is what is a map is the most Important drug there that we have immunomodulatory drugs emits Lena little mice and then we have the newest modality of the monoclonal antibodies CD 38 is one of the target on the plasma cells that we can use to Target the plasma cells and their tumor map is one of the drug that has shown a very good efficacy in in these patients So this was the endometa clinical trial published in NEJM in 2021 which studied the vcd or the cyborg combination And they randomized patients to two arms one arm got the cyborg another arm got just the cyborg and But this this trial excluded patients with stage 3b Cardiac disease amyloidosis But we have shown here that the data tumor map addition Improves the outcome in these patients significantly as compared to just the cyborg D So most of the patient the standard of care for the first line is if they're able to tolerate We start them on the combination chemotherapy with data Valkate cyclophosphamide indexer methazone based therapy And with this treatment, uh, there was significant cardic and renal responses and this is Responsed at six months and 12 months and we showed that With the addition of the cyborg D. There was a 42 percent cardic response as compared to 22 percent just with with the cyborg D and the same with At the 12 month the response it even improved to 57 percent in the data cyborg D as compared to 28 percent of the patients in In the cyborg D. So it's important to get those Patients started on the combination of the data cyborg treatment once we diagnose them with light chain amyloidosis So treatment options start with data cyborg D consider stem cell transplant if they're transplant eligible If transplant ineligible then we continue them on the data cyborg until We have able to achieve a very good hematological response or better if they have a lapse to factory disease then And there are some other treatment options available like formalidomide indexer methazone Lidomide carfilzomib and patients who have 1114 translocation consider venatoclax which is Another targeted Treatment that we can use in these patients that has shown some good results in patients who have 1114 translocation So the take home message here is that consider amyloidosis in patients light chain amyloidosis if patients have non ischemic cardiomyopathy and they have lvh on echo findings and we start with the work up with The aspect immunofixation and free light chain ratio if patients have full neuropathy autoimmune dysfunction compartmental syndrome peri orbital perp macroglossia that Phenotype is more consistent with light chain amyloid So we check see them during electrophysicist Immunofixation free light chain ratio and if monoclonal protein is present as abnormal free light chain Present then we need to get hematology involved for bone marrow and biopsy in fact that aspirate Before ordering a pyp scan. I think because the pyp scan sometimes can you give you false positive There's an in those patients. I think it's important to rule out the light chain amyloidosis first before we jump on to the next step Over this I would like to conclude and thank you everyone for your attention Listening for being our friendly hematologist and sharing your expertise on al amyloidosis Next we are going to bring up dr. Brett Goodman from the Mayo Clinic Brent Goodman, excuse me from the Mayo Clinic. We'll be talking about neurological presentations of ATTR I promise to be a friendly neurologist It's a privilege to be here part of the part of the discussion today My task is to focus on TTR and and neurology I have If I could break it down to maybe three take home points Really I would have three take home points number one would be This really does begin with carpal tunnel syndrome and we need to figure out how to identify patients With carpal tunnel who are going to have or have amyloid Second Unfortunately, we need to rely on neurophysiologic testing when evaluating and caring for these patients I'll talk a bit more about that and third As has been mentioned earlier We need to get treatment started as early as possible Neurological improvement or at least stabilization that really relies on early diagnosis. And so Those are my three main main points today With amyloid particularly with TTR This can do about anything to the peripheral nervous system and we've seen that including carpal tunnel Ridiculopathy spinal stenosis neuropathy autonomic neuropathy It truly can do about anything to the autonomic nervous system Important to recognize it may be The first part of the of The body to be involved if you consider the media nerve running through the the carpal tunnel to be a neurological Symptom or sign I would Important to recognize that Once there is significant neurological impairment it may be difficult or impossible To reverse to significantly Reverse Neurological impairment. So we need to get these folks diagnosed quickly early And get them on treatment and then Many of the patients need symptomatic treatment as well The different forms of neurological impairment may provide clues to the different forms of amyloid or perhaps even the different genetic subtype So the different neurological manifestations the most common that we see would be Carpal tunnel which you could consider orthopedic or neurological Lumbar spinal stenosis peripheral neuropathy autonomic neuropathy. These are the most common things that we see Our tools are the the history of course our neurological examination Most of these pay these patients really do require neurophysiologic testing They need nerve conduction studies and DMG To make these differentiations, and I'll talk a little bit about why here in a second I would advocate for autonomic testing We have a busy autonomic lab at Mayo And I've cared for a number of these patients over the years It can be very difficult to to differentiate autonomic impairment in these patients from cardiac impairment and sometimes You know particularly if they're on anti-hypertensives, etc So what's what's medication effect? What's cardiac? What's an odd? What's the result of an autonomic neuropathy autonomic testing can really help with that We do skin punch biopsies and many of these patients and the role of that is to to establish whether a small fiber Neuropathy is present But that skin can also be stained for for amyloid so that can be helpful particularly in the Pre symptomatic or maybe minimally symptomatic patients in whom you're considering whether to start Let's say silence or treatment on Lumbar MRI of course is important in diagnosing Lumbar spinal stenosis, but Remember after a couple of decades nobody has a normal lumbar MRI So that needs to be put together with the the clinical story and then of course genetic testing So as a neurologist we consider these different forms of of of amyloid S has been discussed um, I would Like to highlight though this the study out of out of Mayo Clinic Rochester Some of the differences between what they called at the time. This was a number of years ago familial amyloid versus AL amyloid and you can see here in their retrospective study peripheral neuropathy was much more common at presentation in The familial amyloid patients as opposed to AL amyloid patients. So Important to recognize that and then autonomic neuropathy also much more common During the course of illness familial amyloid, of course, this was pretty largely pre-treatment So these definitely differences clinically between these two forms of amyloid just generally So, um, I find wild type amyloid a challenge Oftentimes the patients are are older. They may have a number of different medical comorbidities Most of the patients or really all of the patients that I see with wild type amyloid on the neurological side of things Have carpal tunnel and spinal stenosis I can't think of a single patient over at least the last Four or five years who have who hasn't had that history. So that's very typical It can be very difficult to differentiate a neuropathy from spinal stenosis. I'll talk about that in a moment and while it's not Clearly established. I do think that these wild type amyloid cases can have Can develop a very mild neuropathy. Although again that can be very difficult to distinguish from lumbar spinal stenosis The if they develop an autonomic neuropathy, it's subclinical meaning they don't have symptoms But they may have some abnormalities on autonomic testing Carpal tunnel uh syndrome This is hugely important for us to recognize and I think we spoke a little bit earlier about Healthcare systems and how we might do a better job diagnosing early earlier in someone's course The important thing I think with carpal tunnel is This proceeds the development of other things by sometimes many years can be five or ten years so um, we really have to ask all right Did you have carpal tunnel in times past? Did you have numbness tingling in your hands? Did you have surgery for carpal tunnel? It may not be concurrent with their current cardiac evaluation that a person is getting worked up for So remember with carpal tunnel. It's numbness tingling in the hands. It may be pain Not everybody has pain and it's often weakness The clue the helpful clue possibly is is that it's bilateral, but it's also typically fairly symmetric The problem is that carpal tunnel is so common And it's often bilateral It's by if we do an emg on somebody who comes in with Carpal tunnel in their right hand their chance of having it in the left is upwards of 80 percent so That bilaterality is helpful But in amyloid it's often symmetric the symptoms are are often the same in both hands but One of the things that we certainly need to be working on is perhaps what cardiology has done and looking at Perhaps some ai techniques for identifying possible clues to carpal tunnel What are the signatures for for amyloid on on emg testing for example? lumbar spinal stenosis also extremely common often Proceeds the development of other neurological issues cardiac issues You know classically this is back in leg pain. That's Present when upright went with with ambulation that gets better if somebody leans forward But not all patients have That complaint they may just complain of numbness in the legs or feet Which can make this very difficult to distinguish from neuropathy so To make this diagnosis we need a We really need lumbar mri and then an emg To try to differentiate between neuropathy and spinal stenosis The other thing that I look for clinically is asymmetry typically in the lower limbs Neuropathy related to amyloid is symmetric. So spinal stenosis Is going to be Any sensory symptoms related to spinal stenosis that are fixed that are present all of the time that aren't positional Are going to be asymmetric. They'll be worse on the right foot worse on the left foot worse Comparing side to side and in the legs So that's those can be clues to differentiating between lumbar spinal stenosis and amyloid So, you know, it is important to make that distinction. Okay. Is this multiple lumbosacral radiculopathies secondary To amyloid or is this a peripheral neuropathy? so important to make that distinction and The amyloid what it does is it it infiltrates the ligamentum flavum So it results in narrowing of the spinal canal I should have mentioned earlier with carpal tunnel the amyloid Infiltrates the flexor retinaculum within the carpal tunnel and that's why people experience these these issues So peripheral neuropathy and amyloid now with amyloid Putting carpal tunnel aside Amyloid involves the small fiber nerves first So these are the nerves that send in pain and temperature information into the body That's um in distinction to the large fiber nerves which send in light touch joint position sense vibration These are the nerves that help us out with balance The small fiber nerves are the nerves that send in pain and temperature information Small fiber nerves are involved first in amyloid So if I have if I'm seeing somebody with burning in the feet They may actually have a normal emg They may have a small fiber neuropathy That's early due to amyloid the only way I would diagnose that is with the skin punch biopsy so Important to recognize that somebody can have a normal emg very early in the course Because they have a small fiber neuropathy so Important to recognize that typically then If the amyloid progresses it will involve the large fiber nerves It will affect sensation more generally and then affect the nerves to the muscles and cause With a weakness in the legs This is typically It'll start in the feet and then ascend The general rule of thumb for our neuropathy is that you expect the hands to be involved Once the sensation gets to the knees In amyloid it would be common to to hear that history of carpal tunnel first Or and their hands may stay numb in spite of having carpal tunnel surgery five to ten years ago But so this is what you're looking for historically With a neuropathy with amyloid Important to do an emg again to distinguish Electrically with emg for us as neurologists to distinguish that from spinal stenosis can sometimes be difficult And again, remember the the epidermal skin punch biopsy may play a very important role increasingly for us As we decide who to start treatment on in my opinion, it should be started on patients Sooner rather than later So I've mentioned difficult sometimes to distinguish between these different clinical syndromes Autonomic neuropathy can be difficult to distinguish From cardiac related impairments. We're looking for a history Of orthostatic intolerance. So basically any symptom that's present to an upright That gets better when somebody sits or lays down Is a potential autonomic symptom. So typically that's postural lightheadedness They may have syncope as a result of orthostatic hypotension or near syncope They may have gastrointestinal dismotility. They may report Heat intolerance So important to do if not formal tilt table or autonomic testing postural vital signs So I would have somebody supine for five minutes Measure their heart rate and blood pressure Then stand them up take immediate heart rate and blood pressure And then you test them at three minutes So immediate and then at three minutes three minutes if they have a decrease in blood pressure Without any significant change in heart rate Then that's typically compatible with neurogenic orthostatic hypotension Important to do that Sometimes it can be difficult to differentiate between those who have who are on anti-hypertensive medications Most of the time patients with orthostatic hypotension will have a drop in both systolic and diastolic blood pressure With standing so that can be helpful But ideally these patients really I would encourage formal autonomic testing because sometimes Quite often we will pick up Things that you might not have necessarily expected based upon your history And I would also say that You know these autonomic symptoms the orthostatic intolerance They don't correlate super well with what we find on autonomic testing So I would advocate for autonomic testing particularly if you're wondering All right, what systems are involved with this with this disorder? And then also of course think about GI motility testing and those who have who may have symptoms of Abdominal bloating early satiety, which is feeling like you fill it more quickly than you ought to When you're eating a meal Many of these patients have they've made develop a horrible diarrhea Which may be due to amyloid infiltration of the GI system or small intestinal bacterial overgrowth or result from overflow from constipation So um This is a very significant problem if it develops it can be very difficult to treat as a neurologist if I hear a history of peripheral neuropathy Plus orthostatic hypotension and they don't have diabetes I'm doing genetic screening for amyloid for ttr amyloid after doing Serum minifixation working up al amyloid So and then as a neurologist if I have somebody with an Antecedent history of carpal tunnel syndrome and neuropathy and I don't find some other cause of neuropathy I'm doing genetic screening for ttr amyloid. The stakes are high. We have to make this diagnosis And ideally we have to make this diagnosis early So this was I just wanted to show this case. We just had this come through one of our autonomic labs just a few weeks ago and I think it emphasizes What I'm suggesting which is the benefits or importance of early treatment This was a is a 44 year old female. She was diagnosed with ttr amyloid her dad had died after a liver transplant done for amyloid She reported sensory symptoms and also postural lateheadedness, which was present when standing still She had a Actually quite an unremarkable neurological examination Normal strength normal reflexes just very mild sensory loss on her feet And her cardiac Testing was unremarkable. Her EMG was kind of borderline abnormal her autonomic testing, which I'll show in a second was abnormal She was started on ptes around infusions due to the abnormal autonomic testing and the early signs of neuropathy This probably hopefully this comes across. Okay. I included EMG and in In upper left, which was only mildly abnormal um heart stuff Was unremarkable Um, and here's her autonomic testing Up top is uh is sweating and so she had abnormal sweating up top. Those are the If I have a cursor here um anyhow up top is uh abnormal sweating we put capsules on the skin Iant to freeze acetylcholine and make people sweat at four sites Forearm proximal leg distal leg and foot So this is one of the ways we diagnose an autonomic neuropathy And so she had abnormal sweating on the foot which um Would be suggestive of a peripheral neuropathy or an autonomic neuropathy In the middle is cardiovagal testing So we asked people to breathe at six breaths per minute and then measure how much heart rate variability they have We have normal values for that and that was reduced So these are very typical early signs of an autonomic neuropathy and then Her tilt table is down below and you can see that she Supine was 116 over 76 with a heart rate of what is that 51? And then so she drops her pressure a bit with uh with tilt table testing So she was diagnosed with an autonomic neuropathy this in conjunction with her exam and The borderline abnormal emg prompted the initiation of pete saran and So we just recently got her autonomic redid or autonomic testing This is about a year and a half to two years ish and So her heart rate variability has improved her sweating has improved and Her tilt table study it ain't perfect, but I would argue that it's better So I think an important demonstration of The the peripheral nervous system can regenerate if you catch disease early enough And you treat it So I think it's super important and I think this really shows also the value of of doing testing And allowing that to sort of factor into decision-making in some of these Some of these cases So thank you very much appreciate being here So thanks so much for that really fantastic talk. It's my pleasure to introduce dr. Ellen McFail from the Mayo Clinic Who's going to talk to us about pathology And biopsy for those of you who've heard the term mass spectrometry here The Mayo Clinic remains the national treasure and resource for all of us because every time we want to know exactly what the precursor protein is We send tissue to them and dr. McFail is always very helpful in sorting that out. So we're all very grateful Thank you for that really nice introduction. Can you all hear me? Okay Yep, okay. Well, I'm very very pleased to be here at this really wonderful and comprehensive Meeting and so I come from Rochester, Minnesota. I am a he metapathologist. So I'm not a cardiologist. I'm even a cardiac pathologist But since about nine years. I've been part of the mass spec lab and I've been the mass spec medical lab director since 2017 and so since that time I've seen a lot of cases and I've actually learned quite a bit about the whole amyloid world So I hope this is helpful and we'll go let's get started here So no disclosures Um, so Just as a background amyloid oasis involves basically any organ in the body and there are now 42 different types that have been described if you look at the most recent Description now we used to be at 36 but we're up to 42 and they involve Basically every organ you can imagine But fortunately heart is relatively simple because although we have described this is a We wrote a paper about two years ago. We went and looked at our whole mass spec experience at that point Which was about 16,000 cases and then we looked at each type separately So this description here you can see is the heart And you can see that although we had nine different types at that point in fact, we're up to 10 now 98 of them were either ttr or al so in some ways heart is really really easy Because basically that's the question. There are other types The next most common type is a and f which is a localized disease and that only involves atrium So you really don't have to worry about that either. So basically 99 of cases will be ttr or al And it's also important to remember that aside from a and f these are all systemic diseases So they all the patient may not have symptoms in certain organs. Those organs may be involved. So for instance ttr patients may have prostate involvement may have gall bladder involvement may have You know involvement of basically any other organ. It just may not be symptomatic But that's a place where you could possibly go and look to make the diagnosis And then I think it's already been mentioned cardiac involvement is the single most important prognostic marker across all amyloid types So although other organs may be involved and may have some symptoms The heart is really where the money is for prognosis and outcome Okay, so a couple points I'm going to make today This may not be maybe controversial. We'll see if this brings up questions, but For my analysis most patients should not meet a heart biopsy So we'll start out With using the numbers from the paper that we wrote in 2020 Now I think ttr patients are actually a lot more common than this But because they come to a diagnosis later because they're older because the disease is more progressive and indolent They tend there tends to be subclinical disease They don't come to attention are probably under diagnosed more than al is under diagnosed But we'll use these numbers just for argument's sake. So about two-thirds or ttr one-third or al For the ttr patients about through-corrosion will not have an m protein Again, the numbers vary in different studies. It could be higher. It could be lower But we'll use 75 percent as an estimate and for those patients as we already heard the Cintigraphy scanning should be diagnostic of ttr and there should be no need for any tissue biopsy whatsoever About a quarter of the ttr patients will have an m protein and for them as we've heard Cintigraphy is not indicated And for the al's pretty much all of them should have an m protein and again Cintigraphy is not indicated So we'll go on So for those patients who have ttr And have an m protein Those patients will have a ttr Present in a surrogate site such as fat pad and bone marrow about a quarter of the time And similarly for al for those patients Again, who have an m protein so you can't do pyp scan about 75 percent of those will have an m pro Sorry amyloid present in either the fat pad or the bone marrow and again these surrogate sites are overall quite reliable Not a hundred percent, but overall quite reliable So that only leaves The 75 percent of the ttr patients who have an m protein Plus the 25 percent of al patients who absolutely need a heart biopsy So If you do the math this winds up being about 20 percent of all cardiac amyloid patients Now the numbers are all estimates. So maybe it's 30 percent. Maybe it's 15 percent But it's certainly under 50 percent. So that leaves most patients again should be diagnosed without the need for going to the heart So as I mentioned patients Surrogate sites are often often acceptable as a surrogate for the going to the organ of interest So again An al patients about 75 75 percent of fat aspirates And 70 percent of bone marrows will be positive for al amyloid similarly for ttr About 15 percent of their fat aspirates and 30 percent of their bone marrows will be positive for ttr amyloid And then if those sites don't work there are other sites that have been used with with variable success So lip biopsy is actually a pretty good site for al One paper I was looking at show that about 50 percent of patients who had a negative fat 50 percent of al patients who had a negative fat and bone marrow did have lip biopsy positive for al Again, tensinomium is good for ttr patients However, I would not be convinced that a patient who had ttr in their say carpal tunnel Couldn't possibly have al in their hearts. So I wouldn't use that as a great site for a surrogate I think it's an indicator, but it doesn't prove it And then people do use all sorts of other pre-existing sites such as prostate bladder gall bladder injury. I tracked Whether we should use that that we shouldn't it's hard to say But people often will go back to pre-existing specimens and see if they can make the diagnosis without having to you know Subject the patient to a heart biopsy So the next point is about pathology. So if you do need a biopsy, which is going to be just going to be You know at least half the time need a biopsy of some sort Make sure it's reviewed by an experienced pathologist who can confirm the diagnosis So you think this would be easy, but in fact it's not so again the same problem that Plagues clinicians plagues pathologists is that you have to think of it in the first place Uh, it's not so hard to think of it. If someone tells you that's the question So for instance, if someone tells you this is a heart biopsy. Do they have amyloid? That's not so hard What's hard is when you have a patient who has diarrhea as to gi biopsy Because the differential for diarrhea as you all know is quite broad and although amyloids can certainly present with diarrhea So can a lot of other things So again, you got to think of it and so you need a specialist who Uh is has encountered this and knows how to deal with it The next challenge is the conga red stain. We all talk about that like it's just we do it and that's the end of it And in fact it is the gold standard. It's a cheap stain. It's been around forever It's it's in some ways easy to do, but it's technically challenging So everything has to be perfect the pH has to be perfect. Everything has to be made up quick, uh Freshly The thickness of the tissue has to be correct. Everything has to be correct for this test to work Otherwise you want it with false positive and false negatives And another problem though to come up aware of recently is that we used to think it was 100 specific or amyloid In fact, it's not so the rare diagnosis like fibrillary glenreal nephritis that are conga red positive It's a fibrill fibrillary disease, but it's not amyloid. So again, you need to Make sure someone who is an expert is looking at this And then the next challenge. Okay. Now, you know, it's amyloid What type of amyloid is it and of course as this audience knows the treatment for al and ttr is so Uh dramatically different that you really want to get the answer right so Most pre pre mass spec most typing most methods were antigen antibody based methods So this included immunistic chemistry immunofluorescence And it's called immunogol, which is an em based technique and these are all great techniques for a lot of things But amyloid is not one of them. There are problems with amyloid. That's true I mean, this is our the weeds are our workhorses. I see immunistic chemistry. That's all we do Basically, that's the workhorse for a backbone of our practice in pathology, but not so much for amyloid So there's some problems The first problem Is there's a bias toward expected types? So as I mentioned, there are 40 different known types But nobody out there is doing 40 different antibodies when they come along an amyloid case So unless your case is one of the three common types, this is going to be a problem So you either will miss the type it is or even worse Miss diagnosis as a type one of the common types And then the other problem is the can that chemistry is non-specific Again, this isn't a problem for most areas of pathology But it is for amyloid So we end up with a very high inclusive rate and a lot of cross-reactivity so We think that optimal patient care Requires a better method And so it was actually this problem this very problem that prompted our our institution To develop the mass spec test for amyloid. So this was the first test We launched the world's first clinical test to type amyloid by mass spec based shotgun proteomics back in 2008 and And it was developed to solve this this precise problem And it's now considered the gold standard for amyloid typing now perform worldwide And so we have we absolutely did our IHC for all the amyloid proteins back in 2008 because we realize this works so much better And why it's a great test it directly analyzes the proteins of interest It's unbiased it unambiguously and identifies all amyloid types in a single assay Very very high sensitivity and specificity. So sensitivity is about 98 percent The couple percent we miss is usually because there's not enough amyloid present to do the test And then specific specificity is about 100 percent It uses a paraffin tissue so you can go back to specimens that are 30 years old and you can type the amyloid And it requires very very little tissue.  We can't quite get enough But they're very very rare. So even tiny heart biopsies and tiny kidney biopsies This works fine So just to give you a little background are my sort of simplistic way of thinking about amyloid So there are components of amyloid there are the amyloid signature proteins, which I think of as the straw So again, that's the stuff that's They're ubiquitous proteins In the serum that are soluble and they're just there And so like straw they can kind of just move move freely And then there's a unique amyloid precursor protein. That's the mud. So again, that's soluble And it's on its own Is not a problem, but these are not normal proteins. They're abnormal in some way And when the when these get combined under the right conditions or the wrong conditions You wind up with the immovable brick that is amyloid So here's an example The amyloid signature proteins that we use are apalipoprotein e apalipoprotein a4 and serum amyloid protein So there are actually a couple other proteins that are considered Amyloid signature proteins, but those are the three we use in our lab And when combined with say an abnormal lambda light chain You wind up with al amyloid lambda type Here's another example Same same amyloid signature proteins This time the abnormal protein is an abnormal triton So that trans thyriton Put them together and you wind up with t-tior amyloid So here's an example of a case that we ran I don't want to go through all the the specifics of mass spec in the interest of time But you can see that the image On the left is a blood vessel. This is looking at a conga red under UV light with a fluorescent microscope. So it looks different. It looks kind of bright red So that red material is the amyloid. You can see a very very fine Sort of lavender line within that red That's the line of a laser. So what we do is we take the tissue put it on and um Uncover slip slide and we use a laser Look at the we do a conga red on it and we use a laser to cut out just the amyloid That we can see And that tissue falls into the cap and that tissue gets analyzed So it's a it's a very helpful To eliminate to enrich for the amyloid and eliminate the other material That's actually a key component to this test and why it works so well Then we run the mass spec and we wind up with a personalized profile Which you can see here, which are the numbers We run two samples so you get two columns each one's a different sample Just to make sure we're honest And the numbers are what we call spectral counts, which are a semi quantitative measure of abundance so We can read this the top three here. You can see those are our amyloid signature proteins They have high numbers So we this is a way that we proteally prove to ourselves that this is indeed amyloid So it is and the next most abundant protein Is TTR so this is a TTR amyloid case And yes, there are a few Rare gammas and alphas and lambas and kappas, but that's background serum proteins We can't get rid of them 100% so there's always a few around but the numbers are very very low And we know that's just background And in addition this test is kind of even better because we beyond just doing our usual search To identify say the amyloid type say TTR. We can then use the same use a different database, which is a curated mutation profile and look at the same information Run the search and we can identify the mutation So we can we do this in every case if you send us the case we do this automatically And it's not 100% but it's probably above 95% that we can identify the mutation And in some ways is even better because it's disease tissue So you could have an asymptomatic patient a carrier who doesn't doesn't actually have Disease yet but have to carry the gene Well here we can show here that it is amyloid and it also carries the abnormal protein Um, so here's an example of a case just to show you the problems that we can face sometimes So this is a 74 year old man Had a heart biopsy had amyloid no problem It's typed and I can read this this was done somewhere else actually a very very good institution They use amylo fluorescence, which is actually probably better than ihc And they came with a diagnosis of um al capa And then 31 months later the very same heart biopsy so very very same specimen came to us and They're this uh signature protein. So it's no we know it's amyloid And it was ttr So You where So the last point I want to make is although I have already told you that syracous sites are really good They're not perfect. And so if the clinical picture doesn't fit right Then you're going to have to go to the end of the organ, which is the heart So I'll give you three the first example are rare amyloid types. So again, these are super rare um 808 4 is probably the most common one that we deal with That's a problem sometimes because I think even that can give a maybe Matt, you know, but it can give a um a false result using PYP scanning, but I think this is anecdotal at this point. So that's a problem, but it's extremely rare um The second problem is discordance. I'll show an example of that So here's the case 73 year old man had a long standing Type 1 diabetes history.  So they're present. So we know it's amyloid But we found was insulin So this is not al. This is not ttr. This is insulin so um in a insulin amyloid is actually the fifth most common amyloid type that we see It's about 1% of cases. This is not a systemic disease It's a localized disease to where people inject insulin It causes decreased absorption of insulin. It causes masses usually But it's a localized process that basically is a red herring But if you go back to our paper of all our fat pad biopsies, although 60% were al and 30% were ttr a full 10% were insulin So this is not that rare. So it's not un Unheard of that you will encounter this so this happens and basically it's a red herring So our clinicians knew that and they said, yes, this patient still could have cardiac amyloid And so a heart biopsy was done And it turned out to be ttr So In the end this patient had three things. He had the main thing which is cardiac amyloid ttr wild type He had an incidental localized insulin amyloid And he had an incidental mgus So yes, there can be just people can have more than one amyloid type either in different organs or the very same organ And we've written about this other people have written about this. So Is it common? No, does it happen? Yes. So don't be surprised and just keep going if The story doesn't make sense with the surrogate site And the last example, okay, I forgot about this So this is a paper we had written about whether you could use surrogate sites like prostate or bladder or tendon as surrogate for cardiac Amoy because if you think about it who gets cardiac amyloid? Well, it's kind of old guys, right? So the old guys often get prostate biopsies and bladder biopsies So this was kind of an interesting study And so we had 16 cases that had we had a heart biopsy Plus one of these sites and 14 out of 16 would were concordant, which is great But two were not and so it's important that you know about these So the last one, which I think is 29 Was discordant this person had a type of amyloid called seminal gel in which is localized to seminal vesicles and is prostate And this is always localized disease So this one was did not pose a problem because you would know that there's no way that's what was in the heart And the patient had I think al I can't read and read it from here Al in the heart. So that's fine. There's no way that could have been the same thing The other case case 10 was potentially a problem because he had al in his bladder and ttr in his heart So al can be in addition to being a systemic disease can be a localized disease And localized disease al in the bladder is a relatively common clinical pathologic entity So again, this is an example where using the surrogate site Didn't work and the clinical picture didn't fit and the clinicians were astute and went to the heart And diagnosed a circuit type there. So this is just to keep in mind that this can happen Usually it doesn't but it can And the last case this is the one that gave me Endless gray hairs. This was a 91 year old guy who had prominent I'm going the whole story because we're out of time here, but he had prominent interstitial amyloid 98 percent of what these big blobs of interstitial amyloid, which is a typical pattern for ttr And so we typed it It was interstitial agrit and again, it was ttr But the patient didn't behave like ttr. He was treated for ttr and he basically fell off a cliff clinically And so we went back And sure enough if you really hunt hard enough you could find rare vessels that had amyloid That look different. The other interesting thing was this patient had a fat aspirate Which is positive for al amyloid which also posed a big problem because we think that's that Fat aspirates is a perfect surrogate. So how could he have a different type in his heart? So I went back to the heart and we found these rare vessels that had amyloid And we we dissected those out separately and they were so rare that we could only come with a single cap But sure enough we ran it and it was lambda So this patient I don't know if you probably can't see this very well because the numbers are small so small But there was not a speck of ttr in those vessels And similarly there was basically not a speck of al In the interstitial areas. So they were two entirely different amyloid types two different Antitomic compartments in the same heart, but even though 95 plus percent of it was ttr He was behaving like al So we did get treated for al and he improved So again that the amount of involvement of the tissue is not necessarily proportional to what the patient's going to do clinically so This is extraordinarily rare Like this is about the only case ever seen like this But but happen once it can happen again So again, I think the surrogate sites are excellent But if the clinical picture doesn't fit you have to go back to the heart and again Senate to a very good pathologist because these are hard to diagnose So these are my take home messages for one Most patients with cardiac amyloidosis should not need a heart biopsy and about hash at least half should not need a biopsy at all For patients who do need a biopsy surrogate sites like fat aspirin bone marrow are often acceptable If you send them if you need a biopsy Send it to a good pathologist And we recommend typing it by a robust method like mass spec And finally surrogate sites, although very good or not perfect And if the clinical picture doesn't doesn't fit get a heart biopsy So that's it. Thanks for attention Thanks so much. That was outstanding Um, it's my pleasure to introduce the dr. Julie Rosenthal who's going to be speaking to us about emerging therapies and potential obstacles including or navigating prior authorizations Um, I just say parenthetically there are two great things about amyloid as a field one is the patient so lovely and two is Get to watch colleagues like dr. Rosenthal develop really amazing programs all by herself with the help of other colleagues And um, she's become one of the national experts in this arena. So pleasure Thank you matt And thank you everyone for allowing me the privilege to be here with you today It's truly an honor to be at our inaugural asu cardiac amyloidosis symposium today Over the next 20 minutes. I hope to provide you a tour de force of therapies for both ttr and al amyloid These are my disclosures Hopefully what you will appreciate by the end of this morning Is that there's truly been an explosion in the development of therapies for individuals living with amyloidosis We have multiple strategies and no longer do these include only Palliative and pastoral care, but we actually have therapies that will reduce overall morbidity and mortality for our patients living with amyloid So how did we get here? It was almost 150 years ago that dr. Verkow first described this starchy protein. Well called amyloid But only 30 years ago. Did we actually have our first intervention for hereditary polyneuropathy amyloidosis patients specifically with liver transplant And then it was almost 30 years ago that our colleague dr. Kelly at Scripps really described the kinetics that led To understanding how amyloid fibrils of ttr background form Which then launched the work into tofaminis, which ultimately led to the approval Of our first stabilizer in 2019 But silencer therapies hit the market in 2018 and we now have three silencer therapies available for our hereditary Polyneuropathy patients and most recently approximately a year ago or two years this month We had the fd approval for our very first al amyloid drug daratunamab everything else prior to that had been used off label for al amyloid So this is an overview of this morning. We're going to start with Highlighting some therapies for ttr amyloidosis knowing. This is a cardiac symposium. I really just focus our attention today on Tofaminis, but I want to highlight there are several other therapies available Then we'll talk about some plasma cell therapy and some other therapies for our advanced patients So to set the stage, I'd like to begin with a case. We begin with a patient. I share with dr. Goodman He's a 65 year old gentleman with hereditary ttr amyloid 380 ala and he like most 380 alas had a mixed phenotype including both cardiac and neuropathic Phenomenon he was quite advanced when I met him several years ago And his advanced stage was defined by his cardiac involvement as this is the driver of morbid immortality in patients living with amyloid You can see that by his elevated cardiac biomarkers We saw earlier from our colleague dr. Burke some classic features of individuals with amyloid on echo So this is a male apical 4 Hopefully you can all appreciate the bi-ventricular thickening here in both the lv and the rv As well as some bi-atrial enlargement and interatrial septal thickening And on the right you see the classic apical Sparing strain pattern otherwise known as the cherry on top Here is his technesium pyrophosphate scan. You can see here that the tracer lights up Greater than or equal to the bone. So he was a spect grade three consistent with his diagnosis of ttr amyloid So in this setting, what would you do? How many of you would start him on a silencer? Stabilizer maybe enroll in a clinical trial start combo therapy revert advanced therapies How many of you have no idea what i'm talking about? Well, hopefully by the end of the morning You'll feel a little more comfortable Again, I want to set the stage really on stabilizers You've already seen this diagram already this morning in different iterations But I just want to highlight the formation of ttr amyloid again It all begins in the liver the liver makes this tetrameric protein called ttr or transthyretin It's this critical unfolding step of that tetramer that leads the development of amyloid fibrils Which is an ultimately deposit anywhere from head to toe leading to a multi system dysfunction So we have three main pathways to prevent and delay the progression of individuals living with ttr amyloidosis We can start at the liver with silencer therapies again These include patiziran anotiracin butiziran We can actually target this circulating ttr ketrimer itself with stabilizer therapy We'll focus today on tofamidus and perhaps the holy grail will come with actually extraction or removal of fibrils This is otherwise known as degrader There's a lot of work going on right now in the monoclonal antibody arena both for ttr and al amyloid But again, I want to highlight tofamidus today As this is our only approved therapy for individuals living with cardiomyopathy and ttr amyloidosis Again a stabilizer there is to prevent that critical unfolding step So we lead to an increased concentration of serum ttr and subsequently a decrease in deposition For those of you not familiar with tofamidus It really made this stage a couple years ago. Thanks to our champions of amyloid dr. Mauer who's here today and Dr. Epizzi who our community recently lost? Do their work and colleagues for the htr act? Study this was a randomized control trial looking at different doses of tofamidus a high dose low dose and comparing to placebo And overall we saw a significant reduction in mortality You can see separation of curves here at about a year and a half In individuals taking tofamidus compared to those not We saw overall 30 reduction in all-cause mortality The number needed to treat prevent one death at two and a half years is about seven and a half patients And four patients prevent hospitalization at one year Not only does this stabilizer demonstrate a reduction in mortality, but we saw a reduction to overall morbidity You can see there's a significant separation of curves at six months in terms of the decline of a six minute walk So individuals on tofamidus seem to walk longer and stronger at around six months and over time compared to those not on stabilizer Not only do you see improved morbidity from a functional standpoint, but also quality of life Most of the people in the room are familiar with kccq You can see that the decline in kccq scores is less steep than the decline in individuals not receiving drug We once again saw a significant improvement at about six months This was recently presented at isa by my colleague Dr. Martha grogan looking at the long-term extension data from the attr trial on the top You can see individuals who are initiated on tofamidus from the very beginning This is the yellow line as you can see the gray is the placebo But at 30 months individuals in the trial were allowed to cross over and ultimately Allowed to receive stabilizer therapy And hopefully what you can see on the gray curve is that the rate of decline in the Individuals who were once on placebo and converted drug has slowed down And then the decline in the individuals on tofamidus doesn't really seem to be declining anymore It's almost like they've reached a steady state now over a five-year follow-up once again Highlining that their quality of life contains to be better In addition to reduction morbidity mortality We've heard already from my colleagues this morning that timing does matter We know that trying to pick up people earlier in disease Tend to have better outcomes in terms of morbidity as well as mortality with hospitalizations And survival so individuals who are start on treatment later in their stage of amyloid tend to do less Well compared to individuals who start earlier in their journey Also, we know that regardless of dose individuals receiving some form of tofamidus do better than those not receiving tofamidus at all But does dose matter? More recently our colleagues published that yes dose does matter You can see here on the forest plot that dose mattered not only in the initial trial But also in the long-term extension trial those receiving higher dose tofamidus 80 milligrams compared to low dose tofamidus at 20 did better So knowing that we do have multiple therapies, how do we choose? Specific therapy for individual living with teacher amyloid is it based on the organ based on how the drug is administered the cost of the drug Or is it a combination of factors? Obviously this morning I did not go through all the drugs But as I highlighted hopefully for you in that timeline we now have four Approved drugs by the FDA for amyloid but this table that was adopted from dr. Kittleson and colleagues highlights that we have three FDA approved silencers specifically for hereditary pulmonary neuropathy patients We have one stabilizer Approved for our cardiomyopathy patients both hereditary and wild type that is tofamidus And then we have de flunazol, which I think some of us in the community continue to use off label Really because of cost as you can see on the far right hand side here The cost of these drugs is extraordinary as dr. Post alluded to and while there are financial assistance programs available for our patients I think we as a community need to do better and need to do more So getting back to our case of this gentleman I met we initially met in 2017 remember in 2017 Aside from liver transplant for hereditary pulmonary neuropathy patients. There really wasn't any therapies around in 2018 He was initiated on the first drug available, which was a silencer petezeran And over the course of those four years. He actually did much better. He Got off of walking with a walker his heart failure improved clinically. He was doing much better Interestingly in 2021 he develops an intermittent hematuria for this He underwent a renal biopsy that raised question of malignancy And ultimately he underwent an effrectomy and all the nephrectomy showed was oodles and oodles of amyloid So I think that there's still have a lot to learn about how ttr proteins can affect the kidney This gentleman did not have any proteinuria And currently he um continues to be with us, but is living with some progressive heart failure The importance of this case I want to highlight I had to believe it was dr. Vijay who talked to us this morning Meant in survival for an individual with hereditary ttr amyloid used to be about two and a half years Three and a half for wild type, but currently with the advent of all of these therapies We're changing the natural course for these patients and their families So this is a nice summary adopted from dr. Ruber and colleague really just to highlight that we do have options for our patients This doesn't even highlight what's to come Apollo b was recently presented at isa and hfsa and I believe is in progress with the fda So potentially petezeran might be available for our wild type cardiomyopathy patients But for now it's to famine us as well as off-labeled diffusional Again for hereditary patients specifically those with mixed phenotype I think we should consider silencer versus stabilizer the data Has yet to really be presented. You know should we do combination therapy is silencer superior to stabilizer or vice versa I think more to come on that front So switching gears to al amyloid osis and anti plasma cell therapy Like to just start with another case and I think this case highlights a few stereotypes one amyloid is not just a disease for men This is a young woman of jamaican descent Who presented for her third opinion re heart failure and was actually found to have light chain amyloidosis She presented in quite an advanced case. She was stage four with clearly symptoms of failure to thrive She had actually undergone a pericardial window to recurrent pericardial effusions more than a year prior to meeting me She was having recurrent pleural effusions necessitating multiple thoracentesis You heard earlier from my colleague a little bit about mayo staging and whether you use mayo staging for ttr amyloid or al amyloid Once again, it's the cardiovascular pathology. Um that really highlights the morbidity of these patients So here is that al staging curve again And I think one of the thing that I would just highlight in addition is these curves remain quite steep Overall mortality for an individual with stage four amyloid untreated is less than 50 and that's highlighted by The sort of brown curve there Thank you But um these curves like I tried to show you with the ttr case are really changing most of this data stems from Old treatments old chemotherapy based treatments for individuals al amyloid such as the melphalan Prednisone therapies that most of us when we were in training um were most exposed to Cyber D really didn't hit the scene until 2012 But now we have a lot of things in our arsenal and I apologize This is supposed to be not there Um, but basically we have a lot of different agents whether it's melphalan and prednisone But cyber D has really been the standard of care up until more recently with the undramino tile leading to cyber D Dera tuna ma'am This has truly been a game changer And I think more things to come with novel therapies and perhaps targeting cytogenetics to tailor therapy for our patients But and ram and I just want to highlight this was Published just over two years ago and now that led to a game changer for our patients living with al amyloidosis Dera tuna ma'am is a monoclonal antibody targeting the plasma cells and what this trial looked at was a randomized controlled trial Comparing our control group, which was standard of care cyber D Cyclofosamide rotizumab dexamethasone versus the cyber D plus deratuna ma'am What hopefully you can see is that there is a significant risk Reduction in individuals with the cyber D. Dera compared to the control group more than 50% of these patients were able to achieve Complete remission compared to just under 20 receiving our prior standard of care cyber D So getting back to our young lady. She actually started cyber D. Dera prior to the FDA approval We were using off-label Dera back in this time period in august of 2020 It took her two months to normalize her free lighting ratio and at that time she was actually in complete remission This was actually shown in andromeda, which she would have been excluded from because she was in may of stage four So they excluded the the sickest of the sick patients This demonstrates that you can use this regimen in quite sick patients And I recently saw this young woman last month and thankfully she remains in complete remission She is now on surveillance monitoring and just to highlight how much remodeling can change I think you saw a nice example from dr. Goodman When you're thinking about remodeling from an autonomic reflux study and so forth We definitely can see some cardiac remodeling this young lady was requiring 200 milligrams of torsemide daily With intermittent boosters to control her volume status. She was initially getting multiple thoracin tc's Now she has not had a recurrent plural effusion in almost two years And when I saw her in clinic last a few weeks ago, I decreased her torsemide to as needed only She is back to living life But what about patients who are really this advanced patient who I think have missed the boat when it comes to potential turnaround with chemotherapy or stabilizer or silencers You know, we can think about transplant Autologous stem cell transplant is still used for certain individuals living with ale amyloidosis But I think our program is steering more and more away because we are finding that therapies are working for our patients Knowing that I'm a cardiologist and this is a cardiac amyloid symposium I just want to highlight The role of heart transplantation and I'll save stem cell transplant for another time But people back in the day used to think that we could not transplant our individuals living with amyloid And this comes from old data out of male clinic actually showing that individuals with amyloid tended to do worse A more modern cohort looking at our united network of organ sharing data from 2008 to 2013 Demonstrated in fact that individuals with amyloid Can have just as good outcomes as individuals not with amyloid The difficulty with unos data reporting system is it doesn't differentiate between those with ale amyloid Which you have seen perhaps have a greater morbid immortality compared to those with ttr amyloid in some respect And so it's kind of among us as amyloid centers of excellence to kind of look at the data a little bit more granularly Our colleagues at columbia as well as other centers like stanford and cedars have demonstrated while numbers are small Um that these patients whether they have ale amyloid or ttr amyloid can have just as good outcomes as those Not living with amyloid And I think this stems from us understanding as a community Who these patients are what their comorbidities are and making sure patient selection prior to transplant is good And I think what's really interesting now these cohorts that i'm highlighting here This is prior the era of actual stabilizer therapy or silence or therapy So I think there's going to be a lot more to come in the future in terms of how we're managing them And just to show you that um You know since we've all been in the room kind of looking at data points and graphs These are the people we're talking about these are the people who hopefully were impacting their lives As well as their family's lives. I actually just saw this gentleman for his four-year annual follow-up He just finished a 5k back in north dakota. This was actually a patient sent to me from dr. Grogan So this was his one-year heart transplant anniversary But now he's still out there living life and next to him is kathy kathy. We meant after basically one cycle of chemotherapy with cyborg idara on a balloon pump and ultimately we transplanted her and she is going to have her Two-year anniversary this march. She is actually only on surveillance She is not required to stem cell transplant or recurrent chemotherapy And I think that's a question that um myself and colleagues are charging our hematology colleagues You know, how much how long do we need to continue these people on therapy versus just maintenance? So with that what's to come you've already heard from my colleagues dr. Post Sonya sobrowski and others there are so many clinical trials available I would encourage you to go to clinical trials.gov today last night I typed in two keywords treatment and amyloid and more than 500 hits came up alone Cardio transform for any of you in the community who are still enrolling. Um, we're still caring for patients This clinical trial is still enrolling. He lives be hopefully we'll have data come out in a couple more years This is looking at bootes around silencer therapy. It's a depot injection Acoramidus waiting for the results. Hopefully the next year or two. Maybe sooner two years No, no, no June June. Okay. Excellent. Um, what about gene suppression therapy? This is really going to be potentially it'd be a game changer You perhaps have seen a couple years ago with new england journal published a case in our hereditary polyneuropathy patients Seven patients showing one dose wonder. Um, they can really change your entire genetic makeup Phase two clinical trials are ongoing and phase three Are in the works But this really could be a game changer for not only our patients living with teacher amyloid But perhaps other diseases And then a lot of um monoclonal antibody trials are going on right now These are two active trials for individuals with al amyloid and what's nice about these trials is they're including Are really sick cardiac patients a firm al is looking at these mayo stage four patients who otherwise would have been excluded From clinical trial. Um kill 101 is looking at a different staging system. But again Sick or heart patients with mayo stage 3a and 3b So I think lots to come and encourage you And with that I will just close with this image by monay This was the actual painting that launched the movement of impressionism for any um impressionist lovers in the audience This is called la soleil avan or the sunrise really. I just think amyloid targeted therapeutics They're finally here, but there's a lot more to come and I think tailored therapy is certainly on the horizon with gene suppression Maybe looking at cytogenetics and thinking about those who might respond to venetoclax if they're not responding to the cyber de dera And other things So with that I could not be here without my amazing team So I want to thank them as well as all of you for being here. Thank you That was fantastic. Please please don't go away if the speakers could all come up. We'll Begin a little lease panel discussion. Um Suddenly if there are questions from the audience, please raise your hand and we'll get your microphone. So it looks like there's some In the background there. Okay Actually, we'll just start. Um, maybe one question for sonia. So, um, you mentioned this 23 and me genetic testing. So you have a 25 year old who is looking for god knows what but they have a val 122 ILE variant and they show up in your office. Um, no symptoms. So what are you telling them? Yeah, that's a great question and I've actually run into this somewhat recently. Um, so You know, essentially the first thing is I asked them what research they've done on their own Because it's really helpful to have an understanding of where they're coming from and you know What their impressions of are what they've read online or maybe what they've even read from their own genetic test report but The the first thing I tell them is That variant in particular. This is probably a true positive So I I kind of treat the session as if you know, we've already got a positive result But that there is some chance that maybe it's not so we do proceed with a clinical confirmatory testing As I had mentioned before But we we are talking about, you know that that increased risk for the cardiac amylidosis In particular, we talk a little bit about amylidosis in general Implications for family members, you know, like I said really kind of treating it like a positive test report at that point But that we'll have further discussion once the clinical results come back and and usually at that point It's a phone call to confirm That that the results did come back positive And at that point I also talk about our awesome Multidisciplinary clinic and and the providers that we have here I know we just heard from Dr. Rosenthal and Dr. Goodman and and they are really great And so I talk about the support that we have on our team and that there There is support from other clinical standpoints And and the genetic implications of that as well just in terms of What are we thinking about for family planning and and other family members because this oftentimes is a surprise, you know They many times don't even know that this is something in the family or had never heard of this before So there's a lot that we cover in one of those genetic counseling sessions, but It is something that comes up and you know, I Whenever patients ask me about 23 in me testing or direct to consumer testing in general should they do it? Should they not really it's a personal decision and it's up to them But I tell them, you know, there are things that we might find out about that you're not expecting to find out about So certainly worth doing your research ahead of time And considering both what it might need for yourself as well as your family members when you get those results back And maybe I just asked Julie So what do you say clinically to this person who's now been referred to you and their 20s or 30s with v122i for them? I mean And they're asymptomatic Yeah, this is definitely a struggle and I think something myself and colleagues talk about often But just try to reassure them and also just encourage them to follow back You know, typically I've been recommending five years We unfortunately don't have guidelines for this and so I base this office some data from hcm patients and their families in terms of screening But try to provide them some education. We have a great team of nurse coordinators So try to provide them that education of signs and symptoms to look for at the same time as sonia alluded to Sometimes that stigma I think have really mentally affect patients So then they think they have a neuropathy when they don't have a neuropathy or they're worried they have chest pain and there is no chest pain So you do want to be cautious and understand your audience and I think asking them You know what they understand what they know and how they feel but try to provide reassurance and Just bring them back to kind of hold their hand a little some respect Yeah, I just agree. I mean this is a disease that we heard as an age dependent penetrant So we don't see v122i penetrating usually before the age of 50 the opportunity may be that Love ones who are older in their family may actually have a clinical phenotype and maybe those are the individuals So I always encourage older adults who have the disease to get their Not their kids tested but rather their siblings tested question So I work as a hospitalist and I see a ton of heart failure patients You know and usually cardiologists are involved when there is low ejection fraction but then They kind of turf off a lot of diastolic heart failures and you know, a lot of echoes are Not actually read by Experienced cardiologists if I may or it's in the substance and not in the conclusion and a lot of times these are missed So there are a lot of barriers to diagnosing early And also our hospitalized patients have that revolving door mechanism where they keep coming going coming going And a lot of them are 80 plus or 75 plus and now the cost versus benefit as well as What is the you know when you say the biomarkers and you're saying Two out of three makes it stage three or stage four in your life expectancy is 40 months to six months Here you're dealing with our patients already have Multiple medical problems chronic kidney disease their tropes are elevated BNPs high to start with So when you say 40 improvement with treatment, I want to know in years Am I prolonging life or delaying death or I'm actually benefiting this patient? What is a number of life? In years that you can give with treatment and without treatment so I can approach my patient in a positive way I think that's an outstanding question and something that each of us are faced with quite routinely And I think you highlighted that question about the multiple morbidities, right? I think it's if you look at the patient and they can't get out of bed on their own Is this really the patient I want to offer an endomyocardial biopsy to and start thinking about Chemotherapy or is the right thing to do to offer palliative care? So I think you have to treat each patient as individual I don't think we're in necessarily the exact place to judge, you know, what is their life worth to them But looking at the whole picture are my therapies and the treatment's going to ultimately cause harm Or as you said, are they going to cause benefit? But I think that the important thing to know is that this decision does not have to be made on your solar You heard today from a number of colleagues in different subspecialties Amelidosis can affect many things So this can be a team decision and approach to how to help you counsel your patient or also just help counsel the patient and their family But sometimes in my patients who are quite advanced in age 90 plus 85 plus with multiple comorbidities Even if they have TTR amelidosis if I feel they have class 4 heart failure stage D And I don't think they're going to be living more than a year I'm not going to be offering these patients a stabilizer therapy. That's a quarter of a million dollars a year because I'm not sure It's going to provide that benefit We saw even from the ATR ATR trial while there is some initial benefit early on from symptoms It doesn't happen overnight this takes several months and you're not seeing more brutality benefit for more than a year and a half So while things might change For now, I think you just need to continue to approach each patient on individual basis and reach out to your colleagues Who can help provide you some guidance If I can add a little bit to that So I think that's that's a great question. And I as a hematologist I saw see a lot of those patients who have like straight three or straight four And by at your heart failure and they are diagnosed with lighted amelidosis And then are they eligible for treatment and will the treatment improve the their Quality of life and will it prolong the the the life expectancy? So Just to give you an example. I had I saw a patient Like she was in the 60s late 60s and she was diagnosed with state for heart failure at another hospital and then The hospitalist saw the patient cardiologist saw the patient they diagnosed and then she was sent to hospice So she was in hospice for at least like two three months and then She came to see one of our cardiologists Who specializes in Amelidosis and they started the work up and finally diagnosed her with Lights in amelidosis. So then she came to discuss Her options with me and I I had the Discussion with her. Yes, the outcomes of prognosis is not good because you already have state for heart failure But we can at least give a trial of the treatment and see if that improves your quality of life And we started on a single agent to mummab initially to begin with because she was Wheelchair bound and she was not even able to walk on her own And after first couple of months of treatment her symptoms started to improve And now she is able to do her activity. She is able to walk at least She's now six months into the treatment and she's out of the hospice and she's doing really well So some of these patients can be very sick when we start the treatment and experienced positions when we start the treatment and we start Gently and see how they tolerate and if they tolerate it, okay That can help improve their quality of life and also can improve the longevity I don't know whether it's going to be One year two years three years that she's going to live but at least she will have some quality of life and Most of the treatments that we offer these days, especially in the Hematology world and not cytotoxic chemotherapies and most of these treatments are very well tolerated But we have to start gently and build it up slowly and we can improve the quality of life in these patients All right, just to add that I think you're in a unique position as a hospitalist There's data from a national health system in the in the uk in which patients with ttr amyloid Are hospitalized in the last three years of their life 17 times So you talk about the revolving door if you can make this diagnosis You can institute therapy We may be able to as dr. Rosenblum was mentioning prevent some readmissions So, um, you know, that's what we're hoping for other questions in the back Yeah, um, how different is amyloidosis and amyloid plague formation in patients with Alzheimer's So the amyloid type in the brain the for the amyloid amyloid, uh, sorry Alzheimer's patients is a different amyloid type called a beta Uh, so that's a specific amyloid type there, but maybe 16 different amyloid types seen in the brain, but some of those are very very rare So the most common one is a beta and that's the Alzheimer's amyloid Is that the question answer the question? sometimes there can be some confusion particularly with family members who may read about and they have amyloid diagnosed by us say ttr or wild type Or variants And then they may may read about amyloid associated with Alzheimer's, but There really isn't any association and usually it's just a matter of of reassurance but it does get to the To the point that we've been discussing which is these older patients do have multiple comorbidities And so we we do struggle with this and some of the patients who they may For example in neurology, they may come in with a little bit of neuropathy But they may have a lot of dementia for example. That's unrelated So a number of the patients may have other comorbidities which need to be factored into treatment decisions So on So there is the idea There may be amyloid opaths so people who have Amyloid of different types in different parts of their bodies there has some evidence maybe that there is a link between Alzheimer's and amyloid elsewhere But it's kind of tenuous and I think there needs to be a lot more research But that idea is at least floating around out there I would just add that my clinical experience of the overlap is pretty minimal. I'm surprised You know like the average age of these patients is 75 or 80 and most of them are quite erudite and The coexistence of the two at least in my clinical practice haven't seen really a thousand patients with TTR Is much smaller than I would anticipate the other thing I would also submit is I think The cardiac amyloid world has done a much better job of actually taking care of this disease You hear what's coming out of FDA approvals for Alzheimer's disease and it you know is associated with pretty high costs and not much You know necessary clinical benefit But the same argument is being held which is if we can move upstream and identify people earlier In Alzheimer's disease. These therapies might be more beneficial in some regards So I think across all Alzheimer's all amyloid diseases early diagnosis is really critical You know a great Conversation great talks. Oh my god. I'm learning so much already from each of you. It's fantastic So in my reading Therapy Julie or Matt or anyone I think you probably did mention maybe I forgot I missed it Doxycycline plus Toro or psodeoxycholic acid What if it is the data that's one secondly from a patient perspective and you know regular every day After you've seen your patients. We thought of these hot failure or whatever their question. What should I eat? What should I take? You know and you know how much excess those of the most common questions almost on a daily basis with every patient and then some What is that some question What about green tea doctor Rosenthal? What about turmeric? Will it prevent Alzheimer's will it prevent amyloid doses? Is there any data or is there a therapeutic strategy that maybe You know, there is some evidence there. What are your thoughts on that? One question. I think prior to 2018 most of us in the room who are practicing Amyloid physicians. These are the tools that we could reach for in addition to palliative care Um, we were reaching for these things like Tadka and doxycycline and green tea I found doxycycline the state of arizona quite challenging due to photosensitivity seeing lots of sunburns and our patients or gi intolerance That being said, I think the data is quite minimal and There's some data into manual models But we haven't seen on a large scale in human models overall morbidian mortality benefit and due to potential side effects and drug interactions I'm no longer using these in my practice. The clinical trials did exclude patients from taking specifically the green tea I do not know about turmeric, but um, maybe matt can comment on that in the hdr But I know doxy and green tea were excluded from some of the clinical trials. So those are not agents I'm using there was actually some data recently published for our al amyloid patients I think people are now steering away from doxycycline even in al amyloid Which used to be standard of care in that first year. We're giving doxy with the cyborg So I think the community is going more away from those More herbal or other types of agents for treatment of amyloid To answer your second question in terms of what do we educate our patients regarding diet? I think that's a whole one hour lecture in terms of the supportive care from a heart failure standpoint Right for individuals amyloid. We talked this morning or I talked this morning about disease targeted therapy But what about how we treat our patients just from a neuropathy standpoint or heart failure standpoint? Those are whole lectures in themselves from a dietary standpoint. Most of these patients I find are quite Cacetic malnourished due to malabsorption or just poor cardiac output and difficulty absorbing So they get that early satiety feeling So I typically put my patients on a seafood diet. I've coined this term from Eric Steadley Not that they need to eat seafood but meaning they they see food they eat food You know, there's a lot of controversy for those that you attended the ACC Arizona I was a part of a debate with a colleague from Tucson, you know salt restriction versus no salt restriction I do not salt restrict in my practice. I think there is great data out there for salt restriction in the hypertensive heart disease world I think um, dr Maher recently had a paper out in jack with some additional colleagues, you know On what is the optimal diet? And I think trying to tailor to your patient is probably the most important thing and for these patients quality of life Should be at the top of our list. They're suffering in so many ways So for me and for many people food can bring pleasure So I let them eat whatever they want to eat and just might mean some extra torsemide or lacyx or bumex not to provide To any one department. So just let them enjoy Dr. Maher Ellen, I wanted to ask one question before we break for lunch so If we have a 30 likelihood of detecting the monoclonal protein With fat or bone marrow in ttr, but we have a 70 or higher percent in al Should we be preferentially considering cardiac biopsy in patients with suspected attr? And the reason i'm asking this question is It takes time in some institutions to organize a bone marrow biopsy and a fat pet biopsy And by the time you get all that back and it's negative you have a 70 chance Now you're going into potentially cardiac biopsy or you could just preemptively treat them for attr So i'm just sort of wondering. I feel confused as a practitioner What type of biopsies we should be ordering when? That's a great question And in fact, I had put out this conversation with one of our our cardiac amyloid guys Is that mayo rochester a couple days ago? But I think when there's an m protein, you don't know which one it's going to be at that point It could be either one so um That's why we next go to the fat and the bone marrow at that point I suppose if you're really strongly pushing for treat as fast as possible The ideal site is the heart. So I don't think it's ever wrong to go to the heart first but um because at the point With the m protein, you really don't know which way it's going to go If it's al then you have an 80 chance of making the diagnosis with something a lot simpler like a fat or a bone marrow So it's an excellent question. I don't think it's ever wrong to go to the site of interest first Is it okay to treat without having the protein because if you have a negative biopsy then you're empirically treating for attr Is it okay to stop, you know there and say well, we didn't find it in the bone or fat? I'm not sure the clinical But I would be very cautious about trying to treat me without being sure what the precursor protein is I mean, look, these are two Very different diseases if you see enough patients al is a medical emergency So if you get light chains back and they're abnormal These patients usually look very sick and this is something in which you need to move quickly I mean In the days and we started to try to do transplants on patients with al amyloid the median time to death was 56 days Now these are really advanced al patients as we saw and occurs So, you know, you measure light chains and it's abnormal You need to have a clock in your head as martha grogan would say and you need to get that person in And move as quickly as you can whether it's a fat pair first and if it's negative then our biopsy You know ttr is a very indolent disease The other thing just epidemiologically is that you know ttr is the tail that's going to wag the dog Right. It is going to be as we heard. I bet 95 percent of all cardiac amyloid We've seen the future just given the epidemiology who's getting you know amyloid and aging so If you do this enough you get a real good flavor for what people have but I just say You know if you think they have al call all your friends call them quickly your hematologists get consults And do not dawl, right? I would just echo the following. I think if we walk away from anything doctor saying Highlighted in this morning's talk is al amyloid is a heme emergency. So from a cardiologist perspective I hope that each of you think of this as a STEMI time is light change Just like time is myocardium and I would never want to treat these patients blindly You heard from dr. McFall this morning 25 to 40 percent of individuals with ttr amyloid are going to have some kind of mguss And just because they have an mguss they might have al amyloid. They can have wallenstroms They can have ttr. So I had a patient who I for sure thought had al amyloid Fat pad was negative. He went for a bone marrow and turns out he had wallenstroms But didn't fit his cardiac picture. So ultimately he got a cardiac biopsy and turns out he has ttr amyloid So his wallenstroms is now remission and he's on to famine is interestingly his ejection fraction remodeled went from 20 To 65. So I'm thinking this was some light chain circulating toxicity I don't know But I think that we have potential to cause more harm than good if we're treating an mguss blindly I think many of us on this stage in this audience have seen individuals being treated with chemotherapy for ttr amyloid because they had that background of mguss. So really Thanks to our colleague Dr. Dahlgren and colleagues at Mayo in 2009. We developed this technology you heard about this morning with mass spec so I think tissues issue and To stress to each of you in the room, you know, where do I go? You go wherever you can get the fastest Result like who can help you the quickest as dr. Maurer said you call all your friends Fat pad yield is somewhat low for ttr amyloid, but that doesn't mean they don't have ttr And the biopsy of the bone marrow too might not show ttr or al amyloid So you ultimately do have to go to the organ that is problematic. And I think in this day and age Cardiac biopsy is relatively safe. There is about a 1 to 5 percent risk of perforation, but in experienced hands This can be done and should be done All right, that's wonderful. I think we should break for lunch. We'll be back at 12 45 for our keynote address Good afternoon everybody Thank you again for coming out to this inaugural asu cardiac amyloidosis update I think it's really a testament to all of you as well as the individuals who organize this event Dr. Chris vj. Dr. Sandesh chev and jenice guzman for putting on such a spectacular event I have distinct honor and privilege of presenting our keynote speaker Who I believe really does not need any introduction, but here is dr. Matt mower For those of you who have paid attention this morning You would see that there's not an amyloid project that dr. Mower hasn't touched Over the last several decades and it's really a pleasure and honor to share this stage with him today Be someone that I look up to as i'm sure many of you in the audience do so with that Dr. Mower So it's really great to be with everyone and um give this address I say i'm really excited about everything that's happening in amyloidosis But we do have a lot more work to get done I'll try to highlight that and I have support from lots of places including your government So I just wanted to recognize claudio repetsi Who was the co-chair of the attr act study with me who unfortunately passed away suddenly he was A lovely man very curious real master of medicine credited with a paper in 2005 and jack using dbd Centigraphy And if those you knew him he had what we call repetsiasm these ways of kind of making associations that were Kind of unbelievable. So a great loss for the community. There he is presenting the attr act data at the ec in 2018 So this is a disease that's undergone a transformation in a very short period of time We've gone from what we thought was rare to one That's pretty common one that required an invasive End of myocardial biopsy to one that you can diagnose with centigraphy and one in which we had no treatments To one in which we'll have a plethora and so with that background This is a patient that we saw columbia with one of our fellows who became interested in amyloid at the time It's really a typical unfortunate case of a 62 year old african american gentleman Who had acute decompensated heart failure had bad hypertension and aortic dissection and then had you know multiple admissions We heard from one of our hospitals earlier Later on he had a phenotype with a pretty low blood pressure orthostatic. You can see he had an increased wall thickness No aortic stenosis even at rvh And someone had done um light chains on him and they were abnormal These are in milligrams per deciliters lamb is 29 his cap is normal He has elevated troponin in bnp and they order a pyp scan which Literally makes no sense because once you know that they have light chains that are abnormal a pyp won't help you and basically We met him you can see the timing here, but uh, you know many many years after all these tests were done and within About a few days of our evaluating making a diagnosis. He unfortunately passed away And here's a patient who I actually one of my first cases This was a 62 year old gentleman a progressive shortness of breath for two years He had what people thought was a silent mi because his ekg showed pseudo infarcts He initially had a fib that became a persistent after A few paroxysmal bouts and he had a cast to evaluate for coronary disease didn't have much But he had an elevated lvedp No one seemed to notice that they gave a mace inhibitors beta blockers and diuretics He told all the doctors. He felt absolutely miserable. No one seemed to care and Basically had an echo with increased wall thickness and a preserved ejection fraction actually progressed to develop big Right plural effusion that they tapped thinking it might be malignant And two years later now he's in persistent a fib his ef is declined And he gets crazily an avian odoblation and a bivy pacemaker and So this was a guy seen by one of my bosses milt packer and he called me and said I don't know everyone I thought who had hefpef is an elderly woman With hypertension and I got this guy who's in my mind middle age. He's only in the 60s He's a man and he's got low blood pressure And if any of you know milton, he could really kind of summarize some key clues to things pretty quickly This is the guy's ekg for those you can't see it's got the atrial fibrillation Diffused low voltage not only in the limb leads, but precordial And uh, pseudo infarct pattern with poor precordial our way of progression And this was his echo cardiogram At the time we were seeing him. So he's got, you know wall thickness like 25 millimeters He's got no lv chamber capacitance His endiastolic volume is like non existent his atrium or like twice the size of his ventricle And this was years ago. So we didn't have p yp. We're talking, you know, 2000 and two or three So we did a right heart cathina biopsy. These were his filling pressures, which are high I just point out he has no stroke volume, right? So if he has no stroke volume, even though he's tachycardic You can see his cardiac index is 0.97, right, you know And that's why his blood pressure is low because blood pressure is determined by both flow and resistance So if you have no flow out of your heart, you're going to have a low blood pressure And um, we did an endo myocardial biopsy as we heard a relatively safe procedure Especially in amyloid and you'd see pathology like this With a diffuse hyaline material that stains a bipolar eyes the microscopy congo red And if you're really stuck you can kind of do em on the bottom right to look at the amyloid fibrils So um, this is two cases that I wish I could tell you are rare, but they're not and these are data from isabel usada Who runs the amyloid research consortium and she surveyed patients and is what they said I had to wait a long time. I had to see lots of doctors and unfortunately the Provider that's in misses the diagnosis most often is a cardiologist who basically say These patients often have hypertrophic cardiomyopathy. Um so, um We've heard this morning, but just to remind you amyloid is um, uh, a disorder when systemic That is characterized by extracellular deposits of a protein These proteins form fibrils The proteins get stuck in the organ they make the organ not work And there are as we heard dozens of proteins that can form amyloid and various organs in vivo But as I like to jokingly say but probably not untrue cardiologists are not the brightest folks In the don't know nobody's tools in the tool So we don't we only need to know two types of amyloid really al and ttr as we saw and ttr comes as either variant or Wild type which for some reason we used to call senile a cardiac amyloid or age related um And again the key here is to make sure you distinguish these two disorders because they differ not only in the biology The precursor protein, but in their outcomes the prognosis the genetics and most importantly how we treat them Uh, so just to highlight um a l is a disorder of the plasma cell it affects people of all ages But I just uh has an equal male to female distribution I was mentioning to someone earlier if someone calls you with a case on the phone It's a 40 year old woman who has amyloid right? It's al amyloid until proven otherwise epidemiology does matter um Hearts affected in two-thirds of the time the kidney two-thirds So there's a lot of multi systemic involvement and this is the disorder We saw the survival curves where mortality is very very bad especially um with advanced disease All the way to the right is wild type ttr Disorder to date of older adult men probably underdiagnosed in women all of these orthopedic manifestations And we have as we heard stabilizer therapy though probably silence or therapy will work here too And then we have hereditary or variant disease There are 130 different variants in the ttr protein So the phenotype is very dependent upon which mutation you have but it seems to like as we heard The heart and the nervous system as well as um sometimes ligaments and here we have advantages of Silencers and stabilizers So these are our reasons And these are five ways to avoid missing the diagnosis of a cardiac amyloids. We'll go through each of these first is You've got to think about it to diagnose it and it should be included in your differential So this is a really famous article by a famous educator named david eddy. It's really great if you've never read it In the new england journal he analyzed the pathological conferences in the new england journal if you read them every week There's a case and he analyzed, you know, 50 of them and he came up in certain conclusions one of which was Not he said this was fallacious and I mean do but more often the diagnosis was correct from someone from harvard But he attributed that just because they knew about the case and they heard it in the hallway But it's kind of embarrassing to do one of these cases in the england journal actually get it wrong And when people got it wrong, which happened The problem was that they didn't follow what he thought were these main six steps to You know, basically making a diagnosis You listen to the you know chief concern or complaint That gives you a pivot and you generate a list of causes and then you kind of hypothesis test and the key He said was when you have a very short differential. So you walk in the room It's a thick walled heart and it's hypertensive heart disease and you're done. You didn't create a long enough differential So I urge you to put amyloid on your differential Um, uh, second is there's misconceptions. So we think it's rare and we think we got some good screening tests and we don't So, um, this is the impression of most providers are looking for a needle in a haystack And these are the data we heard today, right? 16 percent of patients undergoing a taver of amyloid 13 percent of patients with heart failure to preserve df and an increased wall thickness 6 percent of heft-peft patients in the community 5 percent overall of hcm patients But if you're over 60 One in four and I like to jokingly say if you walk out on broadway and just scan someone who's 75 or above We just saw was one or two percent of older adults going to be asymptomatic but have it So this is not going to turn out to be a rare condition at all Even though, uh, the famine has got approved under the fda designation of a rare disease So these are the data Don't want to rush too quickly. So this is al amyloid. It's a disease that affects one person in a hundred thousand Or 10 per million. So you can do the math. They're about three to five thousand new cases in the u.s Even if they all live 10 years, which they don't, um, you know, there's not going to be a lot of cases This is definitely a rare disease by every designation Variant ttr is not that rare. We heard 3.4 to 4 percent of african americans carry a variant depending upon if they live to be the age of 60 There's estimates that there are 25 000 120 000 african americans who have a variant ttr And that's not included in the other mutations. We heard about so I would say not so rare And a wild type disease is just gonna, you know, explode because the fastest growing segment in the worldwide population are people over the age of 80 So definitely not rare. I think I always ask people which a patient has amyloid. Who says the red ekg just raise your hand No one put their hand up at dr. Steadley did and who says the green ekg And most people and the answer is both of these people have amyloid biopsy proven So we taught people that low voltage is something to look for and it is but it's a very late phase phenomenon If you want to identify amyloid with someone has two feet in a grave That's when you look for low voltage But as you can see here in 210 biopsy proven amyloid patients Low voltage is prevalent in less than a third. So it's not very sensitive much more sensitive is pseudo infarcts Looking formulate the voltage criteria or doing what we ask all clinicians to do Which is look at the ekg and integrate it with the wall thickness on the echo So this is christina cuerto who's a famous amyloidologist phd thesis with claudio in balonia They took a thousand patients and they quickly a third of them had hcm a third had hypertensive heart disease The third have amyloid. Basically if you look at all 12 leads of the ekg Usually every lead has 10 millivolts. So it's pretty simple. It's 120 millivolts And if you divide that by a normal wall thickness that is a number of 12 right if you add up all 12 leads and divide it by the wall thickness of 17 And it becomes seven or six or eight anything below those cut points or basically amyloid So this is a very simple way and as you can see Low voltage not very sensitive but specific increase wall thickness very sensitive But not specific could be anything but the two together much much better The other thing I would just note is that al amyloid can be diagnosed by a fat pad as we heard But if you have a clinical suspicion for al and the fat pads negative You can't stop there. You need to go on because the sensitivity While we talk about it being 70 or 80 percent is nowhere near good enough for a life-threatening disease And so fat pad biopsy negative. You think something's going on got to keep working them up You should know about the clinical clues. We heard about them all this morning But once you know these clinical clues, it's really easy to make this diagnosis Because there are a lot of them for a prayer prepared clinician So we talked about this but this is a disease of heff path usually without and it's later stages hypertension typically with in men You can see pressure volume loops to the right upper right for those of you who don't remember This is how we study physiology, but we are increasing You know the edp vr and upward shifting it and what happens then is the endiastolic volume goes down and so does the stroke volume So your ef stays the same because the numerator and denominator both going down so the ef is preserved But the cardiac output as you can see in the black line goes down and what happens to their blood pressure It goes down over time. So you're removing anti-hypertensives They're getting on less and less medications. Um, these are patients who always have an elevated jvp and right heart failure As I said, I'll show you some data. They don't like ACE inhibitors or beta blockers Um, if you're looking for a big tongue and uh, periorbital purpura shown here for ttr You're never going to find it doesn't exist. It exists in al amyloid But for ttr as we heard there are lots of um, orthopedic clues So we know about bilateral carpal tunnel syndrome. This is lumbar spinal stenosis. I call it carpal tunnel of the spine I'll show you data about a third of patients with ttr have it This is the famous pop-eye sign So you can look like dr. House with the residents if someone has a biceps tendon rupture and uh, their biceps You know muscle looks like that and they have a thick walled heart. You don't even need to do a pyp scan Literally, it's diagnostic. I mean you could you should do it and you will do it, but you could look pretty Um, uh, erudite on rounds And these are the data I was mentioning before that we recently published with mazhana In which the big new news here is 83 of wild type patients have an orthopedic manifestation And in addition to hip and knee replacement shoulder surgery and shoulder issues are very common in these individuals And you can see the hazard ratios. There are odds ratios compared to Population based samples much much higher for knee hip and shoulder arthroplasty Most of us unfortunately don't diagnose things by history anymore or physical exam Unfortunately, we wait to the image and so if you're waiting for that, which is fine There are also lots of clues, which we'll run through So, um, uh, these are the still frame uh echo images that we are all looking for so there's increased wall thickness always usually in amyloid It's not symmetric by the way by mri. It's symmetric in 17 of the patients So just because it's asymmetric doesn't mean it's not amyloid They have as we heard a thickened atrial septum. They have valvular thickening their atrium get big early on They have diastolic dysfunction, but if you miss the boat like in our patient, they'll end up with a low ejection fraction Um, uh, so that's uh, clearly a late phase phenomenon. We heard about pericardial effusions Um mri's are very useful. This is what I used to call the peak in the squeak test You know a colleague in new jersey followed someone with a myopathy for years. They didn't know what it was They got an mri. It showed a relatively preserved lv systolic function and diffused enhancement at the bottom It said think amyloid and they went ah And they referred them off to the amyloid center in part because they were You know unsure what to do and also a little embarrassed that they didn't kind of sort it out sooner So this is become a source of referrals This is the apical sparing we heard about Highly sensitive and not so specific you can see this in chronic kidney disease And hypertension but quite useful which leads to the apical sparing So um lots of clinical clues, right? And you should really understand the non biopsy diagnostic approach because that's critical But there are a few pitfalls and we're seeing this more and more often as awareness goes up. So um Again end of myocardial biopsy is not a bad test It's really hard to do the worst thing and an end of myocardial biopsy which is perforate someone when they have amyloid, right? It's a thick walled heart. So if you're ever in doubt I'm sure my colleagues who are nodding their head who do this all the time agree This is a pretty low risk procedure These are our data that people highlighted previously looking at pyp Syntigraphy member claudio publishes paper in 2005 using dbd. We wanted to use dbd. It's not available in the us It's actually not true. That's the only isotope is pyp. We learned during the You know sourcing pandemic issues that hmdp is available in the united states and can be used And those of us who knew that kept doing scans and those who didn't were like, oh my god What are we going to do? So both are fine. Um mdp is not fine and doesn't work. So don't use mdp Um, and this is how these scans are graded, right? Uh, zero is no uptake. We heard one is uptake Less than the heart twos and threes are positive But the bottom line is you can't use planar imaging anymore You must must must do spec imaging, right? You have to know that the uptake that you see on the x-ray The planar imaging is actually inside the myocardium Because it could not be it could be as we heard blood pool And so these are the current, you know diagnostic criteria and I highlight the important things here You can make this diagnosis non-invasively with a pyp or hmdp scan if they have a phenotype that's consistent with amyloid Right, don't scan someone whose ef is 10 with an eight centimeter ventricle and a thin walled heart. That's not amyloid That's not what it looks like. It doesn't have amyloid that way, right? So they should have a phenotype that you're suggestive or they should be a variant carrier, right? You must obtain monoclonal proteins. You can't order a scan without ordering the monoclonal proteins if you do and You do it without monoclonal proteins you're Committing malpractice and I jokingly say to people I will now testify against you right because it is malpractice, right? You can't interpret the test If the monoclonal proteins are positive You can't use the pyp you need to go on as we heard to biopsy and you have to have Grade two uptake, but you need a spec scan So we try to highlight some of these errors in a paper in jack Mazhana led to charge here With amartha grogan and others but you can see in the upper right as a patient's got a floridly positive pyp scan Right it's in the myocardium, but this person has al amyloid turns out 25 of patients with al amyloid are going to have a positive pyp scan That's why you need to get monoclonal proteins Then there's and this venn diagram is the embarrassing one from columbia that we published These are people who came for our center for clinical testing and you can see how many got all three of the appropriate tests in the middle Only 40 percent right so doctors are ordering pyp and not ordering the monoclonal proteins Second one is I just highlighted here. Here's a grade two scan, but when you do spec imaging What do you see the isotope is inside the chamber? This is not in the myocardium This is a false positive pyp scan and then if you do this long enough You know you will run into some unusual mutations or variants that don't uptake pyp So this is you know a paper we published about pyp use at our center now. We're up to like 300 400 scans a year As dr. McPhail was saying we don't need to do a lot of biopsies you can see the blue is the biopsies It's under 10 percent of the time that we need to do a biopsy For a patient and it's a pretty good test I would just point out because about a third of patients you can see in the line Are positive so what test do you do in medicine? We're a 30 percent of the time you're making a clinical diagnosis It's not perfect though. So people who had grade two scans when we used Specked as the quote-unquote gold standard 64 of them were blood pool not positive scans right not positive So in the community we're seeing a lot more of this planar imaging people getting on tifamidus and they don't need tifamidus It turns out the overall false positive rate is almost 10 percent. So screening is great But you know you'll see you know screening could be associated with some problems So this is what I call the amyloid cascade for decades We were kind of all the way up here looking at symptoms and the ekg and low voltage We used the echo once in a while, but now we have you know techniques that are a lot more sensitive In fact, you can have a normal wall thickness and a positive pyp scan And you would really identify someone who's asymptomatic and early in the course of the illness So these are very busy. I apologize, but this just shows you how much pyp enables an earlier diagnosis Everything about the patient Tested in our lab with pyp versus biopsy is better new york car class biomarkers are low or all of their staging systems are better Blood pressure is higher stroke volume and the key then is that translates into better survival Not because pyp scanning is doing anything Interventionally, it's just you're finding people in an earlier stage of disease Which is where we need to find them to leverage Therapies and for those you don't know there's a fantastic paper by the london group in 20 years like 2,000 patients and they showed this unequivocally why because defamitus is not available in in the uk because it's too much money. They didn't pay for it And in our data here just to show you the older you are like all things the greater your mortality per year Right if you have variant disease, you tend to do a little bit worse But you can see if you're diagnosed by You know a pyp you have a lower mortality, right? And stabilizer therapy is in this multivariate model still highly effective. So all of these things are Leading to much better outcomes So the algorithms i'm never a big fan of algorithms. I quote joe alpert from arizona the editor of the green journal between every Algorithm and a patient needs to be a provider with a brain Make sure that you know what you're doing because every algorithm if you follow it blindly Could lead to problems, but this is pretty simple, right? You basically You know check for monoclonal proteins do a pyp scan and do genetic testing and that doesn't mean you have to do one On each day you can just bring them in and do all three on the same day And you're basically make a diagnosis pretty quickly assuming again They don't have monoclonal proteins if they do you have to go down the other pathway And then you know, I think we really want to as we've been talking about today figure out ways I give you credit at this meeting because it's one of the first to think about what I call active ascertainment I'm not so sure this is screening because people have this disease per se, but maybe it is and all these therapies work better when they're started earlier So, um, sorry, this is the landmark tifamidus paper We heard from dr. Rosenthal about how it works it binds in the dimer dimer interface You can see here and it prevents the protein from dissociating Really an unbelievably effective well tolerated drug unfortunately costs too much, but um But this is probably the most important unpublished data from the trial So in the trial there were 37 the 441 people in the trial 37 with nyha class 1 less than 10% right and they had at the point Confidence intervals in this example are why but just look at the point of students They had a 64 percent reduction mortality whereas Those with class 2 at a 39 percent reduction were telling those with class 3 only had a 16 percent So very clear evidence that if you start this drug earlier I mean, where else do you see more than a 50 percent reduction in mortality, right? I mean like kind of amazing And so this success of the ATTR act trial has led to as you can see over the timeline here Just the plethora as we heard about of new therapies that are coming down the pipeline So what could we do for screening? This is one of the first papers we got interested in with adam castano This is what we called the unveil study in which we took consecutive patients undergoing a TAVR And we found out that a 16 percent overall had amyloid and 22 percent of men Had amyloid so you could start screening all the patients who are getting a TAVR A becky han a famous echo cardiographer taught me that you can just look at the echo and if the S wave on the echo is less than six Everyone who has amyloid has an S wave less than six in this trial because she helped us read the echoes And you got rid of 50 percent of the patients who didn't need to get screen So this now brings the yield to 44 percent in men. So you could that would be an approach everyone getting a TAVR gets an echo This is a study we did more recently screening with our colleagues fin gustason and others in finland and and you can see here They have a national healthcare system We basically found 1179 people who had bilateral carpal tunnel syndrome We called them up and we said hey you have this surgery You know 10 years ago Do you want to come in for screening and we heard that in men who are over 70 with a low bmi by the way clinical clue No one with amyloid almost nobody is fat Almost nobody we published the data a bmi over 30 has a 98.5 negative predictive value Heff path is a disorder of older obese individuals, but not amyloid in our experience But you can get one in five men Who has this particular phenomenon? So um Definitely a very high yield. I think and they summarize the data here. You can see this, you know, one in four one in five prevalence in older adult males So we have a screening study that was funded by your government Called scan and p in which we're focusing on minority populations in particular because they have a The variant that we talked about that's common. It's called scan and p with rick ruburg and we're trying to Again advance early diagnosis by screening This is an 800 person prospective cohort study We have three sites columbia affiliate with harlem hospital boston medical center and now yale university And we're doing phenotyping on patients with increased wall thickness who are over 60 who have a clinical heart failure syndrome Can't tell you all the details yet. Sorry still actively ongoing. We're at about 480 of the 800 subjects And this is a study we did with a nia funding that led to a grant that were thrilled to be working with Mayo clinic and ellen mcvallon So in uh 47 patients at our center who are undergoing back surgery We basically said to the surgeon, please don't throw it in the garbage. Just give it to us We stain the tissue and as you can see um 34 35 of patients had amyloid in their spine um When we sent the tissue to the Mayo clinic to figure out Was it ttr? We found out that two-thirds of it was ttr much more commonly ttr as they got older But not everything in the spine was ttr many of the times a third It was Undefinable amyloid and who knows what that means and whether those patients are going to develop ttr If they're not we're going to start screening lots of people who have amyloid on biopsies and congo red And it would imply a critical role for mass spectrometry to figure it out Or maybe they will develop amyloid and then mass spectrometry won't be a critical So we have hopefully going to start soon a prevalence study In these individuals at five centers And then amongst the patients who we find amyloid in they've had back surgery on average 10 years earlier We're going to call them up and say hey, we found some amyloid in your spine Why don't you come on in and get tested to see if you have it in the heart? And if the data in finland are correct, we're going to find lots of patients who are relatively asymptomatic but have a disease So we're excited. I'm rick ruberg and I wrote this though And I think it's really important if you're thinking about screening and that is the following This is the validation studies that have been done. So the gilmore paper that we all cite from a julian and me and colleagues Half the people in that study of 1300 had amyloid It's really easy to use a test when one in two people walking into your office as amyloid, right? So pyp scanning we saw 90 percent sensitive 100 specific when you exclude monoclonal proteins, but one in two people in the study had amyloid So the pretest probability is usually high. So your positive and negative predictive value are very high no matter what test you have If you start screening people and they have a 5 or 10 percent You will have, you know a very high negative predictive value But your positive predictive value is going to go through the roof You're going to start finding people who you think have amyloid and they don't and so it's going to be really important to use clinical features to increase your pretest probability And to make sure you're doing the scanning test really really really appropriately You need to scan with spec. You need probably scan at three hours to avoid the blood pool at one hour In low pretest probability populations So the second thing I was asked to talk about which i'm gonna, you know, try to run through quickly Is um this very important question now that we have all these patients and we're taking care of them How do we follow them and the short answer is nobody knows right? I mean if someone tells you dogmatically that they know exactly how we should be following these patients We don't know that and we really do but this is the most common question, right? We all get which is hey doc, you know, how am I doing? Is this the feminist thing working as the other drugs? So there's a good rationale for screening, right? I mean for following patients, right? Hopefully you're going to alter intensify. Maybe you're going to get rid of certain therapies Lots of these patients develop conduction disease and need pacemakers We're actually trying to apply right now for a Multi-center grant for bi-v pacing that the government's interested in around the country for patients who have amyloid We have reasons to think of a bi-v pacemaker people who develop atrial fibrillation may need to go in sinus rhythm And then the thing is if we have three or four therapies approved How are we going to switch which one are going to use if you think insurance companies are going to let you Give two drugs that cost three quarters of a million dollars a year for an 80 year old you're you're dreaming, right? I mean the pre-certification process will be cuckoo. So let's just talk about some of these And the data that we have so this is the patient I showed you before Who you can imagine has a blood pressure of 80 over 40 He has progressive as we saw a diastolic dysfunction reduce what I call lv capacitance His ventricular chamber is small his edv and his blood pressure is falling And so there's an essential role in this patient to stop medicines, right? Be a geriatrician shut off the heart failure therapies because they're not tolerating them And we investigated this in our database with richard chang It's actually been published in jaha and these are the data on outcomes and 150 ttr patients for beta blockers and ace inhibitors For mortality the answer is no benefit, but richard because he's astute found this You know, I see patients. They weren't feeling while I shut off their beta blocker So in blue are the people I shut off the beta blocker and in red are the people I didn't by the way I would usually shut off a beta blocker in sicker patients Right, you could imagine and the hazard ratio for deep prescribing the beta blocker is more than 50 percent I saved more than 50. I reduced the chance of dying by more than 50 percent by simply stopping the beta blocker So, you know, want to kill your amyloid patients give them a high dose of beta blocker That would be a sure way to do them in they have a low stroke volume and they need a faster heart rate Don't assume you're smarter than the physiology of the body Um, uh, I think there's a big role for sgl t2 antagonists personally We don't have a lot of data one of our fellows is conducting a study right now We now give this to everybody with amyloid and the reason is as richard showed One of the things that predicts mortality these patients is the dose of their diuretic and you can see survival is Much worse the more loop diuretic you're on normalized for your body size than obviously one way to keep them Uvalemic might be and protect their kidneys might be an sgl t2 So food for thought and people are interested. Um, these are the data from a patient in my colleague Dr. Nebovian's open label study. This is a 90 year old lady who has an nt probing p of 10,000 over 12 weeks Her nt probing p went down to about 8,000 She basically uh, the red is what would have caused us to stop so for cratine, which was already high Would have went up by 30 up by 30 percent or e gfr We would have doubled in the stopping rule and you can see in this study Her cratine remains stable and she required actually less diuretics and that's what we've observed in this 15 person open label study Um, uh, so far that we usually get rid of the metallo zone if they're on high dose or cut their torso might quite a bit These are data from bret sperry in which he took the top cat trial no one knew in this trial I have peft trial who had amyloid But he looked for features that were suggestive of amyloid low tissue Doppler signals And he then analyzed the outcomes of patients who got aldactone Who he thought had amyloid didn't and aldosterone antagonists had a mortality benefit in patients who had a phenotype That looks like amyloid so we often give them mra's Um second is pacemakers and bradycardia. Um, so this is a new focus of our attention These are data from claudio's group again poor claudio. Um, uh, but these are Three risk factors for developing a pacemaker need a pacemaker an amyloid a atrial fibrillation b First-degree heart block can't have the two at the same time But you could look back at their historical e k g and c and c do they have a wide q r s? And just to highlight if you have all three of those things you have a 40 chance of needing a pacemaker within 12 months So those are people who you know, you should start maybe doing long-term monitoring on and check Um, uh, you know, this would be I think a really good place to think about a bivy pacemaker. Why? Because these patients become pacemaker dependent like the many you put the pacemaker in right and like electrical conduction systems frayed with amyloid they have a stroke volume of you know 45 ml's index is 25 ml's and now you start to rv paste them So their cardiac index which was 1.8 now goes to 0.8. You know, they don't feel well And there's data shown here to say that physiologically it makes a lot of sense And there's even a case control study not the greatest, you know evidence In patients from the cleveland clinic showing there's a survival benefit So we think this is the right thing to do and that's why we're advocating to the government to fund a bivy pacemaker trial Which everyone will get a bivy upfront, but for six months we turn it on and turn it off to get the information Oh, so this is the bane of everyone's existence in general cardiology. I call aphid the most overtreated heart rhythm in the world But should we restore normal sinus rhythm? I have no idea This is my approach to aphid for all patients amyloid or not And that is the two by two table of are you really symptomatic or not due to your aphid? Yes or no And are you likely to stay in normal rhythm if I jump through 15 hoops right and start, you know And so, you know, it's very easy for someone who's really symptomatic Right and highly likely to stay in sinus rhythm, but no one with amyloids highly likely to stay in sinus rhythm It's really easy for someone who's got amyloid who didn't notice that they were in into aphid and nothing's different about them I don't do anything by the x but there's a lot in the other groups And the question really here is you just got to get down to share decision making with the patient and chat with them These are the data over, you know, 40 months about who's going to stay in sinus rhythm And the bottom line is early amyloid patients might stay in sinus rhythm After cardioversion or aphid populations, but patients with advanced amyloid almost never do so. I don't rush to do things Um, and then this whole question of you know, well, what if we had two or three treatments on the market? Which we may soon have, you know, how are you going to decide what to switch or what you're going to do? and so again, uh, you know, these are the Current um across the spectrum of disease we used to famine us But certainly for those who have silent who have neuropathy with a cardiomyopathy I and I think all my colleagues in amyloid use Silencer based therapy. We think it's potentially going to be better so um This was a paper that was written by very famous and important folks in the world of amyloid I wasn't a co-author. I don't want to pick on it, but they made this up It's a reasonable starting point, but there are a lot of holes in this So I just want to but these are the things they suggest about monitoring patients You should look at them clinically you could look at lab and you could look at the ekg So let's touch up on each of these the clinical ones So new york art class or recent hospitalization. Are they taking more diuretics or performance based measures? So new york art class Fantastically prognostic you can see there right like the dose of diuretics fagnacically pro prognostic So we use those To modify the mayo and the knack staging system and it turns out they really improve the a you see And so this is what we call the chang or columbia score after richard or our data But it's much much better than the others if you wanted to refine risk and the two things we're adding are new york art class And how much diuretic they're on so it's really not terribly complicated It's a score one to nine and you could put people into early middle and late Six minute hall walk Well, that would be great if we could get the staff and everyone to agree to do it at a set period of time Because their six minute hall walks definitely go down quite a bit over time And as we saw while tifamidus doesn't make the six