Dr Rajeev Mohan discusses the pathophysiology and epidemiology of cardiac amyloidosis, clinic features to be aware of, and current diagnostic and treatment strategies.
Back to Symposium Page » um all right, I think we'll move on Thio Next talk, which might talk about cardiac amyloidosis and then we'll finish up with a couple of cases at the end. Um, after this. So let's see. Here, let me make sure I can. These are my disclosures. Here s own outline for today's talk While we reviewing the path of physiology of cardiac amyloid the differences between a l and T tr amyloidosis. We will look at the epidemiology of cardiac amyloidosis, clinical features of the disease, um, diagnostic considerations for both ale and a T t. R. As well as treatment strategies and kind of contrast the different treatments available for the two diseases. So amyloidosis broadly means extra cellular protein. Deposition, um, in in an organ. Thes proteins are typically in beta pleated sheets that form fiber ALS on. These fibers circulate throughout the blood and can deposit environment of organs. The hard nervous system got kidneys. Um, but when we're talking about cardiac amyloidosis, specifically, about 95% of cardiac amyloidosis is due to one of two proteins. It's either the a. L or from what's called light chain proteins or 80 tr from protein called trans direct, and we'll be reviewing both of these a little bit more details. So Al amyloidosis is essentially a plasma cell disorder, leading the production of a clone of immune immunoglobulin light chains. And there's two varieties of light chains. Either the Kappa variety or land the variety, um, thes circulating light chains can then deposit into various organs. There is very frequently cardiac involvement. Up to 50% of patients can have this on, but also commonly affect the kidneys as well. Um, A J mentioned this earlier in the very beginning of the symposium. It's sort of the differences between amyloidosis, multiple myeloma and guts, and it does get somewhat confusing because there's a lot of overlap in terms of the diagnostic testing that's used. Eso what we can uses this sort of central figure here, this abnormal serum free light chains s so we can actually test in the blood the amount of circulating light chains from those immuno globulin. Since there that's gonna be abnormal in all three of these disease states, um, as well as the protein serum protein, electric electric freezes within unification, that's gonna be abnormal. That's gonna have an abnormal spike reflective of the fact that there's abnormal protein circulating so light chain em Gus or monoclonal grandma. Apathy of undetermined significance is an abnormal amount of light chains that air circulating. Of course, MGA's could be due to other types of proteins that air circulating as well. But if we're talking specifically about light chain MGA's, that's because he's light chains air circulating. Ah, bone marrow biopsy in this particular case would reveal that there is less than 10% plasma cells within the bone marrow producing these light chains, and that there is an absence of end organ disease. So these people are typically, um, followed Clinically. Their light chains are checked periodically, Um, but there's no specific treatment necessarily for patients with us. On the other hand, multiple myeloma is different in the sense that there's a much higher proportion of clonal plasma cells in the bone marrow biopsy. So 10 10% or more. Andi, there's evidence of end organ damage. So this is what's called the crab criteria for diagnosing multiple myeloma. Hyper calc me a renal insufficiency, anemia, little bone lesions s, um, other criteria. If the free light chains ratio is greater than 100. So what happens is this abnormal light chain. Either the Kappa or the Lambda, is significantly elevated out of proportion to normal. So if that ratio of one is greater than 100 times the other, that's consistent with multiple myeloma. If there's greater than 60% clonal plasma cells on the bone marrow biopsy, that's also consistent with multiple myeloma and other imaging modalities, including Emery. If there's little bone lesions a little bit more sensitive, also consistent with multiple myeloma, multiple myeloma and Ella Malouda's is gonna overlap, um al amyloidosis and and, again, multiple myeloma. The plasma cells that are producing Thea at Normal, Uh, proteins can be light chains, or they could be heavy change. There could be other types of immuno globulin proteins. Um, it's not always light chains that are produced by these plasma cells. So frequently. Patients can have multiple myeloma due to a different type of protein, and they won't have light chain amyloidosis on top for that. If they end up having a light chain myeloma meeting these plasma cells air producing light chains out of proportion to normal, then there is the possibility that they can have a L amyloidosis on top of that. So that means those light chains air now not just circulating, but they're depositing in organs and causing on organ damage. So here's where that overlap. This. Patients can have multiple myeloma with amyloidosis, and on the other hand, patients can have amyloidosis l amyloidosis without having multiple myeloma. So if they have plasma cells that are producing light chains, but it's less than 10% they don't meet these other diagnostic criteria. But they're depositing in different organs and causing evidence of of heart damage and that kind of thing that's consistent with Ailes alone. Okay, um, mortality from al amyloidosis is high, which is why we consider it a medical emergency. When we're doing an evaluation for cardiac amyloid on DWI, uncover that they have a L or they may have a L. We get those patients to a human Ecologist urgently, usually within 24 to 48 hours, mostly because you can see here on these curves on the right. Mortality from this is quite high. This is looking at data over the course of three different eras, and certainly it's improved as the treatments have improved. But the median survival going out five months is on the order. Uh, going out five years is quite low. There's a staging system here on the bottom left that looks like cardiac biomarkers, troponin, T and anti pro BNP, as well as the difference between the light chain fractions. And so, if any of these air elevated and that's consistent with the mawr of these that are elevated, the higher the further along theme the disease is, and the prognosis becomes worse as the stage gets gets higher. Um, A T T R. Amyloid, on the other hand, is caused by a completely different protein, so not light chains from bone marrow cells. This is from the protein called transpire written, which is produced in the liver. So this is, ah, protein with 100 27 amino acids. It's a carrier for thigh rocks and then retinal, and it's typically formulated in a tetra for so for individual pieces come together, they form this tetra more that you can see here in the middle of the slide. What happens in T tr amyloidosis is that there's ah destabilization of this tetra mur, the bond holding the Tetra together such that these monomers uh, can then start circulating. They kind of separate into monomers that then miss, fold and deposit into various organs and cause Emily does. So it's really that destabilization of the Tetra more. That's the key. Within a T T r. Amyloidosis. There's two broad subtypes. There is the hereditary form that's AutoZone will dominant. This is caused by a single amino acid mutation in the sequence coding for the T tr protein that ultimately lead to destabilization of the protein. Most common, uh, genetic mutation we see here in the United States is the V 1 22 I Andi. It's thought that up to 3 to 4% of African Americans that actually carry this mutation are there to common mutation seen or the T 68 to be 30 a. M. On the other hand, if it's not hereditary, then it's the wild type variant. So these patients, over time end up having an abnormality in the T tr protein production that also leads it to become unstable. But this is not hereditary, so this is not something that could be passed on from one fam one generation to the next. It's difficult to differentiate between hereditary and wild type strictly from the clinical presentation. Three. Only a couple of the things that may differ between the two is that the hereditary form may present earlier on in life. Where is the wild type form tends to present a little bit later in life. What we do see is a preponderance of men with the wild type disease on the order of 9 to 1 ratio compared to women, where is with hereditary? Of course, it could be different. So for suspecting amyloid in a patient in a younger woman, for example, then we may have a higher, higher suspicion that this may be hereditary versus the wild type form. Again, the mutations here their way highlighted two or three. But there are. There are over 120 different mutations that air in this protein that are known to cause, um, Allied protein formation. And it's not just a cardiac disease. It's really a systemic disease. But one of the other, uh, frequently involved organs is a neurologic system, and you can see here, depending on the mutation. Some of them have mawr neurological manifestations, whereas other has others have more of a cardiac manifestation. and some have more of a mixed a few no type. This is data from, ah, large registry here in the United States, the Taus registry looking at patients with amyloidosis in their genetic breakdown. So about 48% of those patients had wild type on Ben again, As we mentioned earlier, the next most common mutation was the 1 22 I about 23%. So I'm slide on the right shows on increase in the amount of wild type, uh, T T r amyloidosis. Um, that's being diagnosed over the period over a period of time. And part of that has to do with increased awareness of the disease, as well as the increased availability of non invasive ways to make the diagnosis, which we'll talk about a little bit later on. Um, this is a new, interesting article from Cirque heart failure. Looking at a heat map of both the prevalence and incidents of cardiac amyloidosis in the U. S. And comparing the years 2000 and 2000 and 12, so you can see is dramatic increases in both the prevalence as well as the incidents of cardiac amyloidosis on the thought here is that it's not suddenly that there's more people necessarily with amyloid, but that because we're looking form or we're starting to see it more on. What we're finding is that it's actually much more common than what we what we thought before. Clinical features of amyloidosis. Part of the difficulty Part of the problem in making a diagnosis is that it is, uh, sort of systemic. It can affect different organs at different times on DSO by the time they see us is cardiologists. Often it's further along in the disease process. Eso It's really internal medicine doctors, neurologists, those people that may be able to pick this up earlier, Uh, depending on what the clinical presentation is. A sfar US cardiac manifestations. The most common thing that we see is heart failure on day. It's typically a heart failure with preserved ejection fraction that sort of restrictive cardiomyopathy arrhythmia. Also very common Atrial fib relation. Being at the top, a zealous conduction system disease generally so heart block more 1st and 2nd degree heart block is well as bundle branch blocks. Um, aortic stenosis. Also very common, very common contaminant disease. We'll look at some data on that and an intolerance the medication. So patients suddenly are unable to tolerate their anti hypertensive that they've been taking for some time. Um, that's another sort of clinical clue that there may be another process going on. As far as the autonomic system started, the nervous system goes. It could be a combination of both peripheral neuropathy that could be both peripheral sensory and motor neuropathy again, often similar presentation to diabetic neuropathy, which makes the diagnosis employed harder. It was also autonomic dysfunction that scene Ortho static hypertension, erectile dysfunction, bladder, um, bladder issues that that kind of thing. Another very common thing that we see in patients with T with amyloidosis generally is carpal tunnel disease, particularly if patients have had bilateral carpal tunnel disease in surgery that's often seen in the wild. Type 80 tr eso way. Ask a lot of our patients with Hef path, Um, if they've ever had carpal tunnel disease before and often that's a clinical clue that we should be pursuing an amyloid work up, um, lumbar spinal stenosis again. Another very commonly seen could comment diagnosis in these patients with T tr cardiomyopathy, G manifestations air varied. Part of it is actually infiltration into the gut itself, which can lead to absorption issues. That's usually later stage. Patients can end up with weight loss and that kind of thing. Otherwise, it may involve the sort of the nerves in, uh, that feed the G I tract, which can cause motility issues. Diarrhea, constipation, nausea, vomiting, that kind of thing. So, as you can see, you know a lot of non specific type symptoms. Even in the cardiac world, it's it's symptoms and diagnosis that we see very commonly. But we just need to be thinking about amyloidosis more. Um, this is a autopsy study in Europe looking at patients who had a diagnosis of half PF and looked at the age of death. And all of these patients got autopsies looking for amyloid infiltration. What you can see is that, um, in patients that were above the age of 80 and then certainly those with above the age of 90. The amount of amyloid infiltration to the amount of patients that had amyloid infiltration is significantly high. Those that died in 90 plus with the diagnosis of FPF. Nearly 60% of those patients had evidence of amyloid deposits in the heart Andi and, um, those patients on the right here age at the half path diagnosis. So if they were diagnosed with, have pep sort of later in life, greater than 80 Nearly 40% of those patients had amyloid deposits in the heart. So again, much more common than than what we think. This is more recent data that just came out a couple of weeks ago, which was interesting study looking at, um, 108 patients with heart failure with preserved ejection fraction. So a diagnosis of half path who came in to have pet clinic at Hopkins And they did biopsies in all of these patients, um, to see what sort of microscopic and path of the pathologic abnormalities that could work. 93% of those patients had fibrosis, 83 88% hypertrophy. So these are obviously very common things that we see in patients with a diagnosis of health path. But what was interesting is that 14% of those patients how did I gonna had amyloid infiltration into their into the heart muscle? So this is, uh this is unique in in in that this was a biopsy study on patients with FPF but that that clearly shows that there is much more prevalent than what we're realizing. What were some of the, um, kind of clues that lead or what were the sort of commonalities in those patients that have had amyloidosis? All the things that we've been talking about? Lower, older age, lower blood pressure, elevated anti pro BNP and troponin. We're gonna talk about that shortly and higher. L B Mass Index. Another common co morbidity is aortic stenosis, particularly low flow low Grady in New York stenosis. So this was another study that looked at 151 patients who were being evaluated for Taber, and all these patients underwent evaluation for cardiac amyloid. 16% of those patients screened ended up being positive for 80 TR cardiomyopathy. Same clinical characteristics that showed up older adult males, low flow lok, radiant, low systolic, blood pressure, elevated biomarkers, those kinds of things. And we'll talk a little bit more about the e k G and eco findings here shortly. Another, like I mentioned before, carpal tunnel disease. Another study looking at 98 patients who underwent carpal tunnel release surgery. So these were just patients they're walking in for carpal tunnel surgery on day did a study looking at, uh, Cleveland Clinic, looking at tissue collection from these employed deposit, looking for Emily deposits and all the tissues that were collected from surgery in 10 of those patients. So nearly, you know, more than 10% of those patients had, uh, amyloid deposits in the nerves when they were getting carpal tunnel release surgery. What we see often is that the carpal tunnel surgery can precede um, cardiac manifestations by a decade or more. So these are patients that you know we need to potentially be looking at more closely if they have carpal tunnel surgery, particularly that their bilateral in these patients seven of them had a t t R. Two had a L, and one was untie piped. And even though they were coming in for carpal tunnel disease, um, two of them had cardiac involvement already at that point in time. Um, and what we know is that that it's important to make that association between carpal tunnel and cardiac amyloidosis. This is a very large Danish study looking at 56,000 patients who underwent carpal tunnel surgery. They were compared with age matched controls who did not have carpal tunnel disease. And you know what they found was that the rates of diagnosis of amyloidosis in those 56,000 patients with carpal tunnel surgery or 12 times a Xihaigu as those age matched controls who did not have carpal tunnel disease so clearly through the risk of having employed is much higher in patients just generally, who are having carpal tunnel. A surgery done. Their cumulative incidence of heart failure was also significantly higher over this long follow up about 15 years. Eso Clearly, we need to be looking at these patients a bit more closely. So when the suspect cardiac amyloidosis, we've been talking about some of the clinical features already. Heart failure symptoms are very common with heart failure, with with symptoms that we see for other reasons that patients may have heart failure. So shortness of breath, a Dema fatigue, palpitations. Certainly, Ortho static symptoms were really important to keep in mind. The non cardiac symptoms again are harder to tease out there. More non specific. The neuropathy that G. I involvement bladder issues, those kinds of things and, of course, the historical of elements like carpal tunnel disease in the aortic stenosis. Another clue that we see very commonly is is sort of persistently elevated proponent, so patient may be admitted for heart failure. Decompensation there admitted to the hospital. We check a troponin and it's elevated and then, you know, six months later, a za part of and then they you know. Six months later, as part of routine blood work, they get another troponin something like that, and it's still elevate. Or they're back in the hospital and get it checked again, and it's still elevated. So this sort of persistent elevation troponin is also a finding that we see very commonly with cardiac amalie. We see L. V H on echo, which often can mimic HCM. But what's important to keep in mind is that the L V H by Echo is often discordant to the degree of L V H or voltage abnormalities on the E K. G. So it's not necessarily that has to be low voltage on the e k g, but that the degree that the voltage on the K G is lower than what we'd expect given the amount of L. V H we're seeing by Echo three other thing that we come to see is the sort of infiltrated pattern on Echo. It's sort of this, you know. Three echo texture is just different. It's not the usual myocardial texture when we see that in conjunction with this sort of dilated left atrium elevated filling pressures, uh, diastolic abnormalities, tissue Doppler, those of the patients that we do more, you know, further work up for cardiac amylin. Um, characteristic echo strained pattern which will show you on the next slide and then the presence of a pericardial effusion, all clinical clues. So strain we look at, you know, on all of our patients, if we're suspecting cardiac respecting infiltrated diseases generally, we're starting to do that. Do it more and more in just a lot of these patients with L V h. Just to help differentiate between these a couple of different kinds of things. Um, and starting pretty soon our echo, I was actually gonna be having strained done on all echoes which will be interesting to see. So the characteristic pattern of what we see is this bullseye or or cherry on top pattern where the a pickle segments are spared, but the bait mint and basil segments are not functioning as well. The darker red is closer to normal. Where is the lighter? Red and blue is abnormal, so globally there is a reduction and strain, but the apex seems to be spared, so that's another clinical clue. So who's at risk for T. T Are those patients with heart failure and the presence of red flag or red flag signs and symptoms and an increased wall thickness, particularly older males on Guim in that a little bit older, 6 70 years? Or about, um, the red flag signs a reduction in global longitudinal strain with a pickle, sparing that discordance in the e, k G and some of these other patterns that we talked about the A V block infiltrated pattern. Of course, we were using Emery of the patient already had a memory, and we're seeing the scar, Aziz, Doctor Dr Lopez mentioned earlier. That's another clue that we should be looking at that cardiac amyloidosis and some of these other clinical findings. So here's a case of 81 year old male with heart failure, worsening shortness of breath and lower extremities. Dema has had an F of around 45%. He's got a fib. He's got a pacemaker. He had carpal tunnel 10 years ago. In his last echo was two years ago, and because of his worsened symptoms, we ordered another echo. Here's his E K. G. Looking like flutter. And in Cem, a bundle branch block. Here's what is Echo looks like consistent with what we're seeing. And as I mentioned earlier, you know, a lot of this is pattern recognition. And so that's why I put in a lot of echoes of patients with amyloid thio help kind of show those patterns. Eso You could see them over and over again. The strain pattern looking like that. So what's next? What's the next step in our diagnostic algorithm? So here's the diagnostic flow that we use, you know, in a patient that we're suspecting amyloid number one thing is to rule out l amyloid again. That, like we said earlier, is a medical emergency. So how do we do that? We get the serum free light chain radio show so we can actually test again. For the light chains circulating in the blood of that ratio is abnormal or if the urine or serum protein electrophoresis with them. Unification is abnormal, then those patients seem to see human Ecologist. We may continue with the teachers, are work up, but if there's a significant abnormality, we will. We will definitely have them. See he mythology urgently and often they need a bone marrow biopsy occasionally a fat pad biopsy or biopsy of the affected Oregon, including an enemy cardio biopsy. If those air all within normal limits, then we move over to the T TR arm on. Typically, our next step is to get a nuclear power of phosphate skin toe. Look specifically for Emily Deposition. We'll talk about that here shortly, if that's negative, but we still have a high suspicion. Then we will pursue and in the myocardial biopsy to look for protein deposition. If it's normal. Sorry if it's positive, then our next step is to do, um, genetic testing to determine whether or not this is hereditary vs Wild type again, one of the areas where we need to do genetic testing to ensure that we know which of this it is in order for the patient to be able to have counseling with regards to family members. So here's what a nuclear power phosphate scan looks like radio tracers. Take is injected into the blood, the technician para phosphate and we do a sort of semi quantitative assessment and a qualitative assessment. The quantitative assessment over to the right is looking at uptake of the tracer in the heart over compared to the lung on the other side, it's greater than 1.5 the ratio of heart to lung. Then that's considered positive. The qualitative assessment. He was looking at up, taking the ribs, comparing that to the heart. So the more uptake in the heart, the higher the likelihood that it's ah, positive with cardiac Hamlet and the doctor Lopez mentioned earlier, We have to look both at the plane are images, Aziz. Well, a suspect images, and I'll show you some examples of that later. Skip to that for now. So here. So this case one ended up getting a power of phosphates, can you can see here on the bottom right? The expected and just confirmed uptake of P Y. P in the minor card. Um, so he had a diagnosis of amyloidosis. Specifically t t r um, case to his 82 year old male with the history with no history who was getting a routine EKGs part of a clinical study and was found to be in a fib. So he ended up getting an echocardiogram. Um, and, uh, that was very suspicious for amyloidosis. So again, just pattern recognition wanting to show you these echoes to get a sense of what amyloid looks like. So he underwent power phosphate scan, which was again positive for t tr cardiomyopathy. So here's an interesting case. The 78 year old who has spinal stenosis, glaucoma and carpal tunnel syndrome, all symptoms of associative diagnosis that we can see. Here's his E k g. Nothing exciting there in terms of voltage abnormalities. Here's his echo, and you can see that is my cardio texture is a little bit unique and maybe somewhat suspicious. He also has the arctic stenosis with an area of Alberta 0.8. So pretty significant stenosis severe Grady in severe in the severe range. Um, and again, his, uh, strain imaging looks very suspicious is well on day. He was then ruled out for, uh, a l and ended up getting a power of phosphates can, which turned up negative. So we were very surprised to see that this power of phosphate scan was negative, given the clinical history includes that he had. So what are some of the pitfalls of power of phosphate skins? The false negative, false positives could be seen in a level it. So that's what we always want to rule that out. First, there is some overlap, although we can't use it to differentiate between, um, you know, way. It's positive. We always have to. You know, we always want to do a nail work up first before we dio the power of phosphate. Because if the labs for Ailes are positive or slightly abnormal, then our specificity on the power of phosphates can goes down. You hear from other reasons that we can see false positives. Um, and certainly false negatives are also possible. One of the possibilities is early disease. If it's earlier on in the disease process, we may not. We may not be catching it just yet, so treatment principles for Emily, generally retreating a restrictive cardiomyopathy, can be somewhat challenging in managing their fluid levels because we're trying to keep them in sort of this narrow, usually make range. They typically don't tolerate beta blockers and calcium channel blockers because of an exaggerated effect, which makes treating nature population somewhat challenging. And sometimes these patients do need to end up with a B note ablation. Pacemaker implants. We have a very low threshold. Tow anti coagulate these patients, because of their higher stroke risk with atrial fibrillation. Treatment for a L is targeted at the plasma themselves to suppress light chain production on a lot of the medicines overlap with multiple treatment of multiple myeloma and same targeted treatment. Historically, it was a combination of Mel Flynn and Pregnant Zone. But nowadays, to sort of go to regiment is what's called cyborg D or cyclophosphamide. Borte ISM Index Method Zone There is emerging data now coming out about Derrick to mop, which is used in multiple myeloma being used now specifically for a l amyloid. Some positive looking results with regards to that and then also autologous stem cell transplant. Some mixed data on that, and it's used in certain centers. At this point in time, eso Here's another case of 40 76 year old man with the history has seen bilateral carpal tunnel syndrome. He was seen for us for because of by us because of a knee F drop over the course of several years. Um, here's his E k g. And what's interesting about his echo again? Same type of features of what we've been talking about, that infiltrated, pattern restricting looking cardiomyopathy. But we have echoes on him going back a number of years that show this sort of gradual progression change of his cardio texture, overtime going all the way back to 2000 and eight. So we did a work up on him, including the light chains and electrophoresis which were normal, and his para phosphate phosphate scheme was positive. So what are our treatment options for him now? There's several categories of treatment options When it comes to t tr amyloid Onley. This one drug to feminist is the only one approved for T tr cardiomyopathy. A president will look at the data on that, and there are two other drugs that are approved specifically for hereditary Polly neuropathy, but not yet for cardiomyopathy. So they're being studied in that presently, So the pivotal trial, looking at to famine ists for wild type and hereditary cardiomyopathy, was published about two years ago, just looked into feminist versus placebo in the primary outcome was a combination of all cause mortality and heart failure. Hospitalizations on what we can see here specifically on the mortality. There was a 13% absolute risk reduction over the course of 30 months and the patients that were treated with this truck, you can see this sort of separates at about 18 months. Andi secondary endpoints included six minute walk test and quality of life scoring, so you can see that it slows the rate of progression down. So there's still this natural progression of the Emily disease, but it helps slow the rate of progression. How this drug works. That sort of stabilizes that bond to keep the protein in the tetra reform and prevent it from associating, informing those fibers that then go and cause the amyloid infiltration. I saw the benefit more so in Class one, Class two, as opposed to Class three. So the question is, who are the right patients to treat asymptomatic patients who are carriers of the gene? Maybe a little bit too early. Those who were class four and really frail, unable to ambulance that maybe a little bit too late. So it's really that middle ground class to patients who have have pef of had heart failure issues. Those the ones that we kind of target in terms of who we treat. Um well, skip this live for now, just for the sake of time. Um, what I wanted to talk about also is this treatments available for the poly Neuropathy s? Oh, this is a case of a 64 year old who had a very strong family history of cardio of amyloid. But his main complaint was actually G I symptoms. He didn't have any heart failure symptoms at all. But he said, you know, I know my family. There's a family to my family. Can you do a work up? So we did a work up. He was negative for Ailes on it. Turns out he had a gene mutation that was consistent with what we believe his other family members had, and he ended up we had old tissue from a routine colonoscopy that he had a year ago. And so we did standing on that. It turns out there was employed deposition there. That was t tr. So his cardiac work up ended up being positive as well, Despite the fact he didn't really have cardiac symptoms at this time. So what are treatment options available for him? Somebody with G I symptoms. Ortho Stasis some erectile dysfunction mawr of the poly neuropathy type symptoms that he has. So there's two medicines available for this specific treatment now on a Terrasson, which was studied. Both of these papers came out at the same time. This is an anti sense all ago nuclear tied that which blocks production of the TT are protein in the liver and this was studied to assess for neurologic score a swell as quality of life score. And basically this was able to again slow the rate of progression down of the disease by knocking down the TT, our production, another medicine patisserie in the same concept, except that it's an interference in our marina. It blocks production TT are in the liver itself, and the primary outcome in this study was looking at a change in the neurologic score and same thing, except in this case, there was actually improvements in the neurologic scores, while his quality of life compared to the placebo group eso again a knockdown agents and both of these medicines are being studied and cardiomyopathy visas. Well, there is some data to suggest that in the patisserie and group subgroup of 126 patients who had some cardiac involvement that there was some improvements in cardiac specific mom measurements by echo eso some emerging data on that in terms of cardiac benefits. But for right now on Lee approved for hereditary Paul in your apathy So more data on that come So presently to feminists approved for wild type and hereditary TT are cardiomyopathy and patisserie. And and I know Terrasson improved for hereditary Polly neuropathy alone. Um, future directions. There are some new medicines being investigated. Other stabilizers, other interfering. Are Martinez all looking all being actively studied presently? So some take home points. You know, the incidence and prevalence of t t are certainly increasing in the sense that we're looking at it more. We're seeing it more. We have thio be kind of on the look out for it a little bit more. We should have a low threshold for suspicion of these based on the clinical features that we talked about earlier and again, we always have to rule out a lil amyloid with the testing listed there in order to ensure that they don't have that because again, that's a medical emergency. And the red flag signs that in the heart failure clinic that we're always looking for our this reduction in the strain e k g discordance and that sort of mild cardio pack that infiltrated pattern on echo eso. With that, I think I'll conclude Sorry a little bit over time, I think. But we can either transition to cases or take some questions. So the question for you, Raj, any increased incidents off FFP and the patients, uh, on the map or tackling. How do you tackle patients with a lil amyloid while their own treatment say that again, increased incidence of a fib with what? Increasing increasing incidents of a fib with, uh, Derek to move them. Um, I haven't personally, just anecdotally haven't seen an increase in incidents of a fib in those patients. You know, we have a collaboration with our human Ecologist when there, uh, if they're treating patients for either multiple myeloma, where maybe light chain with myocardial involvement or just Ailes itself and many patients we've seen on Dara Tomb, but not necessarily anything that's sort of pointed towards a new increase in a fib. But I don't know if that's been reported in the literature he talks that will tell us. And that question Yeah, Yeah, I I'm unaware of any data showing that I certainly agree. We haven't anecdotally saying that as well. And I'll just mentioned, you know, Dr Marilyn was getting at the dare to map data there was presented but not published yet is the result of the Phase three randomized trial with Dara to mop up front in treating patients with cyborg vs Cyborg he alone. And the Dara Touma bad combined group blew the other group out of the water. So I would say I'll probably already and certainly moving forward shortly. Standard of care for most patients with a lamb. Lee does. This is gonna be upfront. Dara to mob plus cyborg d