Chapters Transcript Video TTR Amyloidosis: An Underrecognized Disease Dr. Tushak describes pathology of amyloidosis and screening algorithm for patient identification and management. Hello, uh, good morning and welcome to our grand round lecture series. My name is Doctor Zachary Tusak. I'm a heart failure and transplant cardiologist. I lead our amyloidosis program here at Centera. And this, uh, lecture is entitled TTR Amyloidosis and Unrecognized Disease. Uh, before we start, I have a few disclosures. I'm a paid advisor for Pfizer, for Bridge Bio and Nylem, and AstraZeneca, which are the big four for amyloidosis treatment. I'm also a paid speaker for Bristol-Myers Squibb for hypertrophic cardiomyopathy. So, our agenda today, so we're gonna discuss what amyloidosis is, the pathophysiology, why it's important, a screening algorithm for our patients. We're gonna review a case, and then finally, we're gonna review treatment do's and don'ts. It really it boils down to what is it? Why is it important, and what do I do about it? And I really have 22 reasons for doing this lecture today. You know, the first is because amyloidosis is my passion area. This is my area of specialization. Um, you know, I represent Tintera in these small groups, and I get to work with other and collaborate with other groups from places like Duke, including Clinic and Massachusetts General Hospital, and it's really rewarding, you know, to treat patients with amyloidosis. It's like being a detective, you know, where you have to try to figure out where all these kind of pieces that don't seemingly relate to each other fit together. And if you hit one barrier, then you move on and and try to figure out the next way to, to get your diagnosis. The second reason for doing this lecture is I really need your help in screening patients. I would argue most centers across the United States could say that they can do a better job at screening patients and diagnosing more patients. I think at the end of this lecture, you'll agree with me. So the question uh for everybody is how many of your patients that you see have underlying amyloidosis? By a show of hands or virtual hands, do any of you guys see patients with amyloidosis? Certainly, a handful of hands in our, in our audience here. Um, so those who didn't raise their hand, how many people have patients who have heart failure? I would say most people, right? How many people have patients with aortic stenosis? A lot of people. A history of neuropathies or carpal tunnel syndrome, when you look back at their, their history, everybody. Who are octogenarians? Everybody, everybody sees people in their 80s and 90s. Well, I would say if any, if you raise your hand during any of these, these subtopics, then you definitely have patients with amyloidosis in your clinic and you just don't know it. So what is it? It's an extracellular deposition of a toxic misful of protein, and this is just a generic term. Amyloidosis is just a generic, a generic term for a normal protein that becomes abnormal in the body and collects in accumulations. In the heart, there are really 4 main types of amyloidosis. We think about AL amyloidosis and TTR amyloidosis as being the two most common types, and our lecture is focused on TTR today. So TTR stands for transthyrene, and actually the name of it describes what its job is. It transports thyroxine and retinol, so it's a tetramer or four-leaf clover-shaped protein that's synthesized by the liver, and it binds to and transports the hormone thyroxine, and retinal binding protein which carries vitamin A in the body within the systemic circulation. And TTR amyloidosis occurs due to a destabilization of the tetramer. That four-leaf clover-shaped protein falls apart into his pieces, into his unstable monomers that then misfold, and then they aggregate as insoluble amyloid fibrils, which then deposit in the tissue. And this process occurs of every second of every minute of every hour after it starts, and this accumulation of protein is irreversible. So the sooner we catch this disease, the better these patients do. And we know that it commonly affects multiple organs, including the heart, the kidney, the GI system, and the nervous system. In the heart, we think of heart failure, we think of arrhythmias, and we think of valvular heart disease, and we'll discuss that in a little bit more depth here in a minute. In the GI system, it's primarily due to our autonomic dysfunction. These patients oftentimes complain of early satiety and gastroparesis, meaning they get easily full fast and they have a lack of appetite. This can result in weight loss, and then they can have constipation or diarrhea, or they can have both. I've had patients who have bouts of constipation for a week that follow a bout of diarrhea for a week, and they go back and forth. In regards to the nervous system, we see autonomic neuropathies including orthostatic hypotension, meaning they get dizzy and lightheaded when they stand up, and this oftentimes results in an intolerance to our blood pressure medicines, to our goal-directed medical therapy for heart failure. They can get urinary retention, which can result in increased risk of UTIs, and they can get erectile dysfunction. For our sensory neuropathies, it's oftentimes rapidly progressive. It's not like our diabetic diabetic neuropathies where it's a numbness and tingling that is usually fairly consistent for time. These neuropathies cause numbness and tingling that rapidly progress to weakness, and it may actually result in patients being unable to perform their ADLs and a decrease in quality of life. They can not even be able to open a jar of peanut butter or walk without the aid of a walker or a wheelchair. And then finally, our musculoskeletal complaints. So we see carpal tunnel syndrome, especially bilateral carpal tunnel syndrome. Very few things cause bilateral carpal tunnel syndrome. So if you see this in your patient history, have a high level of clinical suspicion. It can cause lumbar spinal stenosis, and oftentimes this is accompanied by sciatica or shooting pain down the back of your leg. It can cause bicep tendon rupture and early hip, knee, and shoulder arthropathies. In the heart, it causes progressive deposition resulting in thickening of the myocardium, which causes impaired compliance, diastolic dysfunction, and eventual restrictive physiology. It can get so restricted that the heart can't pump the blood that the body needs. You can see a low cardiac output, and eventually this causes systolic dysfunction. And end-stage heart failure. In regards to the conduction system, we see bradyarrhythmias, heart blocks, and we see tachyarrhythmias such as atrial fibrillation and ventricular tachycardia. And then finally, there's a high rate of valvular heart disease, especially with calcified a stenosis, low flow, low gradient. So there are two subtypes of TTR cardiac amyloidosis. There's the wild type, formerly called senile, but nobody really wanted to call it senile, so they changed the name to it. And there's a hereditary former also called a mutant or variant. For a wild type, it's the unmutated form. It's connected to advanced aging. It's more common than the hereditary subtype by the tune of 80 to 90% of patients with cardiac amyloidosis, and it may represent up to 10 to 17% of patients referred for half path evaluation in their 60s or greater. And then on autopsy they found that 1 in 5 octogenarians had cardiac involvement of amyloidosis on autopsy. The hereditary or mutant or variant of some type is a familial disease. It's passed down through generations in an also more dominant fashion, meaning all you need is one bad copy to be passed down to cause the disease. It's less common when we look at overall ATTR populations to the tune of 10 to 20% of those patients. The mutation can result in syndromes of the heart and nervous system. It can be predominantly cardiac or predominantly neuropathic, or it can be a mixed phenotype of both, and it stems from 100 to 120 potential mutations in the TTR gene. The four most common in the United States are V142I, T80A, V50M early and late onset. When we look at the breakdown of those mutations, we see that the predominant one is V142I to the tune of 45% of all patients with hereditary amyloidosis. The next most common is TADA, which is approximately 20% of those patients, and then V50M both early and late onset, which is 6%. And then finally, 29% is all other mutations. When we break those mutations down further, it's actually very interesting. Based on the mutation, you can predict. If there's a sex distribution, what age of onset there might be, if there's an ethnicity or nationality background that we should be in tune to, and we can, we can also predict the symptoms. So for patients with V50M early onset, such as in our top bar, these are usually females of Portuguese or Japanese descent, and oftentimes these symptoms start in the 30s and 40s, and this occurs as a predominantly neuropathic phenotype with very, very little cardiac involvement. That's in contrast to the late onset of V50M, which is usually males of Swedish descent. Usually, uh, age of onset is 50 to 60 years of age, and this is a mixed phenotype with both cardiac and neuropathic symptoms. V142I is usually males of African-American descent, usually the age of 60 or greater, and this is primarily a cardiac manifestation with some carpal tunnel syndrome, spinal stenosis, and maybe some mild peripheral neuropathies. And then finally, TADA. It's an unknown sex distribution between males and females, but these patients are usually of Irish or English descent, so it's kind of the UK variant. Age of onset is usually 50s and 60s, and we see a mixed phenotype as well with cardiac and neuropathic involvement. And then finally, uh, wild type. So this is primarily male involvement. It can be really any ethnicity, although commonly we see those in Caucasians, and usually the age of onset is above 70. And these patients oftentimes present with a cardiac manifestation with some carpal tunnel syndrome, some spinal stenosis, and very minimal peripheral neuropathies. In a graphical representation we see this is a breakdown. On the left we see neuropathic complaints in blue. On the right we see cardiac complaints in red. In the middle we see a mixed phenotype in purple. V50M, as we discussed at early onset, is to the far left with primarily neuropathic complaints. V142I is on the far right with primary cardiac complaints, and then our TADA and our V50M late onset is in the middle with a mixed phenotype. These are our four most common mutations, but we should still be aware that there are a number of other mutations we see in the United States that fall within that spectrum. So we should know that there are a few red flag signs and symptoms that precede diagnosis by years. Oftentimes we see on the very right hand side here year 0, so it's the year of diagnosis. Approximately 2 years prior to diagnosis, these patients start to develop cardiac symptoms such as shortness of breath, swelling, they may have atrial fibrillation. 5 years prior to diagnosis, oftentimes they present to a provider with autonomic neuropathies or even peripheral neuropathies. 7 years prior, they may have early hip and knee arthropathies earlier, earlier than you would expect based on their age. And then more commonly, We see that these patients oftentimes have bilateral carpal tunnel syndrome with a release 10 years prior to diagnosis. This is something I see commonly in our clinic, that I see a patient. In 2024 and in 2014 or 2015, they underwent bilateral carpal tunnel release. At any point, a provider could have worked this up, could have diagnosed a patient with amyloidosis, and if amyloidosis is a progressive disease where it's a small accumulation of protein over time and it's irreversible, if we had diagnosed a patient early, we could have prevented mortality and morbidity in these patients. So delaying diagnosis can significantly impact the patient. You know, again, symptom onset usually occurs, and there's a first presentation followed by multiple visits to a provider for seemingly unrelated, uh, uh symptoms, and then there's a phase of rapid progression, a decline in quality of life and functional capacity. It starts to cause cardiac complications and repeated re-hospitalizations, and eventually there is increased risk of death. Unfortunately, patients prior to diagnosis oftentimes see more than 4 providers before they're finally diagnosed and started on treatment, and oftentimes diagnosis is delayed by 6 years after index symptom onset. So now we've talked about what amyloidosis is and and what signs and symptoms are associated. Let's discuss now why it's important. So it's a rare disease that really isn't that rare. This is a study out of Mayo, and there were a couple of studies after this, and Dr. Redfield found that up to 10 to 17% of patients being referred for a HEPA evaluation actually had underlying wild type amyloidosis as the cause of the HPA. As mentioned before, about 25% of octogenarians on autopsy had underlying wild type ATTR and it's thought that this is probably a pretty common disease, and the likelihood increases after the age of 65. And then further, there are 4 different studies done in both New York and Pittsburgh that found that about 14% of patients, up to 16% of patients referred for TAVR for severe eric stenosis actually had underlying wild type amyloidosis. And so, you know, eric stenosis, severe aortic stenosis is a rapidly progressive and lethal disease, and they've intervened on one rapidly progressive and lethal disease. And if we had not screened these patients, we had missed out on the opportunity to treat another rapidly progressive and lethal disease. And then finally, about 4% of African Americans are genome positives for the V-142I mutation, which equates to conservatively 1.5 million people in the United States. I know that that 1.5 million patients are not being followed by inlet providers in the United States, so clearly we're missing a large group of people. And then mortality. So after diagnosis of a polyneuropathy variant, patients oftentimes die 5 to 15 years without treatment. With the cardiac manifestation, they oftentimes die 2.6 to 6 years after diagnosis without treatment, and we know that because it's a progressive disease that's irreversible, if we catch them late, these, these numbers are not that different. So let's move on to screening. So who should be screened? In my opinion, the most basic form, if your circle interacts with another circle in this, in this pictogram, then this patient should probably be screened. If a patient has heart failure with LVH, if they have aortic stenosis, especially low flow, low gradient. Or, and or if they have neuropathies, such as polyneuropathies, autonomic neuropathies, or bilateral carpal tunnel syndrome, these patients should probably be screened for underlying amyloidosis. Screening really starts with a good history and physical. It starts with kind of cueing ourselves in to the signs and symptoms. And so we should ask about heart failure symptoms, about neuropathic symptoms. We should ask for a family history of neuropathies and heart failure and sudden cardiac death. Then usually we start with our most basic workup. An EKG may show low voltage here, as seen here, or a pseudoinfarction pattern. Oftentimes we see that a troponin or BNP are mildly elevated, and they've been consistently mildly elevated over the course of time. And we may see renal dysfunction or liver dysfunction on labs. The next test that's oftentimes ordered or oftentimes reviewed is an echocardiogram. I have a number of echo echo techs in the front row, but I, I promised them I would not call on them today. Um, an echo screening tool is non-invasive, it's accessible, and it's quick to perform. So let's review a few echo findings. So here is a perternal long axis, and here we see that there's increased LV wall thickness. We see that see that so-called speckled appearance to the septum. We see here that there is a thickened mitral valve leaflet. Enlarged left atria, And if you squint really hard, you see this very sliver of a pericardial effusion. In parasternal short axis, we see that the heart is homogeneously thick. It's concentrically thick. It's thickened all over, and that's in contrast to other forms of hypertrophied infiltrative diseases. And if we look really close, we also see a, a very trivial pericardial effusion. Here we see an apical 4 chamber. And here we see increased LV and RV wall thickness, so RVH. Again, we see the speckled appearance of the septum we see bi atrial enlargement. We see some intra atrial septal thickening. We see thickening of the mitral valve more so than the tricuspid valve in this example, but we can see thickening of both valves. And we see poor angular motion of the mitral valve, which means that the mitral valve lateral annulus is not moving well towards the apex, annually preferentially deposits in the mid in the base of the heart, and not so much of the apex. And so there's poor annular motion of that valve. And then we also see a small pericardial effusion. In regards to ventricular morphology, historically we thought of LVH as being 1.4 centimeters or greater. For diagnosis. Although more recently we've encouraged people to actually lower their suspicion to 1.2 centimeters or greater. As mentioned, the heart is ho homogeneously thick, unlike other infiltrative diseases where it's like HCM where it's asymmetric. The thickening starts from the outside and actually comes inside and reduces the chamber size. And as I mentioned before, Emily preferentially deposits in the base in the middle of the wall and it spares the apex. And so when we do longitudinal strain, we see that the apex is moving far greater as represented by the darker red and the more negative numbers versus the base and the mid. This makes a so-called cherry on top or bull's eye appearance to the stream pattern. The apex is moving well, but the base and the mid are not. So who should get strained? In my opinion, people who have LV wall thickness and have any of the following should get strain imaging. If your age is above 65 years or older, if you have a history of heart failure, and if you have no history of uncontrolled hypertension, this patient should probably get strained as a way to screen for amyloidosis. In regards to atrial morphology, oftentimes we see bi atrial enlargement. And it actually makes this looks like a so-called ice cream cone. We see that thickened LV that looks like the cone, and we see that enlarged atria actually looks like scoops of ice cream. I've also heard this called the Mickey Mouse ears. Here, we have a 3 chamber, and here we see apical enlargement. Again, we see the mitral valve is thickened. We see poor longitudinal motion of the annulus of the mitral valve. We see increased alveolar thickness, and then finally here we see aortic stenosis. And these are all findings we see commonly in amyloidosis. And then lastly, pericardial effusion. Sometimes you don't see this pericardial effusion. Unless you look in the Pastern long axis or subcos of views. So our next step is to think about could this be something else? Could this be another infiltrative disease like Fabry's or hypertrophic cardiomyopathy or restrictive pericarditis, or could it just be hypertensive heart disease? If it could be something else, then perhaps doing an MRI is your next best step. And on the MRI with amyloidosis, commonly you see elevated T1 values. You can see increased extracellular volume fraction. You can see uh LGE which can be diffuse, subendocardial or transmural. And then finally, you may see abnormal gadolinium kinetics, where the myocardium uh nulls at the same time or before the blood pool. Here we see examples of late gadolinium enhancement in a patient with amyloidosis. This is an example of subendocardial late gadolinium enhancement. And we see with the arrows where the LGE is affecting the heart, we see as pieces of white. Here's an example of somebody with diffuse LGE due to amyloidosis, and we see that the LGE is actually affecting their RV as well as their atria. In the same patient. And then finally gale kinetics, so When you do TI scout imaging, oftentimes the myocardium may null at the same time or before the blood pool, which is very abnormal and only seen in amyloidosis. So if your patient probably doesn't have something else, you think they still have amyloidosis based on your assessment, your echocardiogram findings, and your EKG, the next step of diagnosing a patient with ATTRCM is actually to rule out its myeloma cousin, light chain amyloidosis. So light chain amyloidosis occurs when a cell that's produced by the bone marrow overpopulates. It clones itself. It's called a plasma cell. If every plasma cell makes a little bit of light chain protein, if that plasma cell is cloned over and over again, then you get a lot of extra light chain. And so we should screen these patients by doing serum kappa lambda free light chains and serum and urine immunofixation. If that light chain ratio is abnormally low or abnormally high, or you see evidence of monoclonal spike or monoclonal gammopathy, meaning a singular protein spike, then this patient should be screened for light chain amyloidosis. This is really a hematologic emergency. If patients are not diagnosed, mortality is 50% at 6 months. So make sure you refer these patients to hematology for assessment. If your light chain evaluation is negative, Then you can move on for your, to your TTR specific testing, which is a a pyrophosphate scan. A pyrophosphate scan or a nuclear bone centigraphy scan is an imaging modality where we take images 1 to 3 hours after a radio tracer, either HMDP or technesium 99, is administered, and we actually assess how much of the of the tracer is taken up by the myocardium using using a visual uptake score. It should be known that we no longer use HCL, which is a hard to contralateral ratio, because we found it to be an imprecise tool and cause a lot of false positives and false negatives. The so-called sensitivity is 99% or greater, and the specificity is 86%, although most likely these numbers are skewed as we start to use this test more often. And it should be noted that there's a false positive with AL amyloidosis, so a p pyrophosphate scan does not differentiate light chain versus TTR cardiac amyloidosis. And finally, we should always do PRP scans with SEC CT imaging. Here we have a visual uptake score. And we can see on the left, we have a patient with a VUS of 0. And if we look, we see the sternum in the middle and to the right of the sternum is where the heart should be. We can see that there's no uptake of the radio tracer. There's no evidence of glowing where the myocardium is. Moving to the right, we see a visual take score of one. We see that there is slight uptake in the myocardium, but it's less than the bone, less than the rib. And then following that, a visual take score of 2 means there's uptake, and it glows as bright as the rib. And then finally, visual take score of 3 means the uptake is greater than the rib, and oftentimes when people have VOSs of 3. Oftentimes you see only the myocardium glowing. You see no evidence of bone. Here's an example of a PET uh I'm sorry, a SPECT CT. The reason for using SPECCT is to improve our testing modality, to reduce the rate of false positivity. When you do CT you define the myocardium, and when you do SECT, you actually can judge where the radio tracer is. So here we see the myocardium as defined, and we see in the bottom right, and the bottom left, that the tracer is in the myocardium and not the blood pool. Unfortunately, there's a good number of patients who were referred to our center and on assessment they actually had a false positive PYP scan. I've had people who were on therapies, and when we've looked, they actually didn't have underlying amyloidosis, and that's because either the outside facility took the PYP skin too quickly after administration within the one hour. Which is one possibility, and the other possibility that I've seen before is that patients with heart failure, well, their heart's just not pumping the blood adequately enough, and that tracer is hanging out. And if we had done it with SEC CT, I, I would guess that the tracer was probably hanging out in the, in the, in the LV cavity in the blood pool and not actually here to the myocardium. They actually did not have amyloidosis at all. They just had a low cardiac output. So, all the more reason whenever you do PYP scans, they should always be done with SPEC CT imaging. So if your patient has a visual uptake score of 2 or 3, well, you've officially diagnosed a patient with ATTRCM. Our next step is actually to do genetic testing. If your patient was negative, if the VUS was 0 or 1, then those patients should have further evaluation. At this point, if you have a high clinical suspicion, you shouldn't stop there. You should continue your assessment, whether that's an MRI, whether that's a repeat PIP scan for low-risk patients in 6 months or a year, or whether that's an end a myocardio biopsy or a fat fat biopsy for diagnosis. These patients should continue to be screened in the clinic. So genetic testing, why is it important? It wasn't added to our algorithm for assessing patients with ATTRCM up until 2 years ago. It's important for two reasons. Prognosis is one of them. So patients with hereditary or mutant subtype, they have a worse prognosis than those patients with wild type. Their mortality rate is much higher. So that's one important reason. The other important reason is it allows for cascade family testing. We talked before how this is a progressive disease, how this is irreversible, how it causes irreversible symptoms that can lead to increased mortality and morbidity. So if you diagnose a patient with ATTRCM, hereditary subtype, and they do cascade testing in your office and you find that they have got family members who are either asymptomatic or have mild symptoms, if you catch them early and get them on treatment. Well, you could improve their mortality and morbidity. You could change their quality of life. You could change how long they might live. With early treatment, those patients can actually get back onto a mortality rate equal to their cohorts of their same age. There's a few screening caveats. So, 30 to 40% of patients who are elderly, who have underlying wild type actually have underlying monoclonal gammopathy of unclear significance or MGUS. There's a famous amyloid cardiologist named Dan Judge who said MGUSs actually stands for muscle under skin, so you should do a confirmatory biopsy, either a fat fat biopsy or an endomyocardio biopsy for diagnosis. And there's a few screening feature modalities that have been discussed recently. So MRI has been a very hot topic. An MRI, while great, while it gives a very good definition of morphology, is not a precise screening tool at this point. So it can't tell you if a patient has amyloidosis. It can tell you that the patient has a pattern consistent with amyloidosis. There are a few things that MRI does very well though. And so we've been looking at extracellular volume fractions recently. And so extracellular volume is. Kind of a number or a measurement of fibrosis of, of kind of fibrotic tissue in between the cells. And so we know that patients with amyloidosis have an elevated extracellular percentage, and oftentimes we see at least an ECV of 30%, but a high, so 30% is considered intermediate, but a high likelihood is are patients with an ECV fraction of greater than 40%. And then finally PET CT. So now with PET CT they're actually using these targeted amyloid binding radio tracers, and this, this modality can actually may actually be able to tell us both a qualitative and quantitative assessment of patients with amyloidosis. Before MRI gives you a kind of an indirect measure of amyloidosis, and even PYP scans, a visual uptake score of 2 or 3, while a 3 is a higher uptake than a 2, it doesn't actually tell you disease burden. It can't tell you what severity of amyloidosis patients have. Well, these new radio tracers may actually be able to bind to and tell you 1% of myocardium is being affected by amyloidosis, which is really exciting. So here at Centera, we've, we've tried to make things streamlined. And so with this, if you have a patient you suspect has amyloidosis, if you type amyloid into the order um bar in your epic, An actual order that comes up. And with this, you can either choose inpatient testing. Or outpatient testing. And if you select one of these drop downs, it actually drops down the labs you need and it prepopulates a PYP scan with SPECT. So now that we talked about what amyloidosis is, the signs and symptoms of amyloidosis, and how to screen a patient with amyloidosis, let's move on to a case. And this is Mr. C. So, Mr. C is a 62-year-old male of African-American descent, and he's referred for evaluation of heart failure after repeat treatments for shortness of breath. He has a history of bilateral carpal tunnel syndrome and spinal stenosis, as well as lower extremity neuropathy and hypertension. On review, he actually reported dyspnea after one flight of stairs, lower extremity edema, and orthopnea. And an echo He had LVH, left ventricular hypertrophy, and the EKG showed low voltage. So Mr. C had all the classic signs and symptoms of a patient with amyloidosis. So he went on for testing, and on the right we see his PYP scan, that's a visual uptake score of 3. You see that myocardium is glowing bright white, you know, greater than the rib and bone around it. And on the left we see his MRI and on MRI we see that there is significant subendocardial LGE and we can see he has abnormal gadolin kinetics. On TI scalp. So Mr. C has underlying amyloidosis. Of ATTR subtype. His light chain assessment was negative. And further, he had genetic testing and found that he was homozygous for the V142ITTR mutation, meaning he had both bad copies. That means that both of his parents had a bad copy, then they gave it to him. So, what's interesting about Mr. C is that he doesn't drive, and actually his brother drove him to all his, all his visits. And as we talked to Mr. C, his brother started to note, well, actually I have shortness of breath as well, and I have neuropathies, and I've, I've had these symptoms. Should I be tested for this? And through Cascade family testing, we found that Mr. L, his brother, was heterozygous and his sister Miss T was homozygous. Mr. L underwent PIP scan and MRI, and he's actually found to have amyloidosis. And Miss T, despite being homozygous, despite having both bad copies, she actually didn't have amyloidosis. Mr. C went on for a heart transplant because his amyloidosis was found too late. Mr. L was started on therapy and he's doing well at this moment. And Miss T to this day. Still doesn't have amyloidosis. And so it actually begged the question, is there some kind of spectrum of amyloidosis in regards to B142I? Does it affect? The sex different and how that, how's that based on zygosity? How's that based on which mutation you have and how's it based on how many of the bad copies you get? We know that patients with both bad copies, homozygous for V1142i, they have more extreme disease. They have worsening symptoms. Those with heterozygous disease have less symptoms, and for some reason, women seem to have, seem to develop amyloidosis at a less rate than those of their male counterparts. And we actually published this, this family. So with that, we'll we'll move on to treatment. So oftentimes these patients are intolerant of our traditional GDMT and diuresis due to the restrictive physiology with a fixed stroke volume and autonomic dysfunction. Oftentimes, rate control medications also cause bra arrhythmias. And these patients are intolerant due to the fixed stroke volume. In regards to atrial fibrillation, they're oftentimes intolerant of afib. They lose the atrial kick, and because they're so restrictive, it causes a low cardiac output. In the traditional medicines we use like calcium channel blockers and beta blockers, they're intolerant of those as well due to the bradyarrhythmias, and, and also because of the fixed stroke volume causing low cardiac output. So, it's better to get these patients out of AFib and to keep them out of Afib. As many of you know, I'm very aggressive as referring these patients to EP to consider ablation. The CHADS VAS score does not apply to these patients, so regardless of what you think their CHADS VAS score is, they should always be on anticoagulation, and that's primarily due to the fact they have such a restrictive physiology that there's low flow. There have been cases of patients who have no history of afib, and they still have left atrial appendage thrombus. To date, there is no studies comparing warfarin versus Adoac, and so we use we use them interchangeably. In my opinion, these patients should always undergo a TEE for evaluation for left atrialpanage thrombus. One study out of Mayo found that 33% of patients being referred for cardioversion for Afib who had underlying amyloidosis actually had a left atrial pench thrombus. 46% of those patients, so nearly half, had been on therapeutic anticoagulation or had onset of Afib within 40 hours or less. So these patients shouldn't have had evidence of atrial pee thrombus, and we've actually seen this here at Centera as well. There have been a number of patients who we followed, and they had onset of Afib or they've been on anticoagulation. And for months and months and months afterwards they had a left atrial a left atrial panic thrombus that just never went away. And then finally, if you are going to cardiovert a patient with amyloidosis, they have a higher rate of VTVF postcardioversion, bradyarrhythmias requiring pacing, and a stroke. So we'll move on to our final topic, which is disease modifying treatments. So there are a number of medications that have come around. But it's been in short order. Each individual medication actually affects somewhere along the amylogenic pathway. Here on the left we see the liver, which makes the TTR techmer, which is a four-leaf clover. In order to develop amyloidosis, that tetramer breaks apart into its pieces, it falls apart into its pieces. Those pieces then misfold and they accumulate as clumps, and that clump, those clumps cause dysfunction. So there are 3 classes of medicines that can affect this. There are stabilizers, silencers, and now depleters. So a stabilizer Actually stabilizes that form. It acts on that pathway. It prevents the breakdown, and there are actually two stabilizers that are currently being used. There's steaminous or Vindamax and Acareminus or Arubi. As mentioned, the mechanism of action actually binds to and stabilizes the TTR tetramer or stabilizes that shape and it prevents the breakdown of the protein structure, thereby reducing aggregation. And they seem to work well. I won't belabor some statistics, but the relative risk reduction of all-cause mortality and death in cardiovascular hospitalizations, as well as the number needed to treat to prevent these, is actually pretty impressive. And based on some in vitro and in vivo studies, we see greater than 90% stabilization, so it stabilizes the TTR tetramer, that that that shape 90+% of the time. The next class of medicines are TTR silencers. So a silencer actually acts. In two different ways. To reduce TTR production by 83 to 88% based on which sounds there. And so, silencers included Teetti on patro, and currently approved silencers include batrucerin or Rebutra, lonerson, or Winua. So Vitrusin or Abutra, and these medications were actually originally approved to treat hereditary ATTR with polyneuropathy subtype. Currently, vitruserin or Ambutura is approved to treat cardiomyopathy based on a study that came out called the Helios-B approximately a year ago, and cardiotransform, which is looking at patients with Wanua with ATTRCM, is pending, and we're all anxiously awaiting the results of this. There's one silencer that's being that's being studied in trial, and that's Nicroerin. In the Triton trial, and we're actually part of that. Again, the mechanism of action is it actually acts either by using a small interfering RNA or an anti-sens illegal nucleotide to affect messenger RNA in the liver, thereby reducing TTR production. And again, the relative risk reduction in number you needed to treat for patients with ATTRCM, at least, at least with Invitra, was also impressive. And our final class of medications that's is up and coming are depleters, and depleters actually act by attaching to and breaking apart. The amyla fibrils you have. So where silencers and stabilizers, they prevented the further accumulation and aggregation of amyla proteins, they didn't reverse the irreversible disease. It's potential that this new class of medicines, these depleters, may actually reverse disease. So historically for depletion, we looked at a number of medications. We looked to see if doxycycline and bio acid derivatives were effective, which they weren't found to be effective. We looked at high doses of green tea extract, which wasn't found to be effective, but there are two medications that are on current study. Clearmatug just completed their depleter CM trial. And Kormaug is currently being studied in the Cleopatra trial, and we're we're a part of the Cleopatra trial. The mechanism of action again actually binds to these medicines bind to the misfolded TTR amyla deposits, and they clear them through antibody immediate phagocytosis. So these have potential to actually reverse disease that is currently present. So there are a few frequently asked questions in regards to treatment that I get. So does combination therapy work? Well, there's no data behind this. That being said, when we say combination therapy, we refer to our currently approved medications which include silencers and stabilizers. So there's no current data to say that this works any better than monotherapy. That being said, for patients who have advanced amyloidosis, we oftentimes do do concomitant silencer and stabilizer therapy. And it should be noted that um the silencer studies, HeliosB had a had a small subgroup who had combination therapy, and the cardio transform trial has a subgroup that has combination therapy. So that's one of the reasons why we're anxiously awaiting the results of that. Is there anything I can do to prevent getting amyloidosis in the future? Well, that's a yes and no question. So there's nothing that you can do either by diet or exercise to prevent, to prevent your risk of developing wild type. Or if you have a genetic mutation, there's nothing you can do to prevent the risk of developing their hereditary subtype. However, there are two trials that are ongoing. The first is the ACT Early trial where the folks at Bridge Bio are offering medication to patients who are genotype positive, meaning they have the gene, but are phenotype negative. They don't have the disease. And so they're looking if early treatment actually prevents the occurrence of amyloidosis in these patients who have the gene. And then finally, there's the magnitude trial. And so this magnitude trial actually looked at CRISPR or gene modification to go in and actually modify those abnormal TTR genes in the hereditary subtype. That was on hold for a number of months, but now it's back and it's running. So with that, I have a few pearls for you. So, have a high level of clinical suspicion if a patient has LVH and neuropathic symptoms or bilateral carpal tunnel syndrome. Screening is very important and can be served in your office, but I'm happy to help. So all you need to do is message me. I'm happy to look at your patient's screening. I'm happy to guide that process. And if your patient has some kind of abnormal labs, for instance, I oftentimes get calls about abnormal light chains, I'm happy to advise on what to do next. Traditional volume management strategies and GDMT can be harmful. It can make patients feel more poorly because of the restrictive physiology of amyloidosis. You should be mindful of atrial fibrillation, and you should know that there's a higher risk of complications in left atrial appendage thrombus. I would always refer these patients to EP for early assessment and intervention. Published April 7, 2026 Created by Related Presenters Zackary Tushak, D.O. Sentara Advanced Heart Failure Center View full profile
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