Brian Drachman, MD, Co-Director of the Amyloidosis Program at Penn Medicine, provides updates on Amyloidosis including its role in several cardiac diseases and its current treatment options. He elaborates on the different kinds of amyloidosis, the multi-symptom effects amyloidosis has on the body, and the therapies available at Penn Medicine.
@PennMDForum See Dr. Drachman’s physician profile Amyloidosis Briefing As with all of our talks, please feel free to leave any questions or comments in the chat or the Q and A tabs at the bottom of Zoom. I will be monitoring those and at the end will try to leave about 10 minutes for, ah, question and answers with Dr Jackman. So this week I have the pleasure of introducing our very own Dr Brian Drachma, who will be speaking about cardiac amyloidosis. Brian received his medical degree from Penn and afterwards remain depend for his residency and fellowship. Brian now serves as the co director of the amyloidosis program at Penn and also our associate chief of cardiology at Penn Presbyterian Medical Center. Cardiac amyloid over the years really went from something we all learned about at medical school to becoming a very important disease, and we're learning its role in multiple cardiac conditions. Importantly, it now has several treatment options. Brian has been a great leader, teacher and mentor to many of us, and it's my great honor to introduce him today for cardiology grand rounds. So I'm going to stop my screen sharing, and I'm gonna let Brian takeover the screen share, right? Can you guys. Hi, guys. Hi. I'm glad to talk. Obviously, today it's Thanks for everybody tuning in at 7. 30 in the morning. Can you guys see my first slide there? Yep. Brian, everything looks good. We hear you and we can see your slides. Great. So I'm going to spend about the next 45 15 minutes or 15 minutes or so talking about a number of aspects of them. All of those if we're gonna be talking about some overviews of the diseases that most commonly going to see that we're going to talk about, Um, some of the diagnostic strategies that have changed really over the past several years. And then we're gonna talk about treatment options. It's a lot of information. Please go, Frito, ask any questions and we'll be ableto hopefully share these slides for you guys after we're done. So with that. Okay, So, cardiac amyloidosis, um, isn't a single disease, Andi. In fact, the term amyloid is a generic term that was derived from the Greek word that starts like and it was originally coined in the 18 fifties when Rudolph Vertical began to see under the light microscope and some of his patients and their tissues, a material that he thought looked like starch or glycogen. Today, in 2000 and 20 the term amyloidosis really refers to the experts cellular deposition of inside herbal protein five rolls that have undergone a very specific transformation to form what it called anti parallel beta pleated sheets. Now these they uploaded cheats have a very characteristic appearance under light microscopy and in particular in their ability to buying Congo Red, which sustained and give this apple green appearance. Virtually nothing other than amyloid will stay in this way. And we now know off over 30 different precursor, low molecular weight proteins that conform amyloid. Really, the Onley thing that they have in common is they form display beta of cheap morphology, and they stain in exactly the same fashion. Now these are some of the disease entities that are associated with these various proteins. But for this discussion, we're going to concentrate really on the top three. What? We're going to see that these are the three major types that affect the heart. We're going to see, though, that these were very different diseases with different treatments, different prognosis on different diagnostic strategies, all that they really have totally in common is that they stay in Congo Red exactly the same way. I'm going to start with an overview of what's called a L, which used to be called primary amyloidosis. And this amyloidosis is due to the deposition of approaching that's derived from immune a global lighting fragments. This is a plasma cell disorder, and it's characterized by a monoclonal expansion of plasma cells in bone marrow. We don't really know totally how common it is. We see about 2500 new cases a year, and that's similar to what you might see with Hodgkin's or CML. We used to think that this was the most common form of amyloidosis. But as we'll talk about later wild type diseases clearly, far more common than a L, the median age of presentations in the sixties intensity disease of older individuals all the way. I've seen people in the thirties and age with this. There's a little bit of a male predominance, and about 10 to 15% will have an associative multiple myeloma. The key thing about this disease is that virtually all patients have multi system amyloid Deposition one organ tends to be the predominant clinical manifestation and the heart is that case and about one out of every three cases. But overall, about 60% of patients with A I will have some degree of cardiac involved. Now this is a restrictive cardiomyopathy, and it's characterized by the infiltration and thickening of all for cardiac chambers as well as value of structures. What we most commonly see is a rapidly progressive heart failure syndrome. And although Disney it certainly does occur, the signs and symptoms of right sided heart failure tend to predominate. These people get profound peripheral oedema, and then they get scrotal oedema. They get the sightings and they get diuretic resistant. Pleural effusion. Typical angina does occur, and stretch testers sometimes abnormal in these people, but the epic cardio arteries are spared. The angina is the small vessel infiltration with Emily and sometimes called Emily and geography. And in this form of amyloid, the conduction system is involved pathologically a lot. But in a l high degree, heart block is really not very common. It is much more common, and other types of amyloid is we'll talk about and arrhythmias, particularly a tribulation occur. But again they're more common in other types of amyloid that we'll discuss later during the talk. Now this truly is a multi system disease with multiple working systems almost always involved. In about 20 to 35% of patients will see neurological involvement with a sensory motor and autonomic neuropathy. They get typical numbness and pain. Ortho static hypertension is a big problem with these people. And as we'll see in all forms of Amma, would carpal tunnel syndrome is very common in this entity. Gee, I involvement occurs fairly frequently, in particular had a medley and lft abnormalities. And the pad A medley can be due to right heart failure. But it's often do thio actual amyloid infiltration in the liver and the physical exam findings. And these patients are different. It's not that spongy, tender right upper quadrant that you see with right heart. It's typically a rock hard liver that's nontendered pal patient. They get kidney involvement very common. The hallmark. It's severe protein. Nouriel, often the product range. It can lead to renal failure, but that's usually a slow process. Unless they've got cardio legal, they get a bleeding diagnosis. They get factor 10 deficiency and then about 10 to 20% of patients will see these classic findings of ale amyloidosis macro blossom With seeing the truth, Ridge is actually invent the tongue as well as this peri orbital echo Moses again. Not very common, but if you see it, you should be thinking about a El Amel. Now, in terms of overviews, I want to shift gears and talk a little bit about hereditary or familial family. Now, unlike A L, which is an acquired plasma cell disorder, this is most commonly duty either inherited or spontaneous mutations in the protein. Transparent, transparent is just another name for pre album. It's exactly the same protein, just to name Corey album. T T are the major function of it is. It's a major transport protein, retinol, binding protein and vitamin A. It's a minor transport, uh, protein with high rocks and and in this in the bloodstream that normally exist is a tetra. But mutations in this protein make the Tetra are actually break apart into a liga MERS and monitors. They then recombine. They form this beta pleated feet morphology, and they get Oregon deposition. Now, this stain exactly like a l does with Congo red. But as we'll see, this is a very different disease. Now 98% of teach ER is made and delivered, and that's important for treatment options. The remainder is in the core I plexus and retina on. We now know of over 100 different pathologic mutations in this protein that lead to disease there. Almost all inherited is on Isobel dominance. Most have a very high level of penetrates, but interestingly, the age of onset of disease will vary depending on the mutation and also interesting where you were born. For example, if you have the most common mutation in the world was called the 30 a. M, and you're born in Portugal, you're going to get your disease in your twenties or maybe thirties. If you have the same mutation and you're born swing, you're going to get it about 20 years later. And if you're born in the US with this new changes, you're going to get it even 20 years later than that. So that's uninterested phenomena about this disease now. Although familial amyloidosis is a systemic disorder, the clinical spectrum is far less broad than that with a L disease and the two most common organ systems that are involved are the heart and the peripheral nervous system, the disease presentation, though various, depending on what mutation you're born with. So if you're born with that, be 30 a mutation. You're gonna have mostly neuropathy. If you're born with the V 1 22 I medication, which we'll talk about in a little bit, you're gonna have mostly cardiomyopathy. So the Gina type of the individual dictates their feelings. Neurological e familial amyloidosis is also known as familiar Emily Polly neuropathy. The hallmark of this disease is a severe sensor motor palling around with these people get painful, you know, para sieges, a lot of pain and eventually significant motor weakness. The autonomic nervous system is commonly very severely involved. They get worth the states that they get urinary retention. They're getting continents like a L. Carpal tunnel syndrome is very common, even if you don't have a reason to have carpal tunnel syndrome. But unlike a l, other organ involvement is very uncommon. Despite that, this is untreated of relentlessly progressive disease. These patients eventually lose their ability to walk. As I said, they become incontinent. They lose their ability to eat and they usually die a death, a pretty horrible of malnutrition on inception. What about the cardiac disease in familial amyloidosis like L? It's a restrictive cardiomyopathy with prominently right sided heart failure. But the heart's in. These patients tend to be much thicker than those with a low disease with wall thicknesses that can approach to centimeters. There's much more amyloid infiltration, but patients tend to have less symptoms at least until the end stages the disease. And we'll talk about maybe, why that's the case. When we talk about patients who, how we treat these people, you will really never sleep. A patient with a heart this thick. They are long dead before they get this degree of infiltration. Now, unlike a L, we'll talk more about this later. EKGs normally have most comedy have normal voltage in these patients, although this is a disease of heart failure with reserved dejection crashes, the S do fall later in the disease, and with some mutations, you can have severe LV dysfunction. Now those patients do really poorly. Unlike patients, other patients with severe LV dysfunction. These vegetables don't dialing. They're less particular. In diastolic. Volume remains low. They have a very low stroke volume at a low cardi account of state. We'll talk more about the prognosis of AM in a bit, but this is better than a all the mean. Survival is about five years from the onset of any cardiac symptoms and what we typically see that patients have a prolonged period where they remain clinically stable. As that's, the amyloid continues to build up into the heart. They eventually reached this clinical cliff, and at that point they developed rapidly progressive heart failure that becomes more and more difficult to treat. And they die now. How common is familiar amyloidosis in the US we don't really know. We believe it's less common than a L disease. With the exception of the one mutation that show on this slide. Screening studies have now shown that 3.5 to 4% of the African American population is hetero zegas for the V 1 22 I variant, this results, you know, late onset progressive infiltrated cardiomyopathy. There's little neurological involvement that there is some. It's seen in the African American patients again, mostly after age 60 and this is one of the mutations that we frequently do see severe LV dysfunction late in the disease. The penetrates of this mutation is unclear. We used to think that the penitence was very high. Now it's not as clear, but we do know that this disease is very frequently miss. This is the same patient population, the African Americans who have a lot of hypertension. And when you see L. V H on the echo, they often get blamed on having hypertensive heart disease. On the other hand, if you see an elderly African American man or woman, he's got bad L being she's got bad. LDH has predominantly right sided heart failure. Um, particularly if they've had bilateral carpal tunnel syndrome, think about this disease and working them up in a way that we're going to discuss later in the talk. The last overview I want to talk about it is gonna be wild type amyloidosis. We used to call this senile disease. We don't use that term anymore. Patients hated being called senile. This does not affect the brain. And unlike while unlike familiar disease, this is due to the deposition of amyloid from normal non translate written my cardio. If you look at people over age 80 by autopsy study, About 50 to 80% of it will have a small amount of trance that protecting their ventricles. But occasionally for reasons that we don't understand. Massive infiltration occurs, and this leads to a heart failure syndrome that's similar to that with Ailes or familial amyloidosis. This, though, is almost exclusively a cardiac disease. Um, carpal tunnel syndrome is again a very common and in fact, usually previous cardiac involvement by about five years. Spinal stenosis occurs very infrequently, and biceps tendon rupture is also seen. Occasionally, the amyloid seems to infiltrate the biceps tendon. It's mostly a male disease. There's a 10 to 1 male to female ratio. It's usually seen in patients over age 65 all ages. All races are effective, and these tend to be the thickest hearts with wall thicknesses that could be over two centimeters. Reduced E. It is not rare in patients with wild type amyloidosis, particularly late MSM. Andi. This type of amyloid tends to have a lot of conduction abnormalities. We have to put a lot of pacemakers and these people that get heart block, bundle, branch block, ASEAN and almost half the patients and a state is extremely common in this entity, which estimated that two thirds of patients with wild type disease will develop atrial fibrillation before during the course of their disease. It used to be thought to be very benign, but it's not again. The median survival is on Lee about five years from the onset of any cardiac center, and it used to be thought to be a rare disease. But recent studies have clearly shown that this was a major misconception. There was a study in 2015 in Spain that looked at 120 patients who were just admitted with heart failure with ejection fraction. 13% of them had wild side amyloidosis. My work off Columbia Presbyterian looked at 151 consecutive Patients Central Tavern. 16% of them had a wild type disease and 22% of the men and wild type disease. This was particularly true if they had paradoxical low flow, low grading of normal ejection fraction the North stenosis. At that point, they were three times more like to have wild side amyloidosis. Just this year, Hopkins took 108 consecutive patients who referred to out patients to their clinic. They biopsy them, and 14% of them had amyloid mostly translate written and interestingly, about half of the patients weren't suspected by these heart failure docks of having an immigrant. But they ended up having. And other Syrians have shown that about 5% of elderly patients with hypertrophic cardiomyopathy don't have hypertrophic cardiomyopathy. They've got wild type amyloidosis on. This is particularly true if it's diagnosed after the six decades. So again, this is not a rare disease. So that's the kind of overview. What I'd like to do now is shift gears and talk about some of the diagnostic strategies for suspecting, confirming and typing cardiac amyloid. And although subtle clinical pearls make clue us into the fact that a patient may have a systemic disease like this, is cardiologists the main clues that we're gonna be seeing or cardiac biomarkers? E. K G findings, echo findings and cardiac memory in terms of biomarkers? I didn't put this on the slide, but patients with cardiac amyloidosis tend to have significantly higher levels of pro BNP than other patients With heart failure, we deserve ejection fraction. Also, it's not uncommon at all that they walk around with persistently positive proponents. This is particularly true in L amyloidosis, where ambulatory patients may walk around with a pro BNP level 20 to 30,000. Just don't usually see that in ambulatory patients with other forms of heart failure with the jets and practice so that sometimes it's a clue. What about E K G funding? Well, if you see this e k g low voltage pseudo in far pattern on extreme right left axis deviation, we should really be thinking about cardiac amyloid. But the problem is, is that most patients don't have this e k g a. L. About only 60% of patients will have low voltage. And as I already mentioned in T tr disease, less than a quarter of patients will have low voltage. About 20% will have a completely normal equally G, and a number of them will have LV eight. So the point is that if you see this e k g, think about amyloid. But if it's not present, the CPG certainly amyloid can still be around. What about echo funds? These are three patients with biopsy proven cardiac amyloid, and the first thing I want to point out is that we typically talk about this characteristic granular or sparkling appearance of the myocardial was a clue that the patient might have the disease but realize that even with older echo techniques on Lee, about 25 to 30% of patients would have this pattern and newer check weeks that use things such as total harmonic images make this pattern even less reliable. As you could see, depending on how you set the settings on the echo, the Maya Korean could were completely different. That said, there is a riel set of things that should clue you in that the patient might have cardiac gamboling. Thes pages tend to have small vegetables. They don't dilate. They have LV eight. Which dimension can be very severe, but they also have associate ID right country There might trolling Try custom valves get thick. They're full of amyloid. The intra atrial septum gets. It's full down the Lloyd they get by H one, largely because they have a restrictive physiology, and there's often a small pericardial effusion. So this constellation of findings should be suggestive of cardiac amyloid. Strain imaging has also become an extremely important part of eco imaging in this in these diseases. It seems that there appears to be a dissociation between short access and long access ventricular function in patients with reference triple hypertension. And what this means is that since we measure ejection fraction by short access functions, although the F maybe normal when we do strain images which looked at longitudinal function, we see that the eventual is not normal at all now. Other forms of left ventricular have perfectly also have the same association. But the severity of this association between short and long axis appears to be particularly strong and amyloid heart disease and this pattern on the polar plot. Basically, this kind of cherry red in the middle of the polar plot pattern is fairly unique. Toe amyloid. We didn't really in the past understand why this was wide. The apex of the heart works better than the base, but studies that were actually done here a 10 about a year and a half ago using pet scanning and cut it memory techniques determine. The reason for this is that you get a lot more amyloid mass built up at the base of the heart versus the apex. That's whether the base doesn't work as well. That's why it looks like this. But why amyloid deposits in this unusual fashion? We really have no idea. What about cardiac moron in the right? Under the right circumstances, it can provide evidence that strongly suggested of cardiac gambler. The most useful finding requires contrast, and it's ah, pattern of global transmitter on the subject of cardio delayed gaveling enhancement. And you could see in the Siri's. The sensitivity and specificity is is quite good. They also get uptake of gasoline, even their atrium. They get what's called suboptimal mulling, and they get abnormal. Both non contrast Team one mapping and Post contrast team mapping. This is called extra shelling the volume. But I'll tell you, in practical purposes, I don't use a lot of cardiac memories in my patients. This sensitivity specificity is in in special consented outside of lower volume cardiac emery centers. There's a lot of reader into variability, making the diagnosis not as clear. Secondly, a lot of our patients have renal disease. They've either got the product syndrome because of a l of the cardio renal, and that limits the use of Galilee nian, which is one of the more important strategies that we have. And finally, although Marie can be suggested, were strongly suggested of a cardiac amyloidosis. It's not diagnostic, but we need another algorithm, which I'm going to go over a minute, and other tests to confirm whether or not the patient does indeed have cardiac family. So these are the current consensus guidelines that were published earlier this year in circulation. Hard Player for how we diagnose type, um, type cardiac camellias. You can see it all starts with clinical suspicion. This is important. You have to have a high pre test probability. We'll talk about this in a minute, but load that the next step before we do anything else before we biopsy before we do. Um, P Y P scans, which we'll talk about is we evaluate the patient for a plasma cell dysplasia. This is the major splitting point of the algorithm. Essentially, you need to know, is there a chance that they had a l amyloidosis and this can now be done with three simple screening tests. Free serum like things an s pepper. But you have to have in unification with it. Some labs don't do that, and a you pep with immune fixation. If any of these are abnormal, then a tissue biopsy or tissue diagnosis is going to be necessary. And referral to our hepatology colleagues is probably going to be appropriate. But if all of these are normal, we now have a technique available that for most of the time can diagnose translate written amyloidosis because you've ruled out a L without the tissue. Bynum's so, under these circumstances. Nuclear ski integrity. Using technician pyro phosphate scanning in the US What's called DPD scanning outside of the U. S. Can, in most cases, diagnosed tt our cardiac Emily noses without being kind of biopsies. These were old nuclear bone tracers that we happen to find were taken up in the Maya Kardian in patients that have amyloid in their heart. And there are now both qualitative and quantitative protocols that again, in the absence of a plasma cell, this Greysia have a very high sensitivity and specificity for diagnosis and transparent disease. Simply, scans were ready between great zero and Grade three million. Great zero. There's no cardiac uptake. Great three means there's hard to take greater than bone. Um, and current guidelines now suggest that in the absence of a plazas. All this crazy. Ah, Grade 2 to 3 scam with what's called the heart to contra lateral racial greater than 1.5 virtually diagnostic off. Teach er amyloid with sensitivity on the right settings. That approach is 100%. But again, note. This does not tell you if the patient has wild type disease or familial amyloidosis and after a positive P white piece can genetic testing would saliva or blood is mandatory to determine which of these two diseases the patient has now, why do you have to rule out a L amyloidosis before um, you do a P Y P scam? This is a really important point. The specificity of the P Y P scandal for L for teaching our Emily drops from close to 100%. Down to 85% of you don't rule out a L first. And in MAWR recent studies, it's actually been showing that ALF Eyeballs about 22% of patients with biopsy proven ale disease will have a class to a grade two or grade scan. Simply put, you can't afford to miss failed disease. It's a completely different disorder. It's a lethal disease with a different treatment, So please make sure that you always order work up for a plastic Selves. Greysia. Now, another point I wanna make about P Y P scans. The scans are being performed at more and more. Center providers are not. Following the consensus guidelines to the teeth were both their utilization, as well as how the scan should be performed. This is leading now to a number of false positives that we're seeing that given incorrect diagnosis on an incorrect treatment, I wanna I wanna stress that that high specificity of 100% in the studies or in patients with a high pre test probability, either by clinical symptoms were by imaging studies. And we're now seeing more and more that the scans are being performed in an inappropriate setting. We're actually just being done wrong. As an example I saw recently a 57 year old woman who a year ago was diagnosed with amyloid, she had very severe oh to dependency OPD, and she was found to have low voltage on her e k g. Her outside position actually didn't work up. It was fairly extensive. Echo was completely normal. Marie was completely normal and a transfer. Transfer it on genetically, completely normal. But because they had low voltage, they did a P Y P scan, and it was read a strongly suggestive of cardiac amyloidosis. Um, she was started on two families, which we'll talk about and came to me. As I said for a second opinion, it didn't make sense. This is a 57 year old woman who had a normal eco normal emery normal Genet's why and wild type diseases, usually a nail disease. Why should this woman have wildlife? Amyloidosis? We went back and actually looked at her P Y P scam. We got the images that were done elsewhere, and we saw that, unfortunately, had followed the wrong protocol in actually doing this scam. So we did isn't repeated. The wipes can hear. It was completely normal. No evidence of amyloid up to. So what we did with this woman basically is we stopped our two families and we sent her back to her pulmonologist because that's the reason that she had low voltage on her e k G. The point here is is that if a P Y P scan doesn't make sense in the clinical scenario, Or as I already said three times, if you have a plasma cell discredited, work up, that's abnormal. You're gonna have to reevaluate, and you're almost certainly going to gonna have to go to biopsy in order to confirm what disease they actually have. So if you are going to go to buy on, stand down this side of the algorithm, what tissue do you set? You go out. Traditionally, we talked about abdominal fat cat aspirants that could be done in the office. They've got minimal risk. Um, that could be done even on anti coagulation. But there's some problems with it. Onley 60 to 80% of a all patients will have a positive fact. An aspirin and less than a quarter of wild type disease have positive fact password. So you will missed 75% of wild type disease with fact had asked. In addition, once you do get a positive that that aspect you need to know what type of amyloid is a tissue, and we do that by sending it out for what's called proteomics analysis by mass that prosecuting and in practical purposes, the fact had aspects that we get in the office don't have enough tissue to do that. We need a tissue from another organ in any other. So typically, under these circumstances, I go right to it. And my cardio biopsy. This is the little low risk procedure and maybe even lower risk and amyloid patients because they're right ventricles air thick, so the risk of preparation is probably lower. They have a very high sensitivity over 95% of all forms of amyloid. And there are perfect specimen to send out from mass spec analysis. So we get in a myocardial biopsy, it comes back Congo red positive. 2 to 3 weeks later, we'll get mass spec results and we will know. Do they have a l in their hearts? Where do they have t t r? Now the T T are in their heart by an aspect. They will. They will suggest whether it's wild type, fourth familial, but you still do need to do genetic testing that comes back is T T r. To differentiate which of these two due to diseases that you're dealing. Okay, So I wanna switch gears now and start talking about the therapy for cardiac amyloid. And when we speak about treatment, we should be thinking about two different goals. The first goal is treating the heart failure that's associated with amyloid in the second goal was treating the underlying root cause in other words, impacting the reduction and deposition of the amyloid approaching target organs. And these were some of the drugs that we all know that we use for traditional patients with heart failure. But the problem is that an amyloid there either poorly tolerated there, unproven, where there often detrimental ace inhibitors. We use a sin builders in everybody, but particularly in a l patients and in the familial patients with autonomic involvement there very poorly tolerated hypertension, calcium blockers. And did both of these buying directly to the amyloid fiber roles in the heart into Jackson's case that needs to your hands, toxicity and calcium blockers. It causes profound negative mining trucks effect you should never use, um, Barack Milord, built in a patient with animals. Beta blockers have no proven benefit of this disease. We don't have time to talk about this, but ICD therapy is rarely indicated in a coagulation is important. Almost every patient with amyloid who has a theme should be on lifelong and curricula. Ation thes patients have an extremely high risk of left atrial thrown by and crumble Obama because he's no matter what their chats to bask score is. And other than that, all we have is diuretics and diuretics don't do anything for prognosis. They often just decongest the patient. Um, and it often requires a lot of diuretics decongestant more than you typically need in other forms. Part. So what about going after the amyloid itself? I'm going to spend most of my time talking about familial and wild type disease because in the last 5 to 7 years there's been a dramatic shift in the treatment paradigm for these entities. We're now attacking front t t r at all levels. Its suppression in the liberal, remember, is made in the liver stabilization of in the bloodstream and even maybe removal of it from organ. We're going to start by talking about TT are stabilization. Remember I told you that TT rs in Chechnya and it needs to disassociate into its a liga MERS and monitors so that it can recombine and form beta pleated shoots. Onda then, um one deposition di flu nasal. Those of you who are, uh, been around for a while. Make no dice Lewis was dola bid. This was an old generic, nonsteroidal anti inflammatory agent that we've incidentally, found to bind toe wild type and mutant T T r te tumors in the cinnamon kinetically stabilized. Um, there was a study done in 2013 inches, neurologic form of familial amyloidosis. They looked at hard neurological endpoints, and they found that by a year patients did better on this drug. They were less likely to progress, and they had better call in your life. That's closely is used all over the world for amyloidosis. Um, but there are some problems from a cardiac arrest. It is a potent and say there's all the normal g I cardiac and renal toxicity. That's where these developments, the pain relief. Also, this trial excluded patients with significant cardiac involvement. There's not a lot of data in cardiac patients. There was one trial, for example, that looked at 13 patients with mild cardiac involvement that followed them for nine months, and two of the 13 actually had to stop because their heart failure worsened and there was a time dependent worsening of renal function in these people. So for our cardiac patients or patients with significant renal insufficiency, this is not a good first choice. Two families, on the other hand, was an agent that was developed as a highly selective trends of it stabilizer. It finds that the Iraq's inside of the molecule that has no nonsteroidal effects, and around the same time there was another randomized trial looking at the famine. It's for the neurological form of familial amyloidosis, and again it improved neurological parameters. Interesting, though it was not nearly as good as that fluency, by the way. But it has been approved in Europe for many years now for treating familial. Emelin COLUMN NEUROPATHY The rial change occurred in 2018 when the attract trial was published in the New England Journal. This was a study that looked at a Phase two trial that looked at 440 patients. They were randomized two doses of the feminist versus placebo. We looked at both wild type patients and familiar patients, and we follow them for 30 months. The primary endpoint was a true cardiac and all cause mortality and cardiovascular hospitalizations. Secondary endpoints were all cause mortality ANDAN There was another endpoint. The quality of life measures thes were really hard time efficient. They were class one to class three, but they had to have been hospitalized for heart failure. We're on significant doses of diuretics and their medium probe NPL that was quite high for heart play, with dejection crashing. Their levels were about 3000. These were the key findings. There was a highly statistically significant and very clinically relevant reduction in the primary and again all cause mortality and cardiovascular hospitalizations. The number needed to treat to get to one of these outcomes was only 7.5 patient. That's far better than most other heart failure therapies that we have. There was also a reduction in all cause mortality. This became apparent was 30% became apparent by 18 months and quality of life measures were also better in the famine ist group versus in the placebo group. Although on then we also look at some exploratory measures looking at biomarkers and eco parameters that didn't pan out. But certainly at first glance, this is a markedly positive trial and was very generated a lot of exciting. There are a couple of key points, though that I need to make about two families. This is not a cure. In fact, these patients, even on drug, continued to get worse with time, although at a slower pace than their placebo counterparts. So this again doesn't cure the disease. And secondly, when we broke the patients down into the less sick versus the war sick, the class 123 patients versus the I'm sorry, 1 to 2 patients versus the Class three patients. What we found is that the Class three patients there was only a trend for increased a decrease in mortality, and they were actually more likely to be hospitalized onto families. And then we're on placebo now. There are a number of reasons we could explain this finding, but the point is, is that this drug works best when you get to patients early. And as patients get sicker and sicker, the effect of the drug becomes muted may not work at all of the sickest of the sick patients. So again, we need to be diagnosing these patients early. Now, what about stopping T tr synthesis? Recall that I mentioned that 98% of the T t. R. The body is made in the liver and the familial form the protein associates on forms amyloid Bibles that deposit needed the heart of the peripheral nervous has been depending on the particular mutation, So by removing the liver, you actually remove the source of union protein. And then, theoretically, you could stop amyloid production. And, in fact, liver transplantation has been used for decades on has been shown to slow the course, particularly the neurologic form of the disease, on stabilize quality of life in patients over time. But there's some problems. Most patients aren't a candidate for transplant that you old, they've got come abilities, and obviously we have organ limitation. Secondly, even after liver transplant, the disease progressive it appears that once you have mutant t P R in your part. Now the wild type T T are from the new donor liver continues to deposit in the heart, although at a slower pace than it would have had you not been Liberatore's. There's also little data in the patients with primary cardiac lena type of the 1 22 eyes, the most common in this country. It's ineffective and advanced disease, and it has no role at all in wild type polio doses. Wild type amyloidosis doesn't have meat GTR replaced with a new liver. This again is the most common form of animal in this country. So, given that other methods of getting rid of transfer written have been at the forefront of development for the past 5 to 7 years and by far the most exciting development both reducing amyloid as well as a concept now for treating a number of other diseases in the long term involves the suppression of transfer written to the level of RNA transcription. There are two leading classes molecules. That's what's called small interfering RNAs. In any sense, all of the nuclear ties and these drugs by a variety of methods could be sent directly to the liver and then bind to either permanently either cleave or otherwise disabled. Translate that messenger RNA. Without RNA, you can't make t t r, and we now know that you can actually reduce the amount of circulating both mutant and wild type T tr with these drugs by about 80%. If you don't have any more cheaply are a theory you shouldn't be able to form or family. I mean, this is kind of really a kind of interesting point. This is kind of gene therapy without the Gene Berg, Um, there were two trials, both published in 2000 and 18 million journal. One using a drug called a patisserie and another one using a drug called into tears. Um, um, it looked at neurologic patients that had hard urologic outcomes. They followed him for 15 to 18 months, and the results were pretty astounding. They completely they slowed dramatically, were halted progression of the neurologic disease. And some patients actually began to get better with time. Every subgroup analysis was positive. Every secondary endpoint was met the neurologic form of the disease. This is essentially ah, home run. Um, for these patients and both of these drugs are now FDA approved in the United States. Now, these, um, with neurological runs. Um, what about cardiac issues? Most of the data about these classes of drugs comes from the same study, and most of them are just biomarkers evaluations or imaging studies. There's a post hoc survival analysis, but we don't really have any randomized data. This is data from the patisserie in trial. Um, they had a pre specified group of what they called cardiac patients, it was simply defined as having wall thickness grade in 1.3 centimeters. What you can see is that whose here's my point. Here I seem to have lost my pointer. But on the top portion of the graph, their asses compared Thio Placebo BNP levels fell rather than getting worse on in the Z Bo group. If you look at strange patterns, the graph on the bottom left there. Um, strange states stable over the course of the 18 months but worsened in the placebo group. So I went a little technical issues here. Okay, there we go. And finally Wall think this has actually got a little bit less in the treatment group as compared to staying. Staying in the placebo group there were similar, although not as robust, dated within a person. This suggests that these drugs may have some cardiac effect. However, there are a couple things that we need to think about first. The patients in these trials were not represented mark cardiac patients. They had pro BNP levels of 800 or less. They would not nearly a sick. There were virtually no V 1 22 i patients in these trials again, the most common cardiac education. And there were no wild type patients at all in these trials. We don't really have the data yet on those patients. And secondly, the Onley randomized trial that ever used RNA silencing was done with a drug called Review Sarin. Um, who? Saran, um, was a randomized study that had to be stopped in 2000 and 18 because of an excess of mortality in the treatment group. Now there may have been something wrong with that particular agent, and we're still enthusiastic that these drugs may end out being effective in our cardiac patients. But in the absence of efficacy data and the absence really even of safety data is randomized. Yet their role in cardiac patients is yet to be determined. In that vein, we currently have a pen have three randomized trial, using three different RNA silent through their international studies, and hopefully we'll have the answer for these patients with these drugs in the next couple of years. Okay. Finally, for T t. R realized that all the therapies that I've mentioned so far only hope to slow progression of the disease. Is there anything out there that are Paul Amyloid out of tissue. Interesting. The antibiotic doxycycline, when combined with a particularly really very acid called transit of the optic colic acid, was shown in mouse model to decrease TT. Our deposits in their tissues and there have been on dis is thought to be due to Dr Cycling's matrix of metallic protein. It's, um, in addition properties. There are three phase two trials and GTR that looked at tolerable and possible ethics. See what it seemed to show is that patients seem to remain stable on these drugs, and in many in some cases, maybe there were some improvement in echo parameters. There have also been perspective, retrospective and prospective cases and a L disease, which have suggested and improved early survival in a L disease. Now we actually use Dr Cycling and all of our patients. When we first start therapy and t tr disease, we don't use it as much anymore. We used to, but with all the new drugs and new trials are available, we don't use it nearly as much again. The data is only phase two studies, but it is something that you can consider in patients who are refractory therapy. What about monoclonal antibodies? Um, there was a lot of hope for these. They haven't panned out as well as we had expected so far. Neo D 001 was a monoclonal antibody for a L disease. It didn't hurt people, but it didn't help people. There was an any ASAP monoclonal antibody that would have worked in all forms of amyloid and phase one trials really promising. But it was a really toxic drug, and it had to be abandoned in 2000 and 18. So right now we have one study, one drug in a l. There was a recent phase one trial that chautala, bility and maybe some improvement in strange. There's a Phase two study ongoing and we just completed. We participated in the Pristina PRS four trial. This was a phase one dose escalation trial. It appears that the drug is safe. I don't have all the data and it hasn't been published yet. This drug works by buying the amyloid fireballs, activating our own macrophages and inducing Vegas psychosis. And hopefully there will be a phase three trial for this drug later on this year. Although I have not yet heard from the company to confirm that. Alright, The last section I want to do has to do with the treatment of ale. Amber, we're running a little behind. I'm gonna try and go a little quicker here. Um, remember that unlike TT artisans, remember that this is a disease. Were fragments of light change produced by bone marrow. Undergo a confirmation of change, informed Pamela and multiple organs, with the heart being the predominant Oregon in about a third cases. So the key focus and l disease is to eliminate the production of light chain. There are two reasons for this stuff. One is obviously to prevent progressive accumulation and organs and further organ dysfunction. But the second thing, and possibly more important in the short to intermediate term is that these precursors of amyloid these light chains that circulate in the serum are directly, directly toxic tau myocardial cells similar the way that alcohol could be reversible. Myocardial depressant. When these things were in the serum before they form amyloid, the heart doesn't work as well. So the goal, therefore, is to eliminate the production of these light sheens. How do we do that? Um although it's there's still some debate about this. The best therapy is still thought to be high dose chemotherapy therapy, followed by autologous stem cell transplantation. This results in the deepest responses and longest remissions. It has a good 10 year survival in the right patient, but about 80% of patients who are first diagnosed with male aren't candidates with this. They're too old or too sick they would die with this therapy. So what if you don't treat these patients these next few slides? Airport, Italian? If there's any sign of cardiac involvement all by echo, they living here if they've had clinical heart failure, A list of the nine months this slide puts it another way. This is a simple staging system for the Mayo Clinic that simply looks at BNP levels and troponin levels, and I want you to focus on this stage three patients. If you haven't elevated opponent and BNP on presentation without treatment, you're dead in 3.5 to 4 months. This is an incredibly lethal disease. You'll see. We divide patients into what it called three A and three B. The point is, if you don't get to these people early, they're in big trouble so in that main transplant, indelible patients for 20 years and treated with a combination of aural Mel Flynn and steroids. It didn't work very well. It was a slow onset of action. It could be six months before their light change drop. Onda Genna Siris in 2000 and 10 showed us that the mean survival was a little better, but it was still less than a year. How have things changed? Now we have new first line agents that are far more effective in this disease. The most commonly use agents. The drug called Testament, also known as Bel Cain. This is what's called the Proteus on inhibitor. It stops light chain production in Plaza Sell. It acts early. It gets those light change down early, often within a month. It reduced. It produces deeper human logic responses, and it doesn't destroy patients stem cells. So if their heart gets better because those light change they're gone, they can sometimes be transplant. And again, I want to point out that we talked about untreated. Stage three survived 3.5 4 months at least, the 38 patients the Velcade patients now have about a three year survival that's over 50% so clearly. Much better, however, the sickest of the sick. The three B patients still don't do very well with this drug. They have a survival that even with Velcade based regimen, is less than a year, and many of them die fairly quickly. When we start therapy, we're now using a 2nd and 3rd generation Proteus owned inhibitors were using drugs called in your modulators. You probably heard of Hamelin emitted thalidomide use. Use the second line agents. But most exciting currently is this drug called Dara to the little. This is an anti CD 38 monoclonal antibody that's been approved for multiple myeloma, and we have now extensive case reports as well as good. A lot of political experience that has shown that this drug is very effective in relapse. Emily. Even in patients who have a lot of burden in their bone mouth, it actually really quick it has. It gives you a significant human logic response within two weeks, and it's the most the best tolerated therapy that we have in amyloid today. This hasn't been actually published yet. This is just was presented this year, the European Hematology Association this was called the Drama Trial. It was a Phase three study that combined down into the middle or testament upfront therapy, and the results were pretty pretty fantastic. As you can see with the drug, 53% of people were in a complete remission, versus only 18% without the drug. The likelihood of your heart getting worse was much less if you were on this drug, and about 42% of patients actually had their heart improved within six months as compared to 22% of patients who were not on the drug. This is going to be standard care once the insurers basically actually accept this and are willing to pay for it. Data tube that is clearly going to be up front along, probably with a testament treat choice. And just now we're starting a trial in those sickest of the sick patients with one B patients. The patients who so far don't seem to respond to other therapy. What we're hoping is that because this drug is so effective because it works so fast because it's so well tolerated that it may actually give us some hope for these really, really sick patients. So, in summary, the cardiac amyloidosis, or Siris of different diseases, with the final common pathway being the deposition of a protein nation's material in a variety of organ. It is an incredibly rapidly progressing field with exciting new research, new diagnostic strategies, new treatment modalities that have given this patient population not only hope for the future, but really hope for the present. I want to end basically by just acknowledging Aled, the members of our panel below those program. We have a multi multi disciplinary team based in both president and hop. We have cardiologists. We have he monk docks, we've got kidney docks. We've got neurologists and other other people who play some role as well. We meet every week. We discussed our patients as a group. And again, I just want to thank all these individuals who have devoted a tremendous amount of their time and effort for this, um, very needing and very simple Asian population. And I'll stop there. All right, Brian, that was fantastic. Thank you very much. I'm gonna turn off your screen share. All right. Couple questions for you, Brian. Yeah. The first test to do with and whom should we consider the diagnosis of amyloid. For example, if a patient has worth a static hypertension, we see a lot of patients that have referred to cardiology for that. If we see L v h on the e k g or on the echo, and I'll be honest, I think most of us the threshold for getting an echo is so low now that if you see L v h on the echo, what triggers Further investigation? Yeah. So again, I think we've already said this is this is much more common in these parts. Okay, So some of the things that you wanna be thinking about are some of the other features that are associating with this disease. These disease Excuse, for example. Um, you have ah, elderly elderly man. Okay, again, we're talking mostly now wild type disease, because again, it's much more common than women. Um, had they had carpal tunnel syndrome? Have they had it bilaterally? Okay. Has it been going on for a couple of years? Do you see that? They've got voltage to mass mismatch on their e k g versus directly. Remember? I said these patients don't have to have low voltage, but if you see someone with a 1.6 centimeter wall thickness and the voltage isn't high on their e k g. And they don't have another reason for the messages that COPD patients that should clear and do What's going on? Um do they have, you know, phenomenally, right? Right sided heart failure. Okay. Do they have mawr Dema than you might expect? Um, are they African American? Okay, As I mentioned to you, 3 to 4% of the African American patients are gonna have to be 1 20 talking to our mutation. Um, are there cardiac biomarkers Kind of too high for what you think All the things that we just talked about you clue you in and again, make sure you're doing strain injury. Is there strange pattern? Okay, that's also an important thing. Basically, if they've got reduction global longitudinal strain, um, that's significant. And there it is normal that so it's kind of a clinical distort with a l disease. Um, it's a different issue. They tend to have a systemic process, and they're a little bit trickier to look at because they can masquerade as almost anything but again, the things that we talked about. You know, they have Ortho static. Hypertension is you just said they've got neuropathy that you can expect. It's a clinical issue, but the key thing is suspected, um, and go through the work up. I mean, the work up is fairly, you know, it is fairly straightforward, Andi. It's not really a very expensive work at this point. It's just light chains, and then the next step, I'm sorry. Like changing the next the next. All right. So, Brian, the next question has to do with a l. And with light chains, is there a certain ratio that you use for free light chains? And can a patient with L amyloid have a normal initial screening s pep, You pep like chain evaluation. So there are actually pulled? Well, actually, not screening my slide in my okay. You could go back to screen share if you want to. Okay. It says I am school challenge. Am I well done? Yes. Okay. So if you look here on here, this is what's the normal ratio for, like things. Okay, zero a capital. And the ratio that's less than 1.65 The Katia is that as patients get older and they developed renal insufficiency. This number changes okay, so that basically, you can get a ratio if they've got renal insufficiency that gets closer to or maybe even a tiny bit hired, I would tell you that if you ratio, though, is greater than 2.0, you should at least have a dermatologist look at them to be 100% sure. I don't think that people without the experience of looking at Amazon should make that call it out. But it's a ratio is 1.85 or 1.9 and they've got a creation that's too. That's still normal, but their immune affects. Asians still need to be negative. They are positive you can't do a P Y P skin. Okay, now, if you get a negative, Um, all three of these negative the negative predictive value for L. Emily doses is felt to be greater than 99 eso, you know, unless there's something really, really funny here. And as I said, you clinical situation doesn't doesn't match. You still gotta think about tissue. But if these air negatives, um, you probably don't, you almost certainly don't have with greater than 99%. All right, great. Bryant. Um, next question has to do with anti coagulation. Should all patients, once they're diagnosed with amyloid, be on anti coagulation or just those with atrial fib relation. And the next question is warfarin or a doe AC of the preferred treatment. Um, okay, there is no data at all to suggest using war friend over the direct agents in these patients. We've talked about this at some of our guideline based meetings, and there at this point, although there's no data actually support this, we actually don't recommend one versus the other in terms of anti coagulation of patients in normal Sinus rhythm. If you go back and you look, um, autopsy studies have shown that a not insignificant portion of patients will have thrown bind in their left a tow appendage, even if they're in normal Sinus rhythm. This is mostly in patients with a l amyloidosis. Okay, less so in. Patients with the TT are based disease, and what we usually recommend is is that they have a really diminutive a way on their transmittal. Doppler, Is there a way this is absolutely minimal? Um, there are two approaches. Three approaches that people will take. Some people will just and coagulate all of those patients. Some people will do a TV under those people toe look for the presence of elect atrial promise, and some people will follow the clinic. That said, I certainly have seen patients with L as well as a couple some patients, even with T. T. R. Who have stroked in normal Sinus rhythm from the left atrial appendage clock. What I typically do is that they have a diminutive a wave on transgressive gecko. Is Ali the TV? The market with a l with l. I'll leave the t the Miranda coagulate Don't do that is common, you teat er, because the risk of their cooperation Okay, um, we could try to get through a couple more questions, so maybe we could do in rapid fire here. Brian Thio. Get through them. Um, what percent of patients that have carpal tunnel syndrome or spinal stenosis may also have amyloid? Should all patients, if they're getting a carpal tunnel, release surgery or spinal stenosis surgery? Should those specimens be sent to pathology toe? Look for amyloid at that point? Yeah, that's a very interesting question. And There's actually, um, it's been looked at basically to some degree at the the Cleveland Clinic. The vast, vast majority of patients with carpal tunnel syndrome will not have employed offices. Um, but, um, what we are doing is part of what we're trying to get this together is part of the protocol here is doing exactly that is trying to basically look at every single patient who basically goes to the lab with bilateral carpal tunnel syndrome, sending their specimen off for, uh, Congo red and going from there, I'll tell you that when the Cleveland Clinic did that, um on Lee, even the patients who had Congo red positive in their risk only 10% of them actually had cardiac amyloid when they actually looked. And again, the vast, vast majority didn't have Congo red in the risk. So what we take that, as being is, is that it's one of two things. Either it's an early again. It tends to occur before cardiac disease or it's not relevant. But excellent question. We are looking at that exact question, but the answer is, yeah, it's not a bad idea. Riots in treatment right now is is really best in class one to class to heart failure patients. Um, yet I know we all see patients that the diagnosis wasn't picked up that early and the other presenting with Class three or Class four heart failure. Can you talk a little bit about treatment and those patients and ultimately is transplant bad an option? And how effective are those? Are all of these treatments once you get to Class three and class four, as I mentioned, basically in the in the family's trial, I'm not gonna put up in the interest of time. Um, Class three patients, Um, clearly don't do as well with that therapy. Um, I would say you did not offer to famine is in my class for patients at all. I see that it's really not likely to do anything. It's a $225,000 therapy per year. Um, and there's no data that will do anything in my patients who are, uh, class three. But, you know, sort of like a three. A. If you know what I'm saying, I do offer to them, but I temper their expectations, and the clinical experience honestly has been that once their class three released in my, in my view, that the feminist really doesn't make a huge impact. Life Terms of transplantation? Um, there's a wild type disease, since it's predominantly a cardiac issue with the other criteria. There's good data to suggest that these patients will do well with transplantation. A number of centers are reluctant to do it. On the other hand, um, ailed disease. Probably not for most patients, because it's such a systemic disease. Familial amyloidosis if they don't have a lot of neurologic involvement again, possibly especially the V 1 22 eyes, who tend to get disease in their sixties. That's don't work well with these patients. They've got a restrictive cardiomyopathy with a very small chamber size onda. We tend to have problems with any form of restrictive cardiomyopathy and l values, so we typically do. Not that these patients right? What about heart liver transplant combination versus just just heart or just liver? Well, again, I think liver transplant, as I said was, the was the standard care until we had these other drugs. Um, most people, certainly in the United States, have been shying away from liver transplant with these other two agents that are available. Heart liver is occasionally offered. Um, it's a moving field now, as I said, with these are silencing drugs. But certainly we have done heart liver transplantation and patients who have advanced cardiac involvement on bond on the familial disease. Um, there are some mutations, for example, that have cardiac involvement at a very young ages and Romanian mutation, for example, that causes cardiac involvement in women in their thirties. Uh, they they get heart liver transplant because I also mentioned to you before the data on the predominately cardiac seating type we live. A transportation is not nearly as robust as it is with the neurologic. All right, Brian, two more quick and hopefully maybe these can even be Yes, no. A strain imaging picks up and becomes more routine if a normal, If the patient has normal strain imaging, does that rule out amyloid now? Definitely not. In fact, actually, uh, that trial that I talk to you about from Hopkins specifically showed that the vast majority of people thio biopsy proven disease did not have that April strange habit. No. So that does not really no good. I think that's ah, it's a very important point for folks to understand. Um, next question is, do these patients are have to be bridged with anti coagulation If they have toe to interrupt, Is the risk of clotting that high acumen? And yes, yes, I've risen. Yeah, I know it for the dough acts. I don't. It's kind of hard to bridge. No act quite honestly. Um, but for coming. And yes, I bridge my place. Yes. All right. Fantastic. Brian, that was That was fantastic. Great talk really took a disease that I think a lot of us, uh, felt unclear and overwhelmed with and really nicely summarized it. And I think for the most, cardiologists gave him a nice understanding of what to look for, who to look forward in and how to get the process started. One of the question question I want to make before we is again. I also wanna thank our recent way have a lot of trials here in our research staff here at Penn present as well as the research people in, huh? Have been an enormous help. And I just wanna make sure the big acknowledged as well um way couldn't do anything trials without so thank you for the research people who mayor end up in court. It's Brian real quick. What trials are ongoing right now? Okay, so right now we have, uh, well, the Pristina trial just closed. We have a trial called Apollo B, which is using the RNA inhibitor petit surrounding patients with cardiac amyloid. On top of the feminists, we have a trialing called Helios B, which is using a new experimental RNA inhibitor that only has to be given four times a year in the same patient population. We have a trial for cardio. TT are transformed, which is utilizing third, um, type of RNA inhibitor that has to be given once a month by injection. And we have a try, along with something called the company called Idols that I didn't mention, which is looking at a different, different stabilizing instead of famine. It's basically on we've been utilizing in our patients, for example, can't afford to feminists. Um, it has a similar mechanism of action families. They're all randomized trials. All right, Perfect. Thank you. Everybody for logging in and participating. We'll pick up grand rounds again in September. A za reminder starting in September, our grand rounds will move toe Wednesday mornings instead of Thursday. They'll still be from 7. 30. Day 30 But they will be on Wednesday mornings. Linda, thank you for gonna organizing once again. And you will receive information and a flyer for the fall Siris of Grant Brown starting in September. All right, Thank you. Everybody have a have a great day. And Brian once again, Thank you very much. Fantastic talk. My pleasure.