Chapters Transcript Video Amyloid Everywhere Alright well thanks so much and thank you for attending and thank you for inviting me. So my talk today is amyloid everywhere. Full disclosure, I have no disclosures. My agenda today is to kind of explain what it is, why it's important. A screen protocol. A briefcase review and then treatments. So what is it? So really there's two maybe three types of cardiac amyloid involvement. There's L amyloid which is a game apathy kind of falls more within the oncology realm and there's T. TR amyloid. T T R. Is just abbreviation stands for a transform written. This is a touch more synthesized by the liver and it's used to bind and transport and hormone and retinol binding protein within the systemic circulation. However, in this dysfunctional process and T TR employees is actually a systemic disease where there is a destabilization signified by one here into unstable monomers and those monomers then misfold and then they aggregate into insoluble fiber, ALs and the insoluble fiber is actually deposit within tissue and they call this dysfunction. So two types of T. TR amyloid that we see. There's a wild type formerly called C. Now and there's the hereditary type formally called familial. The wild type is the a mutated form is connected to advanced aging. It's much more common than hereditary variant, possibly up to 24% of patients. And they've actually found in one in five octogenarians on autopsy had had cardiac amyloid of the wall type variant. The hereditary variant is a familiar kind. It's also more dominant. The mutation can result in a syndrome of the heart and nervous system. It can be predominant cardiac it can be predominant nerves or it can be a combination thereof. It actually stems from over 100 potential mutations in the T. T. R. Gene. The most common variant involves the substitution of veiling for I solution at the code on position 1 22. Formerly it was called V 1 22 I. However, recent nomenclature changes have now called A V 1 42 I. And actually 3-4% of African Americans are Gino positive for this. There are other mutations as well that have a ethnic flavor. Early V. 50 Met actually affects younger female patients of Portuguese or japanese descent and it's predominantly neuropathic symptoms they experience late onset V. 50 Met affects middle age, mostly men of Swedish descent and has mixed symptoms. V. 1 42. I as we discussed just a second ago, affects usually males above the age of 60 of african american descent and has mixed symptoms. T. A. T. A. Is primarily middle aged patients, usually of irish or english descent and actually has mixed symptoms as well. And then the wild type or the former C now variant usually affects patients than age 70. It's male predominant. It can affect any ethnicity and it has mixed symptoms as well. So what is it what are the manifestations of this? What should I be looking for. So because it's systemic and because it can deposit within a number of organs. It's really based on where the fibers deposit. So cardiac manifestations can include myocardial dysfunction. Initially that may look like diastolic dysfunction. That progress is too restrictive physiology and eventual systolic heart failure. You can see conduction abnormalities, brady arrhythmias. Heart blocks tacky arrhythmias and then value disease as well. The classic is this calcified aortic stenosis neurological symptoms have a tendency to fall into two categories. That's the peripheral neuropathy here we see prestige and weakness and that's due to small fiber destruction with this we may see medium Europa. These we can see single cranial neuropathy. We see plex open these and usually the classic is a spinal stenosis. And then we also see autonomic dysfunction. These patients have Ortho stasis Ortho static hypotension. They're very intolerant of traditional blood pressure medicines and they're very intolerant of G. D. M. T. We see postprandial diarrhea alternating with constipation, gastro praecis urinary retention and continents. And even erectile dysfunction. And then other manifestations include bicep tendon rupture early hip and knee arthropod these you can see early renal disease out of proportion to their age. And then we also see hepatic abnormalities transit low albumin levels. So why is it important. So the population of the US is about 328 million people and one in five patients one in five people will experience heart failure over the age of 40 half of all those patients have that heart failure have. Then we should be concerned because dr Redfield from Mayo did a study where they took all patients that were sent to them for evaluation and they found about 24% of those patients actually had underlying wild type or C. Now t tr amyloidosis. And then further a group in Colombia. Actually looked at their patients above the age of 65 being evaluated for severe stenosis for tavern and they found that 16% of those also had amyloidosis. In addition the african american population is about 42 million in the U. S. And if 3 to 4% of those patients are gino positive for one V. 1 42 I that really equates to about 1.5 million people that could be geno positive? So taken together this is potentially to two million people that should be screened and we're probably missing. Take into context in our area, the population in the Hampton roads is about 1.7 million. So it's about 400,000 patients that could be affected by this disease process. So now that we've talked about why it's important now it's important to figure out how do we screen these patients? So it really starts first with the history. So does the patient have a history of heart failure. Do they have neuropathic symptoms? Do you have a family history of neuropathy, heart failure or sudden cardiac death? The next step would be getting E. K. G. Do you see low voltage. Do you see cedaw and function patterns And then lab tests we get a troponin nt pro BnP renal function tests and liver function test. The next step is if you're still concerned we should get an echo and some echo findings that should be concerning for Emily doses would be an LV thickness greater than 1.4 centimeters. A loss of global engineering strain with a pickle sparing the cherry on top, low tissue velocities and even pericardial effusion. And at this point we have enough data to try to figure to try to understand. Could this be emulate or not? Could this be something else? And a few of the differentials would be fabric these HCM constrictive pericarditis or even hypertensive heart disease. So if we think it could be something else, then at that point we should get an MRI. Now with the card memory there are a few findings which would be concerning for amyloid and that would be elevated T. One values. You may see increased extra cellular volume fraction. You may see LG or late gadolinium enhancement and you also may see abnormal gadolinium kinetics meaning when they do A. T. I. Scout. Oftentimes the blood pool should null before the myocardial um if you have amyloid because it has all these crevices it can actually know before or at the same time of the blood pool? If we don't think it could be something else then we should screen for a while amyloid and that includes serum free light chain assays, serum and urine immune fixation that's positive. Then this is really an oncological emergency patients with al amyloid 60% will die with. I'm sorry 20% will die within six months. So we should refer to him expeditiously. If that's negative then we should get a technician. Power phosphate scan. Technical Power phosphate scan is a bone photography scan. It actually has a pretty high sensitivity specificity 99% and 86% respectively. However, it does have false positives with Al Ambulance. Hence the reason why we screen them prior. And with your P. I. P. Scan you should always order with spect imaging. We actually I was in a group that published a paper on two patients that was diagnosed with having cardiac amyloidosis. T. TR. But in actuality they had HCM And this happened because it was not a word with this test. And instead of measuring the myocardial, the blood pools measured. And so these patients were falsely funneled into a channel to be treated for T. TR. Amyloidosis. Here we see PHP imaging. Um The scoring itself is based on how much the Myocardial takes up the Tekken Easy. Um And it's called the visual uptake. Score zero is none. So the correct my karma doesn't take up any technology. Um One of the heart takes up some technology. Um But it's less than the value. Two would be the heart is equal to the value and three would be the heart takes up a lot of Tekken Easy. Um And is more than the rib and the sternum or you don't see any ribs or sternum uptake on the left. We see a visual take score zero. We see that the heart is not taking up Tekken Easy. Um We see the sternum is very bright white and to the right we see visual uptake score of three where the heart is very bright. We don't see any of the rib and we don't see any of the sternum. So at this point your P. I. P. Scan will give you a visual uptake score. A score of two or three was considered positive. And now we think this patient has t tr amyloidosis is confirmed by the P. Y. P. Scan. We should do genetic testing. If it's negative then we need to reassess and most likely they will funnel them back into getting an M. R. I. If they had not had an M. R. I. To begin with in a biopsy. So there's there's a screening caveat though because 30-40% of elderly patients with wild type actually have em just as well. And a amyloid famous Dr. Dan judge actually says that stands for must go under skin. So at this point you need to confirm with a biopsy. So I have a few cases to talk to you about. Mr. C. Mr. L. And misty. So Mr C. is a 62 year old African. American male. He was referred for evaluation assurance of breath. He has a history of bilateral carpal tunnel syndrome, spinal stenosis, lower extremity neuropathy and hypertension. MR L. Is 68 years old. He's an african american as well. He was referred for evaluation of shortness of breath. He has a history of hypertension, carpal tunnel syndrome and spinal stenosis, misty is a 64 year old african american female. She was also referred for evaluation of dis miA. She has a history of diabetes, hypertension, carpal tunnel syndrome and renal cell carcinoma. The underwent lab testing we see MR. C. Has abnormal findings in his cardiac biomarkers as well as an abnormal liver function test. But we see MR L. And misty have normal values. Looking at the E K. G. Mr C has low voltage. He has a pseudo infarction pattern. Mr L. Has left ventricular hypertrophy on his E. K. G. And misty has a normal E. K. G. On echo. Mr rossi has severe diastolic dysfunction except the wall thicknesses of 2.1 centimeters, which is very thick in a decreased G. L. S. Mr L. Has malady systolic dysfunction has set the wall thickness at 1.4 centimeters and he has normal G. Ls and misty has a completely normal echo here is Mr imaging to the left. We see is free to the right. We see a scan here. We see at the top of the T. I. Scout we see right here that the myocardial in the blood pool. No at the same time at the bottom we C. L. G. E. That's very diffused and throughout the L. V. And the R. V. And then we see as P. Y. P. Scan on the right here with a visual uptake score of three. Mr Els imaging. However, if we look at the T. I. Scouts of his M. R. I have normal blood pooling on the bottom. We see a very slight subtle LG in the bottom here by the arrows. But we see his skin is actually very positive. Two is probably a two or three for visual uptake score and misty completely normal M. R. I. And completely normal P. I. P. Scan with a visual uptake score of zero. So with this our next step is genetic testing. So all three patients were positive for V. 1 42. I. Mr SEO's Hamas. Agus mr L. Was hetero saugus and misty was Hamas Agus. What's more interesting actually is the fact that Mr C. Mr mr El misti are brothers and a sister. And so actually we published this as a case series about the fanatic spectrum of T Tr within a family. Um a few papers have actually examined this. So homosexuals men have a tendency to have symptoms 10 years prior to heterosexual men and the symptoms tend to be much more severe women also tend to have less symptoms or completely asymptomatic regardless of their inherent pattern. And then because it's also dominant even in the asymptomatic woman it's gonna be very important for family screening and planning moving forward. So next we'll shift the treatment. These patients, as mentioned are often intolerant of traditional G. D. M. T. In diaries. Is and this is due to restrictive physiology, fixed stroke, volume and autonomic dysfunction rate Control medicines may cause bradycardia especially with al amyloid. They can actually bind to the amyloid fiber ALS and cause significant brady arrhythmia. And then there's no evidence for stds in this population. Specifically fibrillation. Um These patients are intolerant of FM and it's really important to get them out of a fib and to keep them out of FM. The Chaz vast scoring system has never been validated for this patient population. So we always into coagulate and then no studies have looked at that warfarin versus no back to back and then further if you're gonna get the patient if you're gonna cardio the patient out of a fib maybe you should always do a T. 11 study out of mayo looked at a case series of patients and of patients with a fib and Emily doses when they did a. T. 33% of the patients had left atrial rhombus And of those, 33%, actually were found to be therapeutic during the four weeks leading up to the cardioversion or they had documented a fib within 48 hours and then also with cardioversion you should be ready for a complication. These patients have a higher risk of VT and VF. They have higher risks of brady arrhythmias requiring pacing and even stroke. So those are traditional treatments. Um now we're gonna talk about disease modifying treatments as the last part of the talk um you know really the history of this disease, there's been nothing that we can that we can do to really to change their course. And that really changed in 2019 with the first medication that was approved by feminists. That was that was very recent. So here we have picked a gram of the production of a dysfunctional T. TR. So to the left we see the liver, we see it forming this te trimmer of T. TR that breaks apart into these old Amir's which then become fiber ALs and then they deposit within the tissue themselves. There are three main categories of treatments that are focused on this T. TR process and it's based on where they act. So the first R. T. Tr silencers. The first two are, in a sense, illegal nucleotides or A. S. O. S. And they bind to M. R. A. M. RNA to decrease the protein expression and that includes the first generation nutrition and the second generation A. K. C. A. A. K. C. A. They actually added a conjugated ligand to improve with potency while actually reducing the amount of side effects. The 2nd 2nd class of medications within this group are participant and veteran sarin and their small interfering RNA silencing RNA and they prevent protein synthesis. The next category of medications act as stabilizers actually just back up for one second. So T tr silencers have been shown to actually reduce the circulating pathological T tr pieces by between 80 to 97% so that they are very very beneficial. The T TR stabilizers include diffuse channel which is actually a an inset analgesic. Originally to feminist which was the original medication that is used in kind of a mainstay of treatment at this point which is a a cell medication in a corner uh which is actually was made using a molecular library where they designed a molecule that had a high affinity to bind into T TR. And then the last group of medications are a little more controversial. Um They include the T. Tr disruptors that includes doxycycline and combined with bile acid derivatives um includes high dose green tea extract. And then this monoclonal, anybody called P. R. X. 004. That's actually designed to bind to a crypto Tope of T. Tr right now, you know defend. This is the only medication that's approved approved for cardiomyopathy. Um On the other side of things with the neuropathic variant called F. Ap. We have three medications are approved. However there are a number of medications are used off label def definitely call doxycycline and green tea. It is noted that with the neuropathic studies they did for johnson and Patisserie in they actually had a subgroup that showed safety in patients with cardiac involvement. So with that participation has the Apollo be trial that's still pending. They're trying to apply that to the cardiomyopathy variant of it. And then further there's a few other medications that are pending on the horizon A. K. C. A. And the cardio transform in the neuro transform. But with the helios B accordance with the attribute trial. So really what I want, what I wanted to kind of impart on you is that before 2018 there were zero treatments as of 2019. There one treatment and now with the future kind of ahead of us there's potentially six treatments. And then lastly the more controversial possible use of CRISPR for gene editing. So, a few pearls takeaway today have a high level of suspicion for this in patients with Vh neuropathic symptoms. Screen is very important and can be started in your office. But we're happy to help with that. Always order a scan with spect traditional volume management strategies and GMT can be harmful in these patients. Be very mindful of atrial fibrillation and no there's a higher risk of complication and left atrial rhombus and there are treatments that can slow the progression of this disease and many additions in the horizon. So with that I feel free to contact me and email me with questions or any patients of interest. Thank you so much. Published December 7, 2022 Created by Related Presenters Zackary Tushak, D.O. Sentara Advanced Heart Failure Center View full profile
