I want to tell you a little story Paul this is kind of sad it's a little dark oh no all right so Paul recently uh a family member of mine passed away in the hospital he had a heart problem you know we're talking about cardiomyopathy today and uh Paul we needed to perform a blood transfusion in order to save this person and unfortunately none of us knew his blood type and as he was dying Paul he kept out screaming be positive but you know Paul it's just so hard without him yeah I've heard variations of that joke it's solid yeah yeah yeah what what did you find so I found an entire page I'm not going to credit it because it's awful um of puns that I don't understand and there's some Cardiology puns so dating a heart surgeon can be a rhythmatic that's the joke my Cardiology Professor likes to keep an aorta diary I need help okay I'm why that's F can I can I try one it's not gonna be funny that's my disclaimer so you do not have an answer for the AA diary thing this is just you changing the subject because I'm really all right okay so what did the heart with Amal liosis say when it saw the EKG results that's a low amplitude beat what I is that off the Dome or did you find this on a website I'm adjusting uh existing jokes I understand the curbsiders podcast is for entertainment education and information purposes only and the topics discussed should not be used solely to diagnos treat cure or prevent any diseases or conditions furthermore the views and statements expressed on the podcast are solely those of the host and should not be interpreted to reflect official policy or position of any entity aside from possibly cash Mor hos and affiliate Outreach programs if indeed there are any in fact there are none pretty much we aren't responsible if you screw up you should always do your own homework and let us know when we're wrong well audience if you're still with us I'm Dr Matthew Frank Wad and this is the curbsiders tonight we're going to be talking about Amal dois with a fantastic returning guest Dr Michelle kson and uh I would like to introduce America's primary care physician and my co-host Dr Paul Nelson Williams Paul how are you doing Matt I'm great it's nice to be recording again after a fairly long winter break so I I feel like we we shook off the dust pretty quickly and got into it with uh what previously had been a very confusing topic to me and I feel much better about it yeah absolutely uh Dr kson such a great guest Paul before we introduce our co-host and read Dr kon's bio can you please remind people what is it that we do on the curbsiders sure Matt thanks for asking we are the internal medicine podcast we use expert interviews to bring you clinical parols and practice changing knowledge and I'm going to take advantage of the segue to introduce our third co-host for the evening Dr Deb gorth Deb how are you I'm doing well I'm just really thankful that you guys are letting me speak after my horrible Cardiology Pond no that's okay it's just like it's kind of like initiation into a gang you just have to you have to do it it was painful for probably a lot of people yeah okay well uh can you tell us uh about our guest yeah so uh we just had a fantastic conversation with uh Dr Michelle kson she is a professor of medicine at Cedar Cy and the Director of Education heart failure and transplantation in the Schmidt Heart Institute um Dr kson is also the interim editor and chief of the Journal of Heart and Lung transplantation she's on the writing committees for the 2020 and 2024 uh hyper trumic cardiomyopathy guidelines and the 2022 heartfelt year guidelines um she's also on the board of directors uh for the heart failure Society of America I'm I'm really just wondering how she had time to do the podcast uh she also chaired the 2023 expert consensus decision pathway document for the ACC on the multi- disciplinary care of patients with cardiac amaly dois and then her essays and poems have appeared in many Premier Medical journals so in this episode um she teaches how to identify suspected amaly dois diagnose the disease um and then ensure that these patients have an appropriate followup so without further Ado let's get into it and a quick reminder that this and most episodes are available for CME through VCU Health at curbsiders dovc health.org and if you want to sign up for bonus episodes and a whole bunch of other cool stuff you can go to patreon.com Dr kson uh we'll we'll call you Michelle for this recording if that's okay because that's our convention but welcome back to the show uh so excited to have you back actually I am totally delighted to be here thank you for inviting me again and the audience you just missed a hilarious conversation between Paul and Michelle where I thought she was an East coaster which was wrong and Paul said he thinks it's because she looks like she would probably walk very fast it's the smartest thing I'll say the entire episode I I am an East coaster because once an East coaster always an East coaster I might be a West Coast transplant but I am type double A I want everything done yesterday and we talked about how I believe I have a very long stride length to height ratio which is a marker of an East coaster yeah this that feels like that could be like one of those uh end of the year articles is it bmj or Lancet the ones that they do Yes you heard of here first I think so if anyone wants to write that up just uh you know Loop in Dr kson but uh think that would be great it's the kson ratio we we've coined it now yes well uh can you remind that I think they just got a a big dose of your personality but can you remind people like what's a little bit about yourself and maybe a hobby or interest that you have outside medicine besides walking fast which is not a hobby it's a lifestyle and a choice thank you so much so yes I am a heart failure transplant cardiologist in Cedar Sinai Medical Center in Sunny Los Angeles California I love nothing more than taking care of patients and trying to teach others how to do the best they can to take care of patients and what I love to do outside of medicine I have two things number one I consider myself a hostage negotiator because I have three children ages 11 eight and six and my second favorite thing is cooking in fact for Thanksgiving I have a very special spreadsheet to make sure everything is done perfectly and right on time this is the least surprising thing I've heard the inter this this makes absolute sense to me good thank you do you think we can link the spreadsheet in the show notes we got the brownie recipe last episode so yeah I you know I've refined this spreadsheet over decades so yes I would be honored to share it all right uh Paul anything else on your mind before we get to the topic there is Michelle I want to ask because I think it feels like it's been 27 years since we recorded I the book is new and I don't know that we mentioned that or even talked about that pre-recording so I'd love we we'll give you a chance to plug it at the end but I just wanted to hear about how your book came together and sort of what that process looked like cuz I was I was fascinated and excited to hear that you did that well thank you so much so uh on Twitter for many years I've had these hasht kitton rules which is basically anything I might rant on rounds I now disseminate to a larger audience than the six people unlucky enough to have to round with me and many people said you should turn that into a book but I thought a list of Kon rules was not satisfying enough so I made a spreadsheet of all the Kon rules and then I organized them by topic and subtopic and created an outline which then turned into this book book which is based on everything I've learned through bitter experience through the medical school years training and Beyond to take the best care we can of patients amazing congratulations thank you I think that everyone in the audience needs to buy a copy uh hand it out and uh try to live by these rules so you can you know we're you're listening to the show to become a better doctor there's we have rules for you how to do that so this is the book for you thank you and I I I can definitely attest to this I've read it cover to cover and I think um if you have uh family member going into medical school I I definitely wish I had a copy you know when I started medical school I think there's you know pearls for every single stage of your medical Journey from preclinical to clinical to just you know how to be a better physician you made my day thank you so much so let's let's start talking about uh amalis uh Deb did you want to give us the first case yeah I can hop right in so um this case is about uh Mr Smith he's a 68-year-old presenting to your office for a transitions of care visit after being hospitalized for shortness of breath he was subsequently diagnosed with heart failure during his hospitalization uh his echocardiogram showed increased left ventricular wall thickness an EF of 55% and grade two diastolic dysfunction he was found to be in a rate controlled Atri fibrillation his proponent was elevated at 0.5 um though his coronary angiogram showed Norm coronary arteries he received IV Lasix and was started on an sgt2 inhibitor he was discharged on Lasix 40 with instructions to monitor his weight and take his lasx pill if his weight increases more than two pounds every 24 hours so why why would I uh pick this case as a case for amiloidosis so I I love this case I love this case because what we're trying to figure out here is the differential diagnosis of a patient who presents with shortness of breath edema and a normal ejection fraction and when you think about that that's heart failure with preserved ejection fraction by definition but I like to always take a step back differential diagnoses are tricky and heart failure with preserved ejection fraction is a diagnosis of exclusion there's not going to be a sign that waves around saying I'm hepf it's that you have to rule out other things before you get there so when you have your patient with dnia edema and a preserved ejection fraction first ask yourself is it the heart's fault maybe it's the kidney wasting protein maybe it's the liver not making enough protein maybe it's portal hypertension but if you truly convince yourself it's not the kidney's fault it's not the liver's fault it is the heart's fault then you have to say is a garden variety heart failure with preserved ejection fraction more common in women older people those with coronary disease hypertension diabetes chronic kidney disease or is there some underlying cause for which there may be disease directed therapy that may help the patient feel better stay out of the hospital live longer and that's the point here don't stop at hepf figure out is there an underlying cause that could be responsible for the patient symptoms yeah my thinking there is that's going to open the door to so many patients because even some of the patients I've seen with cardiac amaly dois which I guess I I think it's been more on my radar maybe because it's just more on everyone's radar now but some of those patients did have some of the traditional risk factors for you know your garden variety hepf as you said so I was I was surprised um so I'm I'm sure we'll we'll want to get into some of the other historical Clues but can you just remind us like just starting about like what is amiloidosis because probably I need to dust this off I learned this like like very early in medical school and then clinically have not really seen it too much until recently me too I remember that cardiac amalo dois was something you learned about in medical school and promptly forgot because it kind of didn't matter and there's a kson rule don't think about anything that won't change your management but through revolutionary advances in diagnosis and treatment it now matters to make the diagnosis so what is amalo dosis it's a condition where there's a protein that the body produces naturally that for reason we don't understand decides to fold up in all kinds of abnormal config configurations turning into fibral and depositing into tissues the two most common ones you'll find in the heart are a ameloid does L for light chain immunoglobuline light chain like a form of a plasma cell dyscrasia on the Spectrum from mgus on one end to multiple Myoma on the other and the second is at a for ameloid TTR for Trans thyro which is also known as pre-albumin which is a transport protein that Minds its own business until it goes from its happy tetramer form into these very nasty fibral that go into the heart yeah that's you know that's Vaguely Familiar Paul do you remember any of this so you know it's funny because you said this is one of those things we learned about medical school and forgot I'm like I don't think I learn about this in medical school there's a lot I didn't pay attention to medical school I I remember learning about it um I think there was like a mad cow lecture and there was like all sorts of things you know like talking about protein misfolding and I yeah well I mean to be also I'm an idiot like I I heard of you know glary frus I'm like that's a word I've never heard before so it can't be a real thing I probably won't ever have to worry about that again and then you know cut too I should probably learn wor about hariry cell lukem I'm like hairy cell are you kidding me do I really have to know this I'm gonna sound like a little a little nuts if I start talking about that I feel your pain yeah so the AL amiloidosis you know you said there's M Gus all the way on the Spectrum to multiple Myoma um and and that can be that can be present uh for that condition with this uh a at the TTR type of amalo can you talk a little bit more about the flavors of that that exist yes so if you have TTR amalo dois the TTR protein that misfolds into these nasty fibral can come from one of two sources either a mutation in the ttrg that's the variant form traditionally called ATV cardiomyopathy or it can be the wild type just minding its own business until it decides not to and that's the attr wild type in the olden days we used to call that scile cardiac ameloid dois but that hurts people's feelings so we no longer call it scile it is now called wild type trans thyen cardiac ameloid dois yeah so the if you're reading about this uh for the audience you might see like at TR WT and that's the the wild type or ATV or ATM and that's the variant or the mutant version and then sometimes they have a a-h CM for like cardiomyopathy right exactly so okay uh Deb is that is that good for now to set things up do we want to get back to the case or is there more we need to delve into let's get back and uh learn a little bit more about our patient so this was his first hospitalization since getting his tonsils removed at 8 years old previously he saw his primary care physician every few years and he really only takes a baby aspirate for primary prevention of myocardial infrction which you promptly stop because that's so 2009 he has no other medical issues uh no history of high blood pressure but sometimes uh he wears wrist braces to help manage his pain during work as a comor uh he was adopted and he doesn't know any of the medical problems that may run in his family so what are some of the components on of a patient's history that could elevate your um diagnosis of amid dosis in your differential this is so important and the key here is that this amalo fibral just doesn't deposit into the heart it goes to other places as well and the other places it goes are the clinical Clues and red flags to heighten your suspicion for cardiac ameloid dois so you take seemingly disperate findings and you combine them into a satisfying unifying diagnosis so let's talk about this guy we said you know the walls of his heart are thicker than normal but he doesn't have a history of high blood pressure he doesn't take anti-hypertensives he had an elevated troponin yet a normal coronary angiogram is this the waist basket diagnosis of demand eskee that no one really knows what it actually means or there something else causing troponin release from injured myocardial cells and what's the deal with these wrist braces I mean I know he's a carpenter and maybe he's got like a repetitive use thing but he's kind of old for carpal tunnel right at 68 so something funny is going on with this guy thick walls I can't quite explain them he's got this jonin bump and I don't exactly know why and carpal tunnel as I think we'll discuss further we're building a case that everything does not appear as Garden variety as hepf as we might like do you have Deb made the genius point that we should have like a stop bang score for suspicion for osis which I love and I and this I had the same thought some of these things you know because of the comorbidities that run along the American population like we see so much obesity and glucose intolerance and sort of all the stuff that kind of sets you up for hepf in general and also sets you up for polyneuropathy even so I guess how would you rank order or can you even like what things really kind of raise a red flying for amid dois versus what things are you know are sort of classically taught that you can see with it like I think Matt and I were talking about I think it's like lumbar spinal stenosis which I think half my patients have and I don't know like so I guess what what especially raises your eyebrows and then what are the things that are maybe sort of less meaningful to you when you're taking a more extensive history absolutely there's actually a really lovely at cardiomyopathy risk score published in jamama cardiology in 2022 first author DAV senior author Redfield that goes through some clinical factors you can have a Point score that gives you a sense of your clinical suspicion those include age so the older you are so 60 to 70 me over 80 that gives you a lot of points male more than W female men are at higher risk for amalo dois whether wild type or variant form if hypertension is present that works against you because then you have another explanation for why their walls must be thick thick walls is one of them um and also thick a relative wall thickness of the septum and the posterior wall so putting this all together it's it's all about you know so much of medicine is pattern recognition I often start with the LV wall thickness in fact one of my pet peeves and as you probably know I have many but one of them gerain to amalo dois is when you read an echo report and it says left in tricular hypertrophy is present no how do I really know it's hypertrophy it's much more accurate to say increased LV wall thickness because that thickness may be from increased muscle I.E hypertrophy or it may be from infiltration into the muscle and if you say LVH you're basically cutting off many things on your potential differential so when you but if you see increased LV wall thickness the next question is can I explain it in some way and if there isn't hypertension that is a little tingle on your spine and that tingling is not spinal stenosis that tingling is telling you there may be something going on um so the increased El ball thickness the other things are remember where else does it go it goes into nerves what kind of nerves often sensories you get a sensory peripheral neuropathy you can get things like erectile dysfunction you can get an autonomic dysfunction which classically presents as of course light-headedness on standing but even more significant someone comes to you with a little bit of hypertension you decide to prescribe a Vaso dilating anti-hypertensive like otene they come back a week later and they say whoa every time I stand up I think I'm going to faint this pronounced intolerance to vasodilating antihypertensives can be a clue so that's a neuropathy then think about the muscular skeletal Orthopedic stuff where else does it like to go tendon Canal type places so you get this carpal tunnel carpent tunnel above the age of 60 not so common red flag especially if by lateral as you said lumbar spinal stenosis other classic things are the biceps tendon rupture the popey sign you can often see if few an in case series done of patients who present with Lumber spinal stenosis or carpal tunnel undergo surgery take the specimens to the pathologist they see amalo deposition that often predates the cardiac manifestations by six to seven years so that can be a really important clinical clue yeah and there uh in the clinic anal had an in the clinic article in 2023 that was really nice they table two in that has some of the ways that it differentiates Al amid ois from the ATR type amalo and it it's I don't know if you think of it that way because it seems like there's a lot of overlap um if you think of them as being like two distinct entities or if there's um if you have any guidance for the audience about how to think about the differences between those yeah I mean Al amalo remember isn't going to have the same age predeliction TTR is going to be a disease of older people whether it's variant whether it's wild type pretty much everyone's over the age of 16 more like 70s or 80s Al can present at any age and often presents much more acutely thick walls bad heart failure restrictive physiology cardiogenic shock make the diagnosis right away time is of the essence in fact if I get a phone call from a a colleague in the community this is this is a this has happened and they say yeah I've got this patient and I check the the the cat Lambda ratios really abnormal and their hearts really thick and I saw them for heart failure I say Do not pass go do not collect 200 I'm going to see them this week I'm make sure the hematologist sees them this week we're g to get them a tissue diagnosis we're going to get them treatment so I think of them at two very distinct diseases in their demographics presentation and of course their treatment um and and when you think about the classic manifestations that are unique to Al it's the things like the macro glossia or the periorbital perpa that is unique to Al whereas these more Orthopedic findings the biceps tendon the carpal tunnel the spinal stenosis are are classic for the TTR okay and then both of them can have the neuropathy it seems exactly okay great all right I think we're getting somewhere Paul is this making sense to you I'm doing great this is more than I learned in Medical School uh Deb any uh anything we're missing here um in this part like of uh history or any more questions about the history or do you want to move on to another part of the case yeah let's let's uh kind of see what he looks like today he's feeling well uh he deny shortness of breath chest pain and abdominal pain he does say that sometimes he feels woozy when he stands up too quickly his blood pressure is 120 over 80 and his heart rate is 70 beats per minute on physical exam his pulse is regular uh you notice a faint systolic ejection murmur at the right stal border his jvp is approximately 6 cm seen at the clavicle while sitting at about 45 degrees he seems like he's in pretty good shape this you know is a a quick and easy visit um but what are some of the other things that we should be looking for on the physical exam to help us in diagnosing amiloidosis you know I I love this physical exam because as you said on the face of it he seems pretty okay but what doesn't make sense again I'm still stuck on why does he have increased LV wall thickness his blood pressure is fine yet he feels light-headed when he stand if you did orthostatic blood pressure readings you'd likely find a significant drop in his systolic and or diastolic blood pressure that you would not necessarily expect for a healthy 68-year-old Carpenter and that's something you would need to explain other things you could uh look for now you mentioned a little bit of a murmur could it be tic stenosis it didn't sound like a severe aortic stenosis murmur as Echo didn't show one but very interestingly in a case series of patients with severe aortic stenosis who presented for transcatheter aortic valve implantation who underwent amalo testing just a case series let's check all of them about 15% had concomittant TTR ameloid dois because the two conditions coexist in older people and why treat one when you can treat both second really fascinating case series of patients who just presented to the hospital in decompensated heart failure with preserved ejection fraction all got tested for amalo about 15% had TTR amalo doses it's not a diagnosis to miss it's a diagnosis that can hide if you don't think about it you won't look for it uh is it like you said they coexist because you know I think of aortic stenosis is like a dise it's a disease of aging and unless they have like bicuspid valve uh dis disase of Aging is is the ATR like also just like if some people live long enough they're just going to have amitosis and heart failure from it is like or cardiomyopathy from it I think that's exactly right and I I you might have said earlier you feel like you're hearing about it a lot more or maybe seeing it a lot more I do think in in a way the heart failure symptoms are the tip of the iceberg right and we have to be aware of What Lies Beneath and What Lies Beneath from a cardiac stand Point could be aortic stenosis atrial fibrillation highly prevalent AV block need for pacemaker kind of raises your clinical suspicion and the other things that lie beneath think about the the neuropathy sensory and autonomic think about the muscular skeletal Orthopedic carpal tunnel spinal stenosis put these little things together to come up with a story in the context of that increased LV wall thickness that you cannot explain every time you read a review it's this this is a rare diagnosis you know eight cases per million or something like that and then you hear numbers like 15% of hepf cases like wait a second that math doesn't check out and then you I just I wonder if you know what we're calling a rare disease is just under diagnosed which is kind of what it sounds like you're telling us so we we're not finding it until we see sort of the later findings and and probably there's opportunities earlier and it's probably more prevalent than we think I couldn't have said it better myself perfect so let let's talk about um what like what should we what should we doing to work this up like once we get you know we talked about um we we've got an echo uh EKG uh troponin BNP like what what's what should be like the basic workup when we start to suspect this as a primary care perfect I'm so glad you asked so let's talk about the EKG briefly for a moment we all memorized a medical school maybe Paul didn't but I think the rest of us might have that when you had they didn't have EKGs back then no wait I'm way older than you you definitely had EKGs you we memorized in medical school that in amalo doses you have low voltage because of an infiltrative cardiomyopathy so the thick heart isn't caused by increased volt in fact only 30% of patients in one case series actually had classic definition of low voltage but it's very common to have discordant voltage so don't just write them off because the voltage isn't low think about a voltage that's even normal that you wouldn't expect if the walls are the harder thick but here's the thing there's no one physical exam finding history finding or lab test that's going to tell you I need to look for this diagnosis that's what makes medicine exciting right we have to those those unconscious clinical algorithms that put make the tingle on the back of our neck that make us dive in so you're starting with a patient who has the cardiac manifestations dadema thick walls adding together potentially neuropathy type findings muscular skeletal Orthopedic type findings and you take it from there the BNP will likely be elevated the troponin may be elevated but really it's taking these findings from the history and physical to order the right tests and this is the key because it's not a test that will show up on your basic metabolic or your CBC you have to order the specific test to come up with the right diagnosis so let me tell you what test I don't think you need you don't uh absolutely 100% need a cardiac MRI to diagnose am Loy dois cardiac MRIs are useful if you have a broader differential I know there's something not quite right here but I'm not sure what it is my patient has disia an edema and a thick heart I think maybe they have a hypertrophic cardiomyopathy their trono is up and they have heart failure I think they might have myocarditis maybe a sarcoidosis uh maybe a hemocromatosis you know they have a lot of Edema maybe they have a paracardial constriction so if your differentials Broad and I'm thinking hypertropic cardiomyopathy prior cardial constriction restrictive an idiopathic restrictive cardiomyopathy a myocarditis then an MRI is beautifully helpful to really look at that muscle and pericardium but if I'm really honing in right on that diagnosis of amalo dois based on these factors we talked about then there's a very simple algorithm of the right tests to order and to check them in the right order in the right sequence to interpret them appropriately so number one like we talked about Alm oloid doses can be a medical emergency you want to diagnose it as soon as possible get them to the hematologist so they can get the right diagnosis and start therapy so the first test you must begin with is the monoclonal protein screen I remember memorizing in medical school the monoclonal protein screen is the spep and upep no no no spep upep not sensitive enough you must order amuno fixation electroforesis of serum and urine it is much more sensitive for those light chains so you have to order serum amuno fixation electropores urine amuno fixation electr frees and serum free light chains Capa Lambda and the three of those together will be used to diagnose a potential monoclonal protein if a monoclonal protein is present if any of those are abnormal Do Not Go pass go do not collect 200 call your friendly hematologist and say I'm going to need to biopsy something then you and the hematologist can decide what to biopsy but we all memorized in med school ameloid dois fat pad biopsy no no no in fact the surrogate sites like the fat pad and the bone are convenient but they are less sensitive especially for TTR so if they are negative you can't stop there you must go to the affected organ heart or kidney and biopsy that so abnormal light chains the patient may ultimately bu them themselves a tissue diagnosis of an endomyocardial biopsy before you can rest and say they don't have Al but say you and the patient are lucky and the monoclonal protein screen is negative then you may order a technum pyrophosphate scan a nuclear medicine test involves in bone craphy a huge advance in the last decade in the diagnosis of T ameloid does because you can make the diagnosis noninvasively because if you have a positive technum Pary phosphate scan and a negative monoclonal protein screen boom you've made the diagnosis of TTR ameloid dosis no biopsy needed however say you get a little lazy and like oh those monoc proteins are so complicated I'm just going to order my technum scan it's so much easier and it's positive are you done no because 10% of patients with Al ameloid dois can have a false positive technum scan so if you take that person with Al ameloid dois and assign them a diagnosis of TTR based on your false positive technum scan what's the median survival of untreated Al ameloid dois it's less than a year you've basically killed the patient right so we have to always make sure that you never interpret your technician pyrophosphate scan with in out of the context of the monoclonal protein screen but if you're very lucky and your monoclonal protein screen is negative and your technum scan is positive then you've diagnosed TTR and then you're going to want to know what their genetic testing shows do they have variant versus while type because that can affect Cascade screening of first-degree relatives and also certain therapies only currently approved for the variant form most important variant to know about v122i v122i is present in 3.4% of black Americans that does not mean that 3.4% of black Americans are all going to get TTR amalo dois there's variable penetrance expressivity but that's an important clue on your history and your physical and your family history when you're coming up with the diagnosis I want to go back uh to the technum pyrophosphate scan because I I hadn't really known what that was and they give you these when you look at the algorithms it says like if it's a score of zero or zero to one that's sort of less convincing if it's two or three that's more convincing but I can't remember if it's was the ACC guideline one of the things I was looking at actually showed pictures of it where basically they're looking at like how much is taken up in the heart and how much is taken up in the bones and if there's more taken up in the heart than the bones that's more convincing and if people look up a picture of it it'll help you remember it uh I don't know if there's anything else you want to say about about that but well you said it so well I hate to woman Spain you but oh please do no it was perfect you're looking at the relative brightness of the heart versus the bone grade two same brightness grade three heart is more brightness that's considered positive okay and when in doubt I'll often have my favorite cardiac radiologist over read a study if if I'm not sure but it is kind of not rocket science which which one's brighter okay and all right so that's so that's sort of you know Paul I think I can I can handle that that s SPF UPF immun fixation electroforesis of the serum and urine and then uh you know don't order the technum pyrophosphate scan unless we already have gotten the you know that we're looking for that like Al amitosis first because you don't want to get a false positive on the technum scan as you said I think we could do that Paul yeah I can I I mean I can say with confidence that I have not misdiagnosed osis with the teum pyrophosphate scan so that's that's one thing I can feel pretty good about uh and the genetic test um can I ask Michelle when you send somebody for the technum pyrophosphate scan that comes back positive and you're concerned for the TTR type are you sending them to a geneticist to to oversee the testing it seems like it'd be pretty specialized to be able to counsel people about multiple variants right cuz there's wild type and then there's lots of variant yeah you know it's a good point there are certain times when I think a genetic counselor is like a th% uh essential and there's times when I don't think it's as important so if I'm have someone with a dilated cardiopathy non-ischemic cardiopathy I'm sending a panel of I don't know hundreds of genes and I know the patients going to come up with some that are maybe pathogenic or likely pathogenic but then there's going to be that huge swap the variance of undetermined significance and no one knows what they mean or what to do it I often like to have the patient meet with the geneticist beforehand to prepare them for the uncertainty and then once the tests come back I have to say that genetic testing for TTR ID is pretty straightforward because I'm only looking at one Gene and it's also pretty straightforward that the pathogenicity of the variance is very well established so they're going to come up with yes you have a variant that causes T TTR amid dois or you don't and there's very well established often geographical and also we often know which ones are more likely to cause a neuropathy and which ones are more likely to cause a cardiomyopathy so when it's the index patient the proband the person who's affected with the disease I find it's pretty straightforward now the tricky part comes with what happens to their first deegree relatives their siblings and Offspring because these people are generally minimum 60 more likely 70 or 80 but what about these siblings and Offspring so siblings often kind of the same deal they're older Offspring is really tricky the current um recommendation if you look at the expert consensus decision pathway document from the ACC published in January on car 2023 on cardiac galid doses it will tell you that if a first-degree relative tests positive they should start screening with an echo cardiogram plus minus biomarkers as the initial screen when they're 10 years younger than when the index Patient First manifested symptoms assuming that there's delays in diagnosis and that way you're going to catch something so if they were diagnosed at 75 you don't even need to be tested till you're 65 but I see a lot of patients who decide to get tested sooner and their 30s or 40s and it becomes quite difficult because there's a lot of anxiety about what may happen and I felt a skipped beat or I I stubbed my toe it could this be amalo and I find that really challenging and we just don't know what to do with asymptomatic Gene carriers we we don't know what to do with them except put a little Alert on your calendar in 2047 that you should come back and get an echo cardiogram so I think that's a major challenge know with what to do when you have too much information yeah that is tough I know what those conversations can be like just in general when someone's worried about something and you don't really have a good answer for them they're just worried about the what if um Paul were you surprised that cardiac MRI was not not an essential test for this like I would have bet so much money that it was like the go-to test yeah I think that's based more I just feel like there's General ambient wild enthusiasm for cardiac amurai or so than thinking about as a specific test for R dois anytime anyone has anything like slightly out of the ordinary with the heart it it feels like from my perspective they're just getting a cardiac MRI not that I'm not the one ordering it either just it just someone orders it you know I feel like I have to step in now or the cardiac I conglomerate may I don't know you might you might not hear from me after this episode so let let me let me talk a little so there are situations where it is helpful like I said first if you have a broader differential I I'm looking for something funny but I don't know what it is like it's a younger patient so you're not not the classic amalo phenotype and you want more hypertrophic myocarditis and other infiltrative disease paracardial constriction the other time it can be very helpful is if you have someone who's been diagnosed with aloid dose based on tissue elsewhere and the hematologist wants to know if it's in their heart because it might change the potions that hematologic potions they give the patient to get rid of the plasma cells in that situation a cardiac MRI is great because I know I have a tissue diagnosis I know it's aloid Doses and and I'm going to give you this super helpful result from a cardiac m i don't have to biopsy something else so I think there are specific situations where it's useful but but if you have a negative monoclonal protein screen and a positive technum scam boom you have made the diagnosis and why waste the resources of our overstretched Health Care system on a cardiac MRI great so we have our patient Mr X he's 68 years old heart failure with preserved ejection fraction apib and we just didn't like the fact that we couldn't explain why he had this increased wall thickness which we're not going to call hypertrophy which implies extra muscle there but uh so we don't want to we don't want to Anchor too soon um so we let's say we've done we've done the testing on him and do we Deb do we want to give him attr or do we want to give him Al amid dois which one did did you wanna I guess we could always start with one and then go switch to the other yeah I think uh his immun fixation comes back negative so then we send him for the nuclear Imaging and that comes back positive so heart lit up more than the bone on the technum pyrophosphate scan yes okay so without a biopsy I'm going to give him a diagnosis of atdr osis and then we let's say we sent him for the genetic testing and I guess we could give him the wild type does if he has the wild type or if he has a variant uh or you know the mutant type is the treatment going to be a lot different can you talk about that yes no I'd be happy to talk about that um do you want me to do a tiny little detour into Al because it's so quick and then we can dive into the meat okay so Al amalo dois which is a plasma cell dyscrasia I tell my patients the hematologist is in charge the hematologist decides Dera cybor D or other things that I have trouble remembering they will quash those plasma cells they will take those light chains away that's their job and as they do that my job is the card ologist is to make sure that your fluid balance is kept as optimal as possible and then the patient's next question to me is well is my heart going to get better and I say maybe if those plas if those free light chains are undetectable there's a possibility six to nine months later or longer your heart may start to improve as measured by less need for diuretics congestion Etc but really Al is all about the hematologist the hematologist is in charge and I am their humble and loyal foot soldier to support the patient along their journey of plasma cell directed therapies now attr in contrast the cardiologist drives the bus captains the ship so we had the most incredible therapy ever for TTR ameloid dois now I mentioned this this revolution in the past decade two revolutions number one now we have non-invasive diagnosis with the technician pyrophosphate scan in the context of a negative monoclonal protein screen and now we have a therapy that works which is why we need to know about it so the treatment is Tous it's absolutely fascinating it takes that happy tetramer of the TTR protein that floats through the body minding its own business and does not allow it to destabilized the fibral that form in tissue so it's a stabilizer it stabilizes the happy Teter and in The Landmark at TTR act trial published in the New England Journal in 2018 they took 44 40 patients with TTR ameloid doses randomized them to teamus versus placebo and found a 133% absolute absolute not relative absolute risk reduction in mortality at 30 months 30 month mortality went from 43% to 30% that's a huge effect size two incredibly important things about this trial number one the survival curves did not separate until 18 months which makes total sense cuz think about it it doesn't reverse what there it just prevents progression so you have to be on it for a while to see the benefit of preventing progression second in subgroup analysis which we all know are hypothesis generating but still in subgroup analyses the less sick you are the more benefit you got which also makes sense because it halts you or at least slows you when you started so the earlier you started the better for the patient so teamus is where it's at it's what we've got it's a super exciting therapy and you can use that for the wild type or the or the variant just n that's correct it's FDA approved for any patient which trans thyro cardiac ID dois and symptoms are there other therapies because I saw you know there's this uh pisan and in in aasan or I'm I'm sure I'm butchering the names but I've seen some of these other ones can you can you talk about those are those as exciting are those U are those being used so and the the types of therapies for TTR amalo doses are very pleasing pathophysiologically because if you got this protein and it's causing trouble what can you do you can stop producing the protein you can stabilize the protein or you could suck the protein out of tissues so we talked about stabilizing the protein with teamus that is the E only FDA approved evidence-based guideline recommended therapy for Trans thyro and cardiac amalo dois now what about these silencers that silence production that's where the pierin and aarin vcin come in these are medications that are mRNA analoges that stop the protein from being produced they have been tested in the variant form with neuropathy and shown to reduce progression of neuropathy and therefore our FDA approved for that indication you got variant you got neuropathy you can be on one of these agents they're subcutaneous or intravenous infusions uh uh VRI the most convenient it's every three months subcutaneous infusion actually eant ton was just approved so now there's four of them on the market variant form with neuropathy but you could say to yourself well this would be very exciting why don't we do a double knockout why don't we silence what's there and any remaining let's stabilize why can't we just give this vcin plus to famus well stay tuned clinical trials are ongoing the Apollo be trial just presented its data was approved proved by the FDA now the Apollo B trial took patients with the TTR cardiomyopathy who had to be on defam you couldn't withhold it it's FDA approved and also randomized them Placebo control to peeran the end point was six minute walk distance at 12 months and if you look the six minute walk distance went down in both groups it's a progressive disease it went down less if you were on pierin the FDA decided they were not impressed and did not approve it I think that was probably the right decision I don't know if the juice is worth the squeeze give someone an IV infusion that costs tens of thousands of dollars every three weeks so that at the end of a year they walk a little farther than they would have otherwise but still less than they walked before but don't lose hope because there are clinical trials ongoing with more uh harder end points cardiovascular death hospitalization those results should be out in 2024 2025 so remains to be seen whether this will be helpful a silencer like pierin implantar vcin in addition to the current FDA approved evidence-based guideline recommended to famus but the silencers as of right now they're they're just for variant form with neuropathy uh they're not they have not been shown to benefit the cardiomyopathy so far that's exactly right do we have like 30 seconds for me to talk about a therapy on the horizon that is so interesting sure if I put it that way how can you say no we would never say no so we talked about this path this pleasing pathophysiological array of therapies you g to stop the protein from being produced a silencer you can stabilize the happy tetramer stabilizer or you could suck it out of tissues not ready for prime time but a fascinating Phase 2 trial in the New England Journal in 2023 took patients with TTR ameloid and gave them a monoclonal antibody that only binds to fibrils and causes antibody mediated phagocytosis another thing we all forgot about from medical school and if you give this to patients and then you do technum scans or MRIs it looks better after receiving this therapy it can reverse disease so there are phase three trials that will be ongoing I'm super excited when you call me back as a guest in five years we'll talk about that yeah that reminds me of course of like the you know the uh Alzheimer's trials and and you know we're still looking there to see how how much it works but uh but they have been able to show there that the the amalo it does seem to reduce amalo we're still waiting to see like is it soon enough to provide the clinical outcomes we're looking for so I'm hoping in the heart it is successful for those hard clinical end points like you said because six minute walk distance is like not a hard Clinic endpoint necessarily but uh I mean I could not agree with you more I I have a a rule in fact that the road to bad outcomes is paved with plausible pathophysiology surrogate endpoints and wishful thinking so you're absolutely right we need hard like that um I I think we have to talk about the cost of teamus I mean the you know when it was first uh there's there's like Journal watch covered it when it first came out in uh and they were saying it was 225 $5,000 a year what what does it look like to get that approved for patients how are people affording it can you talk to that so important I think that gets to one thing I'd say which is how do you know when to send the patient to a specialist and I think that's one of the reasons sadly one reason is you got a monoclonal protein screen that you can't interpret or an equivocal technician scan you don't know what to do with it another reason might be you want the patient to have access to clinical trials find an amalo specialist but one of the reason reasons practically is that the paperwork to get it approved is so onor that you just want to send them to a specialist to have them take care of it and in fact we have one nurse in our office God bless them whose job is essentially to fill out def Fist and January is a big month I think I did 36 signatures today and it wasn't for 36 patients because there's a stack of papers you need to fill out um and it's often it's a game I think one plays but between the insurance company and the patient assistant programs to work your hardest to get it at an affordable amount for the patient have I had patients who cannot afford it yes have I had patients who ask for the 80 milligram formulation which is 20 420 milligram pills instead of the 61 milligram one tab they're both the same efficacy but they ask me to prescribe the 80 milligrams is 20 milligrams tabs it could take less to make it last longer to stretch their dollar further absolutely I've had that happen the third option is defail which is an nsid which might have some stabilizing properties never tested rigorously in a randomized trial in cardiomyopathy but can be used instead I think it's a sad comment on the medical pharmaceutical industrial complex that none of us can solve our dedication is to each patient sitting right in front of us but hopefully as a community we can do better in our patients the the in the clinic article mention things like doxy cyclin curcumin ratol you know some of these things that are presumably much cheaper than uh teamus is that anything that people are using or are your patients sort of finding these on their own I'm sure they're reading things online and what do you think about those we don't they don't work they don't have we don't have evidence they work it's like one of my mentors in medical school said you taking a multivitamin a day in a developed country just makes expensive urine I mean I I don't know what you're what we're doing with these supplements um if someone can afford to famus teamus is the is the only evidence-based FDA approved guideline recommended therapy these other things I say if it makes you feel better to take other stuff I'm happy for you to take green tea a toot cut TCA a supplement um but I just don't have any evidence it truly works Michelle can I ask for so to Fus is probably the one we we're most likely to see out in the wild I'm going to guess at least for right now as a primary care doctor I am unlikely to be prescribing it um or even you know it's it's one of those things the patient can arrives at my doorstep already on the medication or they're prescribed for them but what should I be looking out for in terms of like side effects monitoring and sort of just sort of checking in on the patient seeing how they're doing on the medication like what should I know about it because it's almost certainly be prescribed by someone who actually knows what they're doing well listen primary care doctors know what they're doing you could just you could say some weird thing to me like straight leg raising test and I'd start crying right now because I don't really know what I'm supposed to do with that information so listen you know way more than I do okay so defus is the best it's the best because it's a targeted medicine all it does is stabilize the TTR Teter so there are no side effects I've never had a patient have an side effect for which they had to stop definis and in the clinical trials there's no big signals that come out that defus causes X Y or Z doesn't affect the liver it doesn't affect the kidney it it doesn't cause ration is GI upset basically it's a set it and forget it medication hallelujah it's nice to have one of those the main side effect is poverty it sounds like but that's something I can't but you know what you rais a good point though what else should a primary care doctor know about a patient coming to them with cardiac amid dois let's talk about guideline directed medical therapy for heart failure I mean everyone knows the four pillars of guideline directed medical therapy for Hef ref the Arie Ace or ARB the evidence-based beta block the mineralic cortico antagonist the sglt2 inhibitor then we know for Hef PF we think about the sglt2 inhibitor plus minus the mineralic corticoid antagonist how does that translate into ameloid dois I'm going to tell you two important things think about the pathophysiology of a restrictive cardiomyopathy what's the major malfunction you have a fixed stroke volume if you have a fixed stroke volume and you try to afterload reduce them vasod dilate them in a normal heft ref heart if you vasod dilate the stroke volume goes up and the heart's happy and the cardiac output's great if you have a fixed stroke volume of a restrictive cardiopathy hepf ameloid and you vasod dilet them the heart gets very confused wait a minute I can't augment my increase my stroke volume so now I just have to get pump really really fast and increase my heart rate to maintain my cardiac output they do not tolerate vasod dilation so all those therapies you may give out of the goodness of your heart no pun intended to your patient may be poorly tolerated if a patient comes to me on Ace Arie ARB and they're tolerating it I won't Rock the bat but at any excuse of symptomatic orthostasis or a worsening kidney disease I will stop those agents second important Point remember that fixed stroke volume it means they're highly dependent on their heart rate to maintain their cardiac output if you blunt that heart rate they're very unhappy so beta blockers which have no role in hepf anyway should be stopped and in fact patients think I am like the most amazing doctor in the whole world when they come to me on a high dose of a beta block R and they feel horrible and I stop it and they feel like a million bucks so two important points to keep in mind that think about amalo doses differently than your heart failure gdmt patient I was actually GNA try to go there with the next question and you anticipated it that's how good you are at this this is great yeah all right so yeah because that that was one of the big learning points for me looking at this was that okay uh I shouldn't be so aggressive with with the medication the vasod dilators the afterload reduction you know beta blockers because uh patients aren't going to tolerate it or might not tolerate it so uh that that's fantastic sometimes I do this thing on the show where I say something totally wrong just so uh Paul can correct me but you can you know you can play that role um so there's no there's no need to anti- coagulate patients with uh um if if I had a patient with amitosis and uh their Chad's vascor was only one and they had cardiac amitosis I don't need and they have aib I don't need to worry about anti- coagulating them because they have a low Chads vast score is would I be doing them a disservice if I didn't put them on anti-coagulation I don't know if you heard that but I just went into atrial fibrillation you're Li put me into atrial fibrillation okay this is what you got to remember patients with amalo doses are at very high thrumbo embolic risk you anticoagulate them regardless of their chatu vascular there's three conditions I can think of off the top of my head where you should anticoagulate a fib regardless of chadu vascor I can think of amalo dois hypertrophic cardiomyopathy and a prosthetic valve if you have those conditions and I'm saying bioprosthetic because mechanical you'll be anant anyway if you have any of those three conditions don't do the Chad vas don't pull up the app just put them on a Doak okay and this was because when they were studying patients uh with amiloidosis they were just finding uh cardiac thrombus and it didn't correlate with the Chads vascor so you can't really use the Chad's vas score in these patients okay exactly now the the other part what Deb was bringing up is just sort of symptomatic management like what El what else are you commonly having to manage and what as primary care what else should we think about managing other than the heart when in patients with amid dois one of the most challenging things is the neuropathy and the two types of neuropathy you have the sensory and then the autonomic so sensory or or any type of neuropathy if you have the variant form you can send them to the neurologist the neurologist will prescribe rcin and plin one of the silencers that can reduce progression but if they have the wild type form then they're stuck with the stuff we give um Gaba pentin pre Gab in tricyclic antidepressants delatine the stuff you give for neuropathy anyway but I think the autonomic dysfunction is even more challenging these patients may need things like madrin Fluor cortisone uh do droxidopa abdominal binders compression hose and here where's I find it the most challenging is they have this thing where they have a very narrow therapeutic window of uolia so they're a little bit wet and they're super short of breath they're a little bit dry and they're going to faint so what I tell patients is diuretic therapy and amalo doses or any restrictive cardiomyopathy really is not a set it and forget it it's a you will figure out the right dose for you what do you like better a little bit of swelling or a little bit of light-headedness and titrate your own diuretic accordingly and so I think as primary care physicians one should feel imp EMP powered when it comes to a condition like amalo doses to let the patient be your guide on what the right medications are for them like to fam is fantastic will reduce hospitalizations increase survival but when it comes to the other stuff you're not too happy on the gdmt get rid of the gdmt the diuretics you not show the right dose figure it out through trial and error because really the patient will tell you tell themselves what the right dosages are so I think we need to get the take-home points uh this is has been really fantastic um if the audience were to remember just a couple things what would you want those to be so remember the three challenges your first challenge is to have a high index of Suspicion in the face of clinical clues why are the walls thick why do they have a neuropathy why do they have carpotonal spinal stenosis number two order the right tests in the right sequence remember to rule out your monoclonal proteins with amuno fixation electr freees not just spep serum urine serum free light chains if abnormal tissue is the issue if normal then you're allowed to order your technician pyrophosphate scan and number three order the right therapies to famus and be cautious with the guideline directed medical therapy let the patient be your guide okay and then where can people find your book uh can you tell tell us a little bit about that and and where can they find it yes so the book is based on the wisdom that I've learned from my mentors as well as my own mistakes and life is too short to make all your mistakes yourself learn from others so that's why you should read my book um you can find it on the Springer website you can find it on Amazon or wherever fine online books are sold thank you uh we'll we'll definitely think of a reason to bring you back in the future because you're the best and uh we you know this this has been a lot of fun uh Paul any last words just general thoughts no this was terrific I it's it really helped frame a topic that I've often struggle with and feel kind of nebulous that this was this was great thank you this has been another episode of the curbsiders bringing you a little knowledge food for your brain whole yummy that dead that was your time to shine still hungry for more join our patreon and get all of our episodes add free plus twice monthly bonus episodes at guidelines and news in Internal Medicine and we're committed to high value practice changing knowledge and to do that we want your feedback so please email us at ask curbsiders gmail.com we also appreciate if you subscribe rate and review the show on YouTube Spotify or apple podcast it really does help other people find the show a reminder that this and most episodes are available for CME for all health professionals through VCU Health at curbsiders dovu health.org the special thanks to our writer and producer for this episode Dr Deb gor and to our whole curbsiders team our technical production is done by pod paste Elizabeth fro runs our social media Jen wad is in charge of our patreon Chris the chum man Chu moderates our Discord and Stuart Brigham composed our theme music and with all that until next time I've been Dr Matthew Frank W and I have been Dr Deborah gorth and as always I remain Dr Paul Nelson Williams thank you and goodbye a