The Curbsiders (00:00.206) 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, a family member of mine passed away in the hospital. He had a heart problem. You know, we're talking about cardiomyopathy today. And 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 did you find? So I found an entire page. I'm not going to credit it because it's awful. Puns that I don't understand. And there's some cardiology puns. So dating a heart surgeon can be a arithmetic.

That's the joke. My cardiology professor likes to keep an aorta diary. I need help. OK, I'm going to try one. Can I try one? OK, Deb. It's going to be funny. That's my disclaimer. So you do not have an answer for the aorta diary thing. This is just you changing the subject because I'm really. All right. OK, so what did the heart with amyloidosis say when it saw the EKG results?

That's a low amplitude beat. What? Is that off the dome or did you find this on a website? I'm adjusting 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 diagnose, treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of those and should not be interpreted to reflect official policy or position of any entity aside from possibly cash like more hostile and affiliate outreach programs. If indeed there are any, in fact, there are none.

Pretty much we are responsible if you screw up. You should always do your own homework and let us know when we're -

The Curbsiders (02:01.806) Well, audience, if you're still with us, I'm Dr. Matthew Francois, and this is the Curbsiders. Tonight, we're going to be talking about amyloidosis with a fantastic returning guest, Dr. Michelle Kittleson. And 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 feel like we shook off the dust pretty quickly and got into it with a...

previously had been a very confusing topic to me and I feel much better about it. Yeah, absolutely. Dr. Kittleson, such a great guest. Paul, before we introduce our co -host and read Dr. Kittleson'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 pearls 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 pun. 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, can you tell us about our guest? Yeah. So we just had a fantastic conversation with Dr. Michelle Kittleson. She is...

a professor of medicine at Cedars -Sinai and the director of education in heart failure and transplantation in the Schmidt Heart Institute. Dr. Kittleson is also the interim editor -in -chief of the Journal of Heart and Lung Transplantation. She's on the writing committees for the 2020 and 2024 hypertrophic cardiomyopathy guidelines and the 2022 heart failure guidelines. She's also on the board of directors for the Heart Failure Society of America.

I'm really just wondering how she had time to do the podcast. She also chaired the 2023 expert consensus decision pathway document for the ACC on the multidisciplinary care of patients with cardiac amyloidosis. And then her essays and poems have appeared in many premier medical journals. So in this episode, she teaches how to identify suspected amyloidosis, diagnose the disease.

The Curbsiders (04:23.758) and then ensure that these patients have an appropriate follow -up. So without further ado, let's get into it. And a quick reminder that this and most episodes are available for CME through vcuhealth at curbsiders .vcuhealth .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 slash curbsiders.

Dr. Kittleson, we'll call you Michelle for this recording if that's okay, because that's our convention, but welcome back to the show. 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 am an East Coaster, because once an East Coaster, always an East Coaster. I might be a West Coast transplant, but I am type AA. 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. That feels like that could be like one of those end of the year articles. Is it BMJ or Lancet, the ones that they do? Yes. You heard it here first.

I think so. If anyone wants to write that up, just loop in Dr. Kittleson, but I think that would be great. It's the Kittleson ratio. We've coined it now. Yes. Well, can you remind, I think they just got 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 Cedars -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.

The Curbsiders (06:38.2) ages 11, 8, and 6. 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 in the interview. 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 know I've refined this spreadsheet over decades. So yes, I would be honored to share it. All right. 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. 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'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. Because I was I was fascinated and excited to hear that you did that.

Well, thank you so much. So on Twitter for many years, I've had these hashtag Kittleson 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 Kittleson rules was not satisfying enough. So I made a spreadsheet of all the Kittleson rules and then I organized them by topic and subtopic and created an outline, which then turned into this 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, hand it out, and try to live by these rules. You're listening to the show to become a better doctor. We have rules for you how to do that. So this is the book for you. Thank you.

And I can definitely attest to this. I've read it cover to cover. And I think if you have a family member going into medical school, 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 amyloidosis.

The Curbsiders (09:00.014) Deb, did you want to give us the first case? Yeah, I can hop right in. So this case is about 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, 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 atrial fibrillation. His troponin was elevated at 0 .5, though his coronary angiogram showed normal coronary arteries. He received IV Lasix and was started on an SGLT2 inhibitor. He was discharged on Lasix 40 with instructions to monitor his weight and take his Lasix pill if his weight increases more than two pounds every 24 hours.

So why would I pick this case as a case for amyloidosis? So 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 gonna be a sign that waves around saying, I'm HEPPF. You have to rule out other things before you get there. So when you have your patient with dyspnea 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 it 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...

The Curbsiders (11:16.526) point here. Don't stop at HEP -PEPF. Figure out is there an underlying cause that could be responsible for the patient's 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 amyloidosis, which I guess 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 HEP -PEPF as you said. So I was

I was surprised. So I'm sure 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 amyloidosis? Because probably I need to dust this off. I learned this, like, very early in medical school and then clinically have not really seen it too much until recently. Me too. I remember that cardiac amyloidosis was something you learned about in medical school and promptly forgot because it kind of didn't matter. And there's a Kittleson rule.

Don't think about anything that won't change your management, but who revolutionary advances in diagnosis and treatment, it now matters to make the diagnosis. So what is amyloidosis? It's a condition where there's a protein that the body produces naturally that for reasons we don't understand decides to fold up and all kinds of abnormal configurations turning into fibrils and depositing into tissues. The two most common ones you'll find in the heart are AL amyloidosis,

L for light chain, immunoglobulin light chain, like a form of a plasma cell dyscrasia on the spectrum from MGUS on one end to multiple myeloma on the other. And the second is ATTR, A for amyloid, TTR for transthyretin, which is also known as prealbumin, which is a transport protein that minds its own business until it goes from its happy tetramer form into these very nasty fibrils 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 learned about this from medical school. There's a lot I didn't pay attention to in medical school. I remember learning about it. 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...

The Curbsiders (13:32.238) Yeah. Well, I mean, to be fair, also, I'm an idiot. Like I heard of, you know, glomerulonephritis. 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 to, I should probably learn about the kidneys. I that way about hairy cell leukemia. I'm like, hairy cell? Are you kidding me? Do I really have to know this? I'm going to sound like a little, a little nuts if I start talking about that. I feel your pain. Yeah. So the AO amyloidosis, you know, you said there's MGUS.

all the way on the spectrum to multiple myeloma. And that can be present for that condition with this ATTR, the TTR type of amyloid. Can you talk a little bit more about the flavors of that that exist? Yes. So if you have TTR amyloid doses, the TTR protein that misfolds into these nasty fibrils can come from one of two sources, either a mutation in the TTR gene, that's the

variant form traditionally called ATTRV cardiomyopathy or it can be the wild type just minding its own business and the list decides not to and that's the ATTR wild type. In the olden days we used to call that senile cardiac amyloidosis but that hurts people's feelings so we no longer call it senile it is now called wild type transthyretin cardiac amyloidosis. Yeah so if you're reading about this for the audience you might see like ATTR

WT and that's the wild type or ATTRV or ATTRM and that's the variant or the mutant version. And then sometimes they have a dash CM for like cardiomyopathy, right? Exactly. So, okay. Deb, 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 learn a little bit more about our patient.

So this was his first hospitalization since getting his tonsils removed at eight years old. Previously, he saw his primary care physician every few years, and he really only takes a baby aspirin for primary prevention of myocardial infarction, which you promptly stop because that's so 2009. He has no other medical issues, no history of high blood pressure, but sometimes he wears wrist braces to help manage his pain during work as a comparator. He was adopted and he doesn't know any of the medical problems that may run in his family.

The Curbsiders (15:55.982) So what are some of the components of a patient's history that could elevate your diagnosis of amyloidosis in your differential? This is so important. And the key here is that this amyloid fibril 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 amyloidosis.

You take seemingly disparate 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 antihypertensives. He had an elevated troponin, yet a normal.

coronary angiogram. Is this the wastebasket diagnosis of demand ischemia that no one really knows what it actually means or is 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? It's 68. So something funny is going on with this guy. Thick walls. I can't...

quite explain them. He's got this japonin 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 heff -peff, as we might like. Do you have, Deb made the genius point that we should have like a stop -bang score for suspicion for amyloidosis, which I love. And I had the same thought. Some of these things, you know, because of...

the comorbidities that run along the American population. We see so much obesity and glucose intolerance and all the stuff that sets you up for HEP -PEP in general and also sets you up for polyneuropathy even. So I guess how would you rank order or can you even, what things really raise a red flag for amyloidosis versus what things are classically taught that you can see with it? I think Matt and I were talking about it. I think it's lumbar spinal stenosis, which I think half my patients have. And I don't know. So I guess what...

The Curbsiders (18:05.198) 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 ATTR cardiomyopathy risk score published in JAMA Cardiology in 2022, first author Davy, 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 men over 80, that gives you a lot of points. Male more than female, men are at higher risk for amyloidosis, 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.

and also thick, a relative wall thickness of the septum and the posterior wall. So putting this all together, 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, germane to amyloidosis, is when you read an echo report and it says, left ventricular 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 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. So the increased LB wall thickness. The other things are, remember, where else does it go? It goes into nerves. What kind of nerves? Often, sensories. You can get a sensory peripheral neuropathy. You can get things like erectile dysfunction. You can get an autonomic dysfunction, which classically presents...

The Curbsiders (20:19.886) as of course lightheadedness, outstanding, but even more significant, someone comes to you with a little bit of hypertension. You just decide to prescribe a vasodilating antihypertensive like amlodipine. They come back a week later and they say, whoa, every time I stand up, I think I'm gonna faint. This pronounced intolerance to vasodilating antihypertensives can be a clue. So that's a neuropathy. Then think about the musculoskeletal orthopedic stuff. Where else does it like to go? Tendon canal type places.

So you get this carpal tunnel, carpal tunnel above the age of 60, not so common, red flag, especially if bilateral. As you said, lumbar spinal stenosis. Other classic things are the biceps tendon rupture, the Popeye sign. You can often see in a few, and it's case series done of patients who present.

with lumbar spinal stenosis or carpal tunnel undergo surgery, take the specimens to the pathologist, they see amyloid deposition, that often predates the cardiac manifestations by six to seven years. So that can be a really important clinical clue. Yeah, and they're in the clinic, Annals 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 amyloidosis from the ATTR type amyloid. And it's, I don't know if you think of it that way, because it seems like there's a lot of overlap. If you think of them as being like two distinct entities, or if there's, if you have any guidance for the audience about how to think about the differences between those. Yeah. I mean, AL amyloid, remember, isn't going to have the same age predilection. ATTR 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, restricted physiology, cardiogenic shock, make the diagnosis right away, time is of the essence. In fact, if I get a phone call from a colleague in the community, this has happened.

The Curbsiders (22:23.918) And they say, yeah, I've got this patient. And I checked the Kappa Lambda ratio is really abnormal. And their heart's 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 weekend. I'm going to make sure the hematologist sees them this week. We're going to get them a tissue diagnosis. We're going to get them treatment. So I think of them as two very distinct diseases in their demographics presentation and, of course, their treatment. And when you think about the

Classic manifestations that are unique to AL, it's the things like the macroglossia or the periorbital purpura. That is unique to AL. Whereas these more orthopedic findings, the biceps tendon, the carpal tunnel, the spinal stenosis 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? We're doing great. This is...

More than I learned in medical school. Deb, anything we're missing here in this part, like a history or any more questions about the history, or do you want to move on to another part of the case? Yeah, let's kind of see what he looks like. Today he's feeling well. He denies 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. You notice a faint systolic ejection murmur at the right sternal border. His JVP is approximately six centimeters seen at the clavicle while sitting at about 45 degrees. He seems like he's in pretty good shape. This is a quick and easy visit. But what are some of the other things that we should be looking for on the physical exam to help us in diagnosing amyloidosis?

You know, 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 lightheaded when he stands. 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...

The Curbsiders (24:48.756) 68 year old carpenter and that's something you would need to explain. Other things you could look for. Now you mentioned a little bit of a murmur. Could it be aortic 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 amyloid testing, just a case series, let's check all of them, about 15 % had concomitant.

TTR amyloidosis 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 and decompensated heart failure with preserved ejection fraction all got tested for amyloid. About 15 % had TTR amyloidosis. 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.

Is it like you said they coexist because you know, I think of aortic stenosis as like a disease. It's a disease of aging and unless they have like bicuspid valve disease of aging is is the ATTR like also just like if some people live long enough, they're just going to have amyloidosis and heart failure from it is like or cardiomyopathy from it.

I think that's exactly right. And you might've said earlier, you feel like you're hearing about it a lot more or maybe seeing it a lot more. I do think 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 standpoint 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 neuropathy, sensory and autonomic. Think about the musculoskeletal, 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, this is a rare diagnosis, eight cases per million or something like that. And then you hear numbers like.

The Curbsiders (27:02.318) 15 % of HEPF -PEF cases and like, wait a second, that math doesn't check out. And then, you know, 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 were not finding it until we see sort of the later findings 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's talk about, um, what, like, what should we, what should we be doing to work this up? Like once we get, you know, we talked about,

We've got an echo, EKG, troponin, BNP. What should be 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 in medical school, maybe Paul didn't, but I think the rest of us might have, that when you have We didn't have EKGs. They didn't have EKGs back then. No way. I'm way older than you. You definitely had EKGs. We memorized in medical school that...

In amyloid doses, you have low voltage because it's an infiltrative cardiomyopathy, so the thick heart isn't caused by increased volts. 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 of the heart are thick. But here is the thing. There's no one physical exam finding

history finding or lab tests that's gonna tell you I need to look for this diagnosis. That's what makes medicine exciting, right? We have to have those unconscious clinical algorithms that 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, dyspnea, dimethic walls, adding together potentially neuropathy type findings, musculoskeletal 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 absolutely.

The Curbsiders (29:23.37) 100 % need a cardiac MRI to diagnose amyloidosis. 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 dyspnea and edema and a thick heart. I think maybe they have hypertrophic cardiomyopathy. Their tropona was up and they have heart failure. I think they might have myocarditis, maybe a sarcoidosis, maybe a hemochromatosis.

You know, they have a lot of edema, maybe they have a pericardial constriction. So if your differential is broad, and I'm thinking hypertrophic cardiomyopathy, pericardial constriction, 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 amyloidosis based on these factors we talked about, then there's a very simple algorithm.

of the right test 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, AL amyloidosis 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 immunofixation electrophoresis of serum and urine. It is much more sensitive for those light chains. So you have to order serum immunofixation electrophoresis, urine immunofixation electrophoresis, and serum -free light chains, kappa 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 pasco, do not collect 200. Call your friendly hematologist and say, I'm gonna need to biopsy something.

then you and the hematologist can decide what to biopsy, but we all memorized in med school, amyloidosis, fat pad biopsy. No, no, no, in fact, the surrogate sites, like the fat pad and the bone marrow 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.

The Curbsiders (31:40.622) So abnormal light chains, the patient may ultimately buy 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 technetium pyrophosphate scan, a nuclear medicine test, bone scintigraphy, a huge advance in the last decade in the diagnosis of TTR amyloidosis because,

you can make the diagnosis non -invasively. Because if you have a positive technetium paraphosphate scan and a negative monoclonal protein screen, boom, you've made the diagnosis of TTR amyloidosis, no biopsy needed. However, say you get a little lazy, like, oh, those monoclonal proteins are so complicated. I'm just going to order my technetium scan. It's so much easier. And it's positive. Are you done? No. Because 10 % of patients with AL amyloidosis can have a false positive technetium scan.

So if you take that person with AL amyloidosis and assign them a diagnosis of TTR based on your false positive technetium scan, what's the median survival of untreated AL amyloidosis? 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 technetium pyrophosphate scan out of the context of the monoclonal protein screen.

But if you're very lucky and your monoclonal protein screen is negative and your technetium 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 wild 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 gonna get TTR amyloidosis. There's variable penetrance, expressitivity, 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 wanna go back to the technetium pyrophosphate scan, because 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,

The Curbsiders (34:04.238) 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 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. I don't know if there's anything else you want to say about that, but.

You said it so well, I hate to a woman's plane you. 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. And when in doubt, I'll often have my favorite cardiac radiologist over read a study if I'm not sure what it is. Kind of not rocket science. Which one's brighter? Okay. And all right. So that's sort of, you know, Paul, I think I can...

I can handle that, the S -PEP, UPEF, immunofixation electrophoresis of the serum and urine, and then, you know, don't order the technetium pyrophosphate scan unless we already have gotten the, you know, that we're looking for that, like, AL amyloidosis first because you don't want to get a false positive on the technetium scan, as you said. I think we can do that, Paul. Yeah, I can—I mean, I can say with confidence that I have not misdiagnosed—

with the technetium pyrophosphate scan. So that's one thing I can feel pretty good about. And the genetic test, can I ask Michelle, when you send somebody for the technetium pyrophosphate scan, that comes back positive and you're concerned for the TTR type, are you sending them to a geneticist to oversee the testing? It seems like it'd be pretty specialized to be able to counsel people about multiple variants, right? Because there's wild type and then there's lots of variants. Yeah, you know, it's a good point.

There are certain times when I think a genetic counselor is like a thousand percent essential. And there's times when I don't think it's as important. So if I have someone with a dilated cardiopathy, non -aschemic cardiomyopathy, and I'm sending a panel of, I don't know, hundreds of genes, and I know the patient's gonna come up with some that are maybe...

The Curbsiders (36:23.502) pathogenic or likely pathogenic, but then there's gonna be that huge swath of variants of undetermined significance and no one knows what they mean or what to do with. 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 amyloid is pretty straightforward because I'm only looking at one gene. And it's also pretty straightforward that the pathogenicity of the variants is very well established. So they're gonna come up with yes,

You have a variant that causes TTR amyloidosis 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 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 degree 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 recommendation, if you look at the expert consensus decision pathway document from the ACC published in January on, in 2023 on cardiac amyloid doses, it will tell you that if a first degree relative test positive, they should start screening with an echocardiogram.

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 gonna 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 in 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 bead or I stubbed my toe, could this be amyloid? And I find that really challenging. And we just don't know what to do with asymptomatic gene carriers. 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 echocardiogram. So I think that's a major challenge, you know, with what to do when you have too much information. Dr. Justin

The Curbsiders (38:43.534) 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. Paul, were you surprised that cardiac MRI was 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 MRI. Yeah. Or something about as a specific test for preemolidosis.

Anytime anyone has anything like slightly out of the ordinary with the heart, it feels like from my perspective, they're just getting a cardiac MRI. Not that I'm not the one ordering it either. It's just someone orders it. You know, I feel like I have to step in now or the cardiac MRI.

conglomerate me, I don't know, you might not hear from me after this episode. So let me talk a little, so there are situations where it is helpful. Like I said, first, if you have a broader differential, I'm looking for something funny, but I don't know what it is. Like it's a younger patient, so you're not the classic amyloid phenotype, and you want more hypertrophic myocarditis and other infiltrative disease, pericardial constriction. The other time it can be very helpful is if you have someone who's been diagnosed with AL amyloid doses,

based on tissue elsewhere. And the hematologist wants to know if it's in their heart because it might change the hematologic potions they give the patient to get rid of the plasma cells. In that situation, a cardiac MRI is great because I know that I have a tissue diagnosis. I know it's AL amyloidosis. And I'm gonna give you the super helpful result from a cardiac MRI so I don't have to biopsy something else. So I think there are specific situations where it's useful.

But if you have a negative monoclonal protein screen and a positive technetium scan, boom, you have made the diagnosis. And why waste the resources of our overstretched healthcare system on a cardiac MRI? Great. So we have our patient, Mr. X. He's 68 years old, heart failure with preserved ejection fraction, AFib. 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...

The Curbsiders (40:55.434) So we don't want to anchor too soon. So let's say we've done the testing on him and Deb, do we want to give him ATTR or do we want to give him AL amyloidosis? Which one did you want to... I guess we could always start with one and then go switch to the other. Yeah, I think his immunofixation comes back negative. So then we send him for...

the nuclear imaging and that comes back positive. So the heart lit up more than the bone on the technetium pyrophosphate scan. Yes. Okay. So without a biopsy, I'm going to give him a diagnosis of ATTDR and lydosis. And then we, let's say we sent him for the genetic testing and I guess we could give him the wild type. Does it, if he has the wild type or if he has a variant, uh, 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. 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? Sure. Okay. So AL amyloidosis, which is a plasma cell dyscrasia, I tell my patients the hematologist is in charge. The hematologist decides, Dera -Cyborg -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 as the cardiologist 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 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, et cetera. 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 amyloidosis. Now I mentioned this revolution in the past decade.

The Curbsiders (43:18.478) two revolutions. Number one, now we have non -invasive diagnosis with the technetium 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 tefamidus. 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 destabilize the fibrils that form in tissue. So it's a stabilizer.

it stabilizes the happy tetramer. And in the landmark ATTR -AX trial published in the New England Journal in 2018, they took 440 patients with TTR amyloidosis, randomized them to defamidus versus placebo and found a 13 % 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 because think about it. It doesn't reverse what's 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 our 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 defamidus 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 variant, just any ATTR? That's That's correct. It's FDA approved for any patient with transthyretin, cardiac, amyloidosis, and symptoms. Are there other therapies? Because I saw there's this Patirosan and Inaterosan, or I'm sure...

butchering the names, but I've seen some of these other ones. Can you talk about those? Are those as exciting? Are those being used? Yes. And the types of therapies for TTR amyloid doses are very pleasing pathophysiologically. Because if you've 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.

The Curbsiders (45:42.766) with tefamidus, that is the only FDA approved evidence -based guideline recommended therapy for transthyretin cardiac amyloidosis. And what about these silencers, it's silence production. That's where the patisserin and otiracin and vrutricerin come in. These are medications that are mRNA analogs 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. There are subcutaneous or intravenous infusions. Futriserone is the most convenient. It's every three months, a subcutaneous infusion. Actually, E. plantaricin 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 it?

Double knockout, why don't we silence what's there and any remaining, let's stabilize. Why can't we just give this vatricerine plus defamidus? Well, stay tuned, clinical trials are ongoing. The Apollo B trial just presented its data, was approved by the FDA. Now the Apollo B trial took patients with a TTR cardiomyopathy who had to be on defamidus, you couldn't withhold it, it's FDA approved, and also randomized them, placebo controlled, to paticerin.

The endpoint 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 patisserin. 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 harder endpoints, cardiovascular death, hospitalization. Those results should be out in 2024, 2025. So it remains to be seen whether this will be helpful. A silencer like patisserin and plantaricin and vortisserin, in addition to the current

The Curbsiders (48:08.458) FDA approved evidence -based guideline recommended to faminists. But the silencers as of right now, they're just for variant form with neuropathy. 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. 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 can stop the protein from being produced, a silencer. You can stabilize the happy tetramer, stabilizer, or you could suck it out at tissues, not ready for prime time, but a fascinating phase two trial in the New England Journal in 2023 took patients with TTR amyloid and gave them a monoclonal antibody that only binds to fibrils and causes antibody -mediated phagocytosis, another thing we all forgot about for medical school.

And if you give this to patients and then you do technetium 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 Alzheimer's trials and we're still looking there to see how much it works.

but they have been able to show there that the amyloid, it does seem to reduce amyloid. 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 endpoints, like you said, because six minute walk distance is like not a hard clinical endpoint necessarily, but. I mean, I could not agree with you more. I have 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 endpoints. I think we have to talk about the cost of tefamidus. I mean, when it was first, there's like Journal Watch covered it when it first came out and they were saying it was $225 ,000 a year. What does it look like to get that approved for patients? How are people affording it? Can you talk to that?

The Curbsiders (50:34.126) 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 technetium 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 amyloid specialist. But one of the reasons, practically, is that the paperwork to get it approved is so.

onerous 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 to family. It's in 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. And it's often, it's a game, I think one plays 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, for 20 milligram pills, instead of the 61 milligram one tab? They're both the same efficacy, but they ask me to prescribe the 80 milligrams as 20 milligrams tabs so they can take less to make it last longer, to stretch their dollar further.

Absolutely, I've had that happen. The third option is deflunosil, which is an NSAID, 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...

In the clinic article, mention things like doxycycline, curcumin, resveratrol, you know, some of these things that are presumably much cheaper than tefamidus. 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—

The Curbsiders (52:45.678) What do you think about those? They don't work. They They don't have, we don't have evidence they work. It's like one of my mentors in medical school said, you've taken a multivitamin a day in a developed country just makes expensive urine. I mean, I don't know what you're, what we're doing with these supplements. Um, if someone can afford to Famidus, to Famidus 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 Tudka, T -U -D -C -A, a supplement. But I just don't have any evidence it truly works. Michelle, can I ask, Brice, Tifamidus is probably the one 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.

or even, you know, it's one of those things that the patient can arrive 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 and monitoring and sort of just sort of checking in on the patients, 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 can just, you could say some weird thing to me like straight leg raising tests 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.

Defamidus is the best. It's the best because it's a targeted medicine. All it does is stabilize the TTR Tetramer. So there are no side effects. I've never had a patient have a side effect for which they had to stop defamidus. In the clinical trials, there's no big signals that come out that defamidus causes X, Y, or Z. It doesn't affect the liver. It doesn't affect the kidney. It doesn't cause rashes or 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... I mean, I can't... Well, you raise a good point though. What else should a primary care doctor know about a patient coming to them with cardiac amyloidosis? Let's talk about guideline -directed medical therapy for heart failure. I mean, everyone knows the four pillars of guideline -directed medical therapy for HFREF, the ARNI, ACE or ARB, the evidence -based beta block or the mineralic corticocardia antagonist, the SGLT2 inhibitor. Then we know for HF...

The Curbsiders (54:59.438) PEPF, we think about the SGLT2 inhibitor plus minus the mineralocorticoid antagonist. How does that translate into amyloidosis? I'm gonna 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, vasodilate them, in a normal HEPF -REF heart, if you vasodilate, 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 cardiomyopathy hef -pef amyloid and you vasodilate 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 pumped really, really fast and increase my heart rate to maintain my cardiac output. They do not tolerate vasodilation. 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 -ARNI -ARB and they're tolerating it, I won't rock the boat. 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 HEPPF,

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 blocker 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 amyloid doses differently than your heart failure GDMT patient. I was actually going to 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 was one of the big learning points for me looking at this was that, okay, I shouldn't be so aggressive with the medication, the vasodilators, the afterload reduction, you know, beta blockers, because patients aren't going to tolerate it or might not tolerate it. So that's fantastic. Sometimes I do this thing on the show where I say something totally wrong, just so Paul can correct me, but you can, you know, you can play that role.

The Curbsiders (57:20.334) So there's no need to anticoagulate patients with, if I had a patient with amyloidosis and their CHADS VASC score was only one and they had cardiac amyloidosis, I don't need, and they have AFib, I don't need to worry about anticoagulating them because they have a low CHADS VASC score. Would I be doing them a disservice if I didn't put them on anticoagulation? I don't know if you heard that, but I just went into atrial fibrillation. You're a lie.

Put me into atrial fibrillation. Okay. This is what you got to remember. Patients with amyloidosis are at very high thromboembolic risk. You anticoagulate them regardless of their CHAD2 vascular. There's three conditions I can think of off the top of my head where you should anticoagulate a fib regardless of CHAD2 vascular. I can think of amyloidosis, hypertrophic cardiomyopathy, and a prosthetic valve.

If you have those conditions, I'm seeing bioprosetic, because mechanical you'll be an anticoagulant anyway. But if you have any of those three conditions, don't do the CHAD -VASC score. Don't pull up the app. Just put them on a DOAC. Okay. And this was because when they were studying patients with amyloidosis, they were just finding cardiac thrombus and it didn't correlate with the CHAD -VASC score. So you can't really use the CHAD -VASC score in these patients. Exactly. Okay. Now...

The other part, what Deb was bringing up, is just sort of symptomatic management. Like, what else are you commonly having to manage as primary care? What else should we think about managing other than the heart in patients with amyloidosis? 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 any type of neuropathy, if you have the variant form, you can send them to the neurologist. The neurologist will prescribe vutricerin and platericin, 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, gabapentin, pregabalin, tricyclic antidepressants, deloxetine, the stuff you give for neuropathy anyway. But I think the autonomic dysfunction is even more challenging.

The Curbsiders (59:35.534) These patients may need things like midadrin, flujo cortisone, droxidopa, abdominal binders, compression hose. And here where I find it the most challenging is they have this thing where they have a very narrow therapeutic window of uvolemia. So they're a little bit wet and they're super short of breath. They're a little bit dry and they're gonna faint. So what I tell patients is,

Diuretic therapy and amyloid 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 lightheadedness and titrate your own diuretic accordingly? And so I think as primary care physicians one should feel empowered when it comes to a condition like amyloid doses to let the.

patient be your guide on what the right medications are for them. Like defamidus, 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're not sure 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. This has been really fantastic. 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 carpal tunnel spinal stenosis? Number two, order the right tests in the right sequence. Remember to rule out your monoclonal proteins with immunofixation electrophoresis, not just S -PEP, serum urine, serum -free light chains. If abnormal, tissue is the issue.

If normal, then you are allowed to order your technetium pyrophosphate scan. And number three, order the right therapies to famidus and be cautious with the guideline directed medical therapy. Let the patient be your guide. Okay. And then where can people find your book? Can you tell us a little bit about that and where can they find it? Yes. So.

The Curbsiders (01:01:47.342) 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. You can find it on the Springer website. You can find it on Amazon or wherever fine online books are sold. Thank you. We'll definitely think of a reason to bring you back in the future because you're the best. And, you know, this has been a lot of fun. Paul, any last words?

Just general thoughts. No, this was terrific. It really helped frame a topic that I've often struggled with and felt kind of nebulous. So this was great. Thank you.

The Curbsiders (01:02:31.022) And this has been another episode of the Curbsiders, bringing you a little knowledge food for your brain hole. Yummy? Dad, that was your time to shine. Still hungry for more? Join our Patreon and get all of our episodes ad -free, plus twice monthly bonus episodes at patreon .com slash curbsiders. You can find our show notes at thecurbsiders .com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice changing articles, 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 askcurbsiders at gmo .com. We also appreciate if you subscribe, rate, and review the show on YouTube, Spotify, or Apple podcasts. 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 vcuhealth at curbsiders .vcuhealth .org. A special thanks to our writer and producer for this episode, Dr. Deb Gorth.

And to our whole Curbsiders team, our technical production is done by Podpaste. Elizabeth Proto runs our social media. Jen Watto is in charge of our Patreon. Chris DeChumanchu moderates our Discord. And Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto. And I've been Dr. Deborah Gorath. And as always, our main Dr. Paul Nelson Williams. Thank you and good -