Caitlin Whyte Host): Welcome to another episode of Flourish, the podcast brought to you by PRISMA Health. I'm your host, Caitlin Whyte. Today we are delighted to have Dr. Jason Guichard, a prominent Cardiologist from PRISMA Health.

Dr. Guichard will help us navigate transthyretin amyloid cardiomyopathy, or ATTR-CM, a rare and often misunderstood heart condition. Well, Doctor, my first question for you today is what should we know about the rare heart disease ATTR-CM?

Jason Guichard, MD, PhD: ATTR-CM, as you've suggested already is a rare disease, however, it is probably not nearly as rare as we think it is. Up until recently when there were actually therapies to treat this disease, most people wouldn't even look or even pay attention to the disease kind of pragmatically, you know, if thinking that if there's nothing we can do about it, then why even look for it anyway?

It's probably short sighted thinking, but that was for a while, the thinking. So, these therapies were developed, it was largely believed to be a rare disease. But now that we have therapies and awareness and, and looking for the disease, it is not nearly as rare, as we're thinking.

 But it is still relatively new. So getting awareness and getting people to understand the disease process and the treatments for it is important. So in short, ATTR-CM is an amyloid process. So amyloid simplistically, is any protein that's in your body that can misfold or form groups of proteins and then deposit in the various organs in your body, whether that's your heart or your brain or your liver, your kidneys.

There are at least known 53 different proteins that can cause amyloid. One that everyone is probably well aware of is Alzheimer's. You know, everyone kind of knows that the beta pleated sheets that form the fibrils and deposit it in the brain and causes the brain to be dysfunctional.

 So you can kind of think of ATTR-CM in a simplistic view is kind of like Alzheimer's for the heart. So there's a protein called transthyretin, the abbreviation for that is TTR, is made in the liver. And this protein has four components or subunits, tetramer, if you will. And what happens in the blood, that tetramer breaks apart into the monomers, or just the single units, and those single units, kind of reform together abnormally, and form kind of a glob, if you will, and then those globs deposit in two main things for TTR, either in the heart or in the nerves.

So this disease process ATTR will deposit in those two main organ systems. It can deposit elsewhere as well, but those are the two main organ systems that it targets, just like for Alzheimer's, you know, targets the brain; these various different amyloid proteins will target different organs.

So rare disease protein that's formed in the liver, then gets into the blood and disassociates or, or forms small pieces that then form the amyloid protein that deposits in the heart and the nerves. Based on where it deposits in the nerves, obviously, as you might imagine, nerve dysfunction can manifest itself as neuropathy, numbness, tingling, pain in the hands and feet, are kind of the main symptom of the TTR polyneuropathy or PN. So ATTR-PN is the transthyretin amyloid polyneuropathy. And then, of course, what we're talking about today is the ATTR-CM or cardiomyopathy, where these will deposit in the heart.

And what happens is this makes the heart either stiff or weak or both. It can lead to heart failure symptoms and that is a cluster of different symptoms that include tiredness, fatigue, being short winded, both either at rest or with exertion otherwise known as dyspnea on exertion.

And can lead to what we call volume overload or accumulation of fluid, either in your legs or in your tummy, in your chest, that can exacerbate some of those same symptoms. So that's kind of the classic formation of what we call heart failure, having that symptom set, that's kind of the end of process of the disease.

Host: Got you. Well, now that we know that, who is at risk for ATTR-CM?

Jason Guichard, MD, PhD: So there are two different types of ATTR-CM. There's what we call a wild type. Wild type is the new name. There was, there's been historical names. The first that it was called, I like telling the story, it was called senile, but no one likes to have a, a senile disease or even be called senile.

 That name was abandoned a little while ago. And then It was called age related, after that, but of course, you know, people don't like to be called old, so age related kind of dropped off and they settled on wild type, and wild type sounds like a weird word. If you're not in the medical field, wild type basically just means kind of the normal protein, so it is a, the wild type form of ATTR-CM.

It's just the normal protein that, you know, all of us make. However, oddly in certain people, that protein decides to break apart and deposit in the heart. So it's not everybody, it's just certain people, which we haven't sorted out or figured out exactly, you know, why that is in some people it forms this disease and some people it doesn't.

 So as you might imagine, in the wild type form, you know, like we've talked about already, it's a disease of aging. So people in their 60s, 70s, 80s and 90s, is kind of the typical demographic, often seen in Caucasians. So kind of the, the key demographic, that we often see is older white males, are kind of susceptible and have the highest propensity for the wild type ATTR-CM.

 So the second type of ATTR-CM is what we call hereditary. So it's also had some, some names as well, which we'll go through the history, which is kind of fun. So the, First, adjective was mutant. It is due to a mutated gene, which causes a mutated protein, but of course people don't like to be called mutants, I guess, unless you're an X-Men.

 So the mutant word kind of went to the wayside, and then it was called variant, was kind of like the, the next word. But variant, you know, it doesn't really sound very nice either. So the word that's kind of landed on currently and may change in the future is called hereditary. It's a very kind of benign, happy word.

So you can have hereditary ATTR-CM. And as we've kind of talked about before, this is having an abnormal gene. So the TTR gene you know, which makes the normal protein can have abnormalities in that gene, which makes a, abnormally functioning gene, a gene that's actually more susceptible to breaking apart.

The protein is more susceptible to breaking apart and then depositing in the heart. So kind of the classic demographic in the US is actually African Americans. So this, abnormal mutation in this TTR gene, there is a variant that has an affinity or has a high propensity in African American population.

 There's a lot of things that are genetically, you know, inherited, will start younger in life. So in the hereditary form of TTR, sometimes patients in their forties and fifties and sixties will start developing it a little bit earlier than the wild type. Those patients obviously, you know, we would like to identify them sooner, get them screened, and as you might imagine with anything that's genetically related, it can be a little bit more aggressive.

So not only does it start earlier in life, but can also be more aggressive as far as the polyneuropathy as well as the cardiomyopathy. So those are kind of the two main types, you will, of the ATTR. CM is both wild type, which is kind of older white males, and then the hereditary, which is kind of younger African Americans, in the U.S. That's kind of the two main types that you generally see clinically.

Host: All right. Well, thank you for that answer. On that note then, what really causes this ATTR-CM?

Jason Guichard, MD, PhD: So, like we've touched on a little bit earlier, that protein that's made in the liver, gets into the blood, kind of breaks apart, forms those amyloid structures and then deposits in the nerves or in the heart, and then that, you know, causes the heart to be stiff or weak, and then, you know, some of those same symptoms that we talked about. The two different types, whether it's wild type or hereditary, you know, can, suggest if it's going to advance quicker or maybe not as quick, as well as the age of onset.

Host: Why is ATTR-CM so difficult to diagnose then?

Jason Guichard, MD, PhD: So it is an excellent question. So two things, number one, hard to diagnose because the awareness isn't there. if you think about it, you know, if someone at your house, gets a sore throat and the sniffles, you know, we just say you have the cold, right? It's the common things being common. Because it's been difficult to diagnose, you know, mainly because the awareness isn't there.

So people often think of other things when someone's complaining of, you know, numbness or tingling in their hands and feet, right? That could be lots of different things. When people complain of being short winded, either at rest or with short distances, sometimes people will blame, you know, oh, it's your lungs, or, you know, a lot of other things kind of get blamed, or maybe you have pneumonia and that sort of thing.

So we see a lot of patients who initially get treated for either lung issues, or other issues first, you know, before ultimately they continue to work down the process of evaluation, and it comes to light that they actually have ATTR-CM. Average diagnosis time for a lot of these rare diseases, is anywhere from two to four years, believe it or not.

So from the onset of symptoms to actually establishing the diagnosis can take years. So a lot of these patients, you know, struggle, sadly, and this is true for a lot of rare diseases, not just ATTR-CM. These patients struggle for a while, you know, before being diagnosed or finding a specialist, you know, that is aware of some of these kind of cluster of symptoms or red flag symptoms, as we like to call them, at least point you in the direction, that this could be ATTR-CM, and then ultimately get treated.

Host: Well, let's talk about that now. How is ATTR-CM treated and is it curable?

Jason Guichard, MD, PhD: So that is a good question. There's a lot of information and data and research going into these treatments. Currently, there are four treatment groups, so four different treatment modalities. We'll kind of go through all of them. Two of them are clinically approved that you can use in patients.

And two of them are still experimental. So we can just kind of go chronological order. So the first class of therapies are what we call stabilizers. So as you remember, when we talked about the disease process, when the protein is made, in the liver, and then gets into the blood and then breaks apart.

Well, what if the protein never broke apart and then it would never have the opportunity to form the amyloid fibrils and then ultimately deposit in the nerves or in the heart? So the first class of medications is called the stabilizers. So there are two medicines in this class, tafamidus and acoramidus, which was just recently approved.

And these medicines bind the protein and keep it from falling apart. And if you keep the protein from falling apart, then it doesn't have the opportunity to form those bad amyloid deposits and then deposit in the, the heart and nerves. So these were well tested medications. Tafamidus was, first out there, I believe approved in 2019.

 So we've been using it for a number of years now and patients have done very well. The clinical trial for that initially, was very positive. There was a mortality benefit, so anything in medicine where you're able to extend life, that's obviously a very good thing. Also improved symptoms, and clinically we see that. We've got a number of patients on the medicine and they do very well.

The second class of medications are what they call silencers, so we talked about before the protein is made in the liver, but what if we never allow the body to make this protein to begin with, and that's what the silencers do.

They go in on the gene level, and actually prevent the gene from ever being transcribed or turned into a protein. So those silencers are currently approved for the polyneuropathy form of the hereditary version of ATTR-CM. There are ongoing clinical trials and approvals for the cardiomyopathy as well,

for both hereditary and wild type. So very soon we will have the silencer class of medications available to us to use for patients. That'll prevent the protein from ever being formed. Which would be great.

So the third class of medications are what they call depleters. So we've had our stabilizers, our silencers, and now we have our depleters. So as the name suggests, these medicines actually act like little vacuum cleaners, little antibodies, act like vacuum cleaners to suck out the abnormal protein. from the heart and from the nerves, which is awesome.

 So all those, there's kind of two main antibodies are currently in clinical trials. Here at PRISMA Health in Greenville, we're actually a clinical site for one of those depleter, it's called depleter CM trial.

So we've got a handful of patients going through that process and it's been very well tolerated. We're very excited about it. And I think it's going to be an amazing class of medications to help ATTR-CM patients.

And then the fourth, class of medications is actually gene editing. So everyone has probably heard or seen you know, information on gene editing. So it's the CRISPR-Cas9 system, which is a system that actually goes in and deletes out genes. And you can either, you know, specifically delete out genes or insert other genes. It's a very phenomenal biomedical technology that's been used in research for a long time and is now making that plunge into the clinical arena.

So actually, believe it or not, ATTR-CM was actually the first clinical in-human use of this CRISPR-Cas9 system, in humans. This was published a few years ago, and is now kind of in the various stages of clinical trials. But as you might imagine, so this is given to a patient, it's just a one time dose, goes into the liver and actually splices out or cuts out that abnormal or TTR gene itself, and then the protein is never created. It's a, a one-time dose and basically at that point, I mean, does it cure?

Does it not cure? You know, now you're on that gray area of treating a disease versus actually curing it. So very exciting stuff in the field of ATTR-CM, both just the disease itself, but also just the crossover, you know, with kind of other rare diseases. A lot of excitement and a lot of hope moving forward, you know, as far as treatments go for this disease process.

Host: Well, alongside those treatments, what can patients do to best manage this disease?

Jason Guichard, MD, PhD: Yep. So there are things that patients can do as well. So number one is, take your medicines as prescribed, you know, for not only the ATTR-CM, but of course for other diseases, that you may have as well, because, you know, a lot of times, you know, high blood pressure and diabetes and all the kind of typical things stuff that we see can sometimes make these processes worse.

So obviously, staying on your medications and you know, listening to your doctor's advice is always important. Number two, staying away from salt. So if you struggle with a weak heart, you can accumulate fluid. And as we all know, salt can exacerbate that or make that worse. We've all had, you too many pieces of pizza, you know, one night and the rings get a little bit harder to, to pull off in the morning.

 So that is just kind of exacerbated, you know, when your heart's a little bit weak to where, you know, if you do that now, you know, it just makes it hard to get the rings off. But if you do that when your heart's weak, you can wind up in the hospital. So being careful with salt intake, that's probably a good advice for anyone, whether your heart is weak or not. You know, Americans have a salt problem, you know, so that's number two.

And number three is staying active. So activity is important, not only for your heart, but for your muscles and your body, as well as just kind of brain health. So taking your medicine, staying away from salt and staying active are probably the biggest things that patients can do on their end.

And there is some evidence for green tea or green tea extracts can actually help with the amyloid deposition as well. So as a, I guess, a holistic or non pharmacologic approach, you know, green tea or green tea extracts, have also been shown to be helpful as well.

Host: To wrap us up today, Doctor, is there anything on the horizon that could help improve care for patients with ATTR-CM?

Jason Guichard, MD, PhD: The four classes, the stabilizers, the silencers, the depleters, and of course the gene editing technology. As far as I know, those are the biggest things, but you know, there could be things in the future. There is the opportunity for heart transplants.

So, if your, you know, heart is very weak or very stiff, you're struggling with all these symptoms of heart failure, and you know, refractory, to a therapy, then for certain patients that qualify for a heart transplantation, that can be done. So I guess that is another therapy that we didn't talk about, that's you know, still being used in research today.

But I think we've pretty much touched on everything. We've tried to keep this as cutting edge, as possible. And I think those are the biggest things.

Host: Thank you so much Doctor for being on the show and for shedding some light on this rare heart condition.

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