 Actually, I'll just start. Maybe one question for Sonya. So you mentioned this 23andMe genetic testing. So you have a 25-year-old who is looking for God knows what, but they have a Val122 ILE variant and they show up in your office. No symptoms. So what are you telling them? Yeah, that's a great question, and I've actually run into this somewhat recently. So you know, essentially the first thing is I ask them what research they've done on their own, because it's really helpful to have an understanding of where they're coming from and what their impressions of are, what they've read online, or maybe what they've even read from their own genetic test report. But the first thing I tell them is that variant in particular, this is probably a true positive. So I kind of treat the session as if we've already got a positive result, but that there is some chance that maybe it's not. So we do proceed with clinical confirmatory testing, as I had mentioned before. But we are talking about, you know, that increased risk for the cardiac amylidosis. In particular, we talk a little bit about amylidosis in general, implications for family members. You know, like I said, really kind of treating it like a positive test report at that point. But that will have further discussion once the clinical results come back, and usually at that point it's a phone call to confirm that the results did come back positive. And at that point, I also talk about our awesome multidisciplinary clinic and the providers that we have here. I know we just heard from Dr. Rosenthal and Dr. Goodman and they are really great. And so I talk about the support that we have on our team and that there is support from other clinical standpoints and the genetic implications of that as well, just in terms of what are we thinking about for family planning and other family members because this oftentimes is a surprise, you know, they many times don't even know that this is something in the family or had never heard of this before. So there's a lot that we cover in one of those genetic counseling sessions, but it is something that comes up and, you know, whenever patients ask me about 23andMe testing or direct to consumer testing in general, should they do it? Should they not? Really it's a personal decision and it's up to them, but I tell them, you know, there are things that we might find out about that you're not expecting to find out about. So certainly worth doing your research ahead of time and considering both what it might mean for yourself as well as your family members when you get those results back. And maybe I just asked Julie, so what do you say clinically to this person who's now been referred to you in their 20s or 30s with V122I for them? I mean. And they're asymptomatic. They're asymptomatic. Yeah, this is definitely a struggle and I think something myself and colleagues talk about often, but just try to reassure them and also just encourage them to follow back. You know, typically I've been recommending five years. We unfortunately don't have guidelines for this. And so I base this office of data from HCM patients and their families in terms of screening, but try to provide them some education. We have a great team of nurse coordinators. So try to provide them that education of signs and symptoms to look for. At the same time as Sonia alluded to, sometimes at stigma, I think can really mentally affect patients. So then they think they have a neuropathy when they don't have a neuropathy or they're worried they have chest pain and there is no chest pain. So you do want to be cautious and understand your audience. And I think asking them, you know, what they understand, what they know and how they feel. But try to provide reassurance and just bring them back to kind of hold their hand in some respect. Yeah, I just agree. I mean, this is a disease that we heard as an age dependent penetrant. So we don't see v122i penetrating usually before the age of 50. The opportunity may be that loved ones who are older in their family may actually have a clinical phenotype and maybe those are the individuals. So I always encourage older adults who have the disease to get their not their kids tested, but rather their siblings tested question. So I work as a hospitalist and I see a ton of heart failure patients. And usually cardiologists are involved when there is low ejection fraction, but then they kind of turf off a lot of diastolic heart failures and a lot of echoes are not actually read by experienced cardiologists, if I may, or it's in the substance and not in the conclusion. And a lot of times these are missed. So there are a lot of barriers to diagnosing early and also our hospitalized patients have that revolving door mechanism where they keep coming, going, coming, going. And a lot of them are 80 plus or 75 plus. And now the cost versus benefit as well as what is the you know, when you say the biomarkers and you're saying two out of three makes it stage three or stage four in your life expectancy is 40 months to six months, here you're dealing with our patients already have multiple medical problems, chronic kidney disease that tropes are elevated BNPs high to start with. So when you say 40% improvement with treatment, I want to know in years, am I prolonging life or delaying death or I'm actually benefiting this patient, what is the number of life in years that you can give with treatment and without treatment so I can approach my patient in a positive way. I think that's an outstanding question and something that each of us are faced with quite routinely. And I think you highlighted that question about the multiple morbidities, right? I think it's if you look at the patient and they can't get out of bed on their own, is this really the patient I want to offer an endomyocardial biopsy to and start thinking about chemotherapy or is the right thing to do to offer palliative care. So I think you have to treat each patient as individual. I don't think we're in necessarily the exact place to judge, you know, what is their life worth to them, but looking at the whole picture of my therapies and the treatments going to ultimately cause harm or as you said, are they going to cause benefit? But I think that the important thing to know is that this decision does not have to be made on your shoulder. You heard today from a number of colleagues in different subspecialties, amyloosis can affect many things. So this can be a team decision and approach to how to help you counsel your patient or also just help counsel the patient and their family. But sometimes in my patients who are quite advanced in age 90 plus 85 plus with multiple comorbidities, even if they have TTR amyloosis, if I feel they have class four heart failure stage D and I don't think they're going to be living more than a year, I'm not going to be offering these patients a stabilizer therapy that's a quarter of a million dollars a year because I'm not sure it's going to provide that benefit. We saw even from the ATTR act trial, while there is some initial benefit early on from symptoms, it doesn't happen overnight. This takes several months and you're not seeing more fatality benefit for more than a year and a half. So while things might change for now, I think you just need to continue to approach each patient on individual basis and reach out to your colleagues who can help provide you some guidance. If I can add a little bit to that. So I think that's that's a great question. And I, as a hematologist, I see a lot of those patients who have like state three or state four NYHA heart failure and they are diagnosed with light enamel idosis and then are they eligible for treatment and will the treatment improve the quality of life and will it prolong the life expectancy. So just to give you an example, I saw a patient like she was in her sixties, late sixties and she was diagnosed with stage four heart failure at another hospital. And then the hospitalist saw the patient, cardiologist saw the patient, they diagnosed her and then she was sent to hospice. So she was in hospice for at least like two, three months. And then she came to see one of our cardiologists who specializes in amyloidosis and they started the work up and finally diagnosed her with light enamel idosis. So then she came to discuss her options with me and I had the discussion with her. Yes, the outcomes of prognosis is not good because you already have state four heart failure, but we can at least give a trial of the treatment and see if that improves your quality of life. And we started on a single agent to MoMAB initially to begin with because she was wheelchair bound and she was not even able to walk on her own. And after the first couple of months of treatment, her symptoms started to improve and now she is able to do her activity. She is able to walk at least she's now six months into the treatment and she's out of the hospital and she's doing really well. So some of these patients can be very sick when we start the treatment and experienced physicians when we start the treatment and we start gently and see how they tolerate and if they tolerate it, okay, that can help improve their quality of life and also can improve the longevity. I don't know whether it's going to be one year, two years, three years that she's going to live, but at least she will have some quality of life and most of the treatments that we offer these days, especially in the hematology world are not cytotoxic chemotherapies and most of these treatments are very well tolerated, but we have to start gently and build it up slowly and we can improve the quality of life in these patients. I just add that I think you're in a unique position as a hospitalist. There's data from a national health system in the UK in which patients with TTR amyloid are hospitalized in the last three years of their life 17 times. So you talk about the revolving door. If you can make this diagnosis, you can institute therapy. We may be able to, as Dr. Rosendahl was mentioning, prevent some readmissions. So, you know, that's what we're hoping for. Other questions in the back? Yeah. How different is amyloidosis and amyloid plague formation in patients with Alzheimer's? So the amyloid type in the brain, for the amyloid, amyloid, sorry, Alzheimer's patients is a different amyloid type called A-beta. So that's a specific amyloid type there, but maybe 16 different amyloid types seen in the brain. But some of those are very, very rare. So the most common one is A-beta and that's the Alzheimer's amyloid. Is that the question? Answer the question? Yeah, no, sometimes there can be some confusion, particularly with family members who may read about and they have amyloid diagnosed by, say, TTR or wild type or variant. And then they may read about amyloid associated with Alzheimer's, but there really isn't any association. And usually it's just a matter of reassurance. But it does get to the point that we've been discussing, which is these older patients do have multiple comorbidities. And so we do struggle with this. And some of the patients who they may, for example, in neurology, they may come in with a little bit of neuropathy, but they may have a lot of dementia, for example, that's unrelated. So a number of the patients may have other comorbidities which need to be factored into treatment decisions. That's terrible. Just so on. So there is the idea that there may be amyloidopaths. So people who have amyloid of different types in different parts of their bodies. There is some evidence, maybe, that there is a link between Alzheimer's and amyloid elsewhere, but it's kind of tenuous. And I think there needs to be a lot more research, but that idea is at least floating around out there. I would just add that my clinical experience of the overlap is pretty minimal. I'm surprised, you know, like the average age of these patients is 75 or 80, and most of them are quite erudite and the coexistence of the two, at least in my clinical practice, haven't seen literally a thousand patients with TTR is much smaller than I would anticipate. The other thing I would also submit is I think the cardiac amyloid world has done a much better job of actually taking care of this disease. You hear what's coming out of FDA approvals for Alzheimer's disease, and it, you know, is associated with pretty high costs and not much, you know, necessary clinical benefit. But the same argument is being held, which is if we can move upstream and identify people earlier in Alzheimer's disease, these therapies might be more beneficial in some regards. So I think across all Alzheimer's all amyloid diseases, early diagnosis is really critical. Yeah, a great conversation, great talks. Oh my God, I'm learning so much already from each of you. It's fantastic. So in my reading, therapy, Julie or Matt or anyone, I think you probably did mention maybe a forgot, I missed it, doxycycline plus toro or sodium deoxycholic acid, what it made of the data that's one. Secondly, from a patient perspective, and regular every day, after you've seen your patients, we thought of these hot failure, whatever their question, what should I eat? What should I take? You know, and you know, how much excesses those of the most common questions almost on a daily basis with every patient and then some. What is that some question? What about green tea, Dr. Rosenthal? What about turmeric? Will it prevent Alzheimer's? Will it prevent amyloid diseases? Is there any data? Or is there a therapeutic strategy that maybe, you know, there is some evidence there? What are your thoughts on that? One question I think prior to 2018, most of us in the room who are practicing amyloid physicians, these are the tools that we could reach for in addition to palliative care, we were reaching for these things like Tadka and doxycycline and green tea. I found doxycycline in the state of Arizona, quite challenging due to photosensitivity, seeing lots of sunburns in our patients or GI intolerance. That being said, I think the data is quite minimal. And there's some data into animal models, but we haven't seen on a large scale in human models. Overall, morbidity and mortality benefit and due to potential side effects and drug interactions, I'm no longer using these in my practice. The clinical trials did exclude patients from taking specifically the green tea. I do not know about turmeric, but maybe Matt can comment on that in the HTR. But I know doxy and green tea were excluded from some of the clinical trials. So those are not agents I'm using. There was actually some data recently published for our alamyloid patients. I think people are now steering away from doxycycline, even in alamyloid, which used to be standard of care in that first year we're giving doxy with the cyborg. So I think the community is going more away from those more herbal or other types of agents for treatment of amyloid. To answer your second question in terms of what do we educate our patients regarding diet? I think that's a whole one hour lecture in terms of the supportive care from a heart failure standpoint, right for individuals amyloid. We talked this morning or I talked this morning about disease target therapy. But what about how we treat our patients just from a neuropathy standpoint or heart failure standpoint? Those are whole lectures in themselves. From a dietary standpoint, most of these patients I find are quite cacetic malnourished due to malabsorption or just poor cardiac output and difficulty absorbing. So they get that early satiety feeling. So I typically put my patients on a seafood diet. I've coined this term from Eric Steadley, not that they need to eat seafood, but meaning they see food, they eat food. You know, there's a lot of controversy for those that you attended the ACC Arizona. I was a part of a debate with a colleague from Tucson, you know, salt restriction versus no salt restriction. I do not salt restrict in my practice. I think there is great data out there for salt restriction in the hypertensive heart disease world. I think Dr. Maher recently had a paper out in Jack with some additional colleagues, you know, on what is the optimal diet. And I think trying to tailor to your patient is probably the most important thing. And for these patients, quality of life should be at the top of our list. They're suffering in so many ways. So for me and for many people, food can bring pleasure. So I let them eat whatever they want to eat and just might mean some extra torsumide or Lasix or Bumex not to provide to any one department. So just let them enjoy it. Dr. Maher, Ellen, I wanted to ask one question before you break for lunch. So if we have a 30% likelihood of detecting the monoclonal protein with fat or bone marrow in TTR, but we have a 70 or higher percent in AL. Should we preferentially considering cardiac biopsy in patients with suspected ATTR? And the reason I'm asking this question is it takes time in some institutions to organize a bone marrow biopsy and a fat pet biopsy. And by the time you get all that back and it's negative, you have a 70% chance now you're going into potentially cardiac biopsy or you could just preemptively treat them for ATTR. So I'm just sort of wondering, I feel confused as a practitioner what type of biopsies we should be ordering when. That's a great question. And in fact, I had sort of this conversation with one of our cardiac amyloid guys at Mayo Rochester a couple of days ago. But I think when there's an M protein, you don't know which one it's going to be at that point. It could be either one. So that's why we next go to the fat and the bone marrow at that point. I suppose if you're really strongly pushing for treat as fast as possible, the ideal site is the heart. So I don't think it's ever wrong to go to the heart first. But because at the point with the M protein, you really don't know which way it's going to go. If it's AL, then you have an 80% chance of making the diagnosis with something a lot simpler like a fat or a bone marrow. So it's an excellent question. I don't think it's ever wrong to go to the site of interest first. Is it OK to treat without having the protein? Because if you have a negative biopsy, then you're empirically treating for ATTR. Is it OK to stop there and say, well, we didn't find it in the bone or fat? I'm not sure the clinical circumstances you're describing, but I would be very cautious about trying to institute treatment without being sure what the precursor protein is. I mean, look, these are two very different diseases. If you see enough patients, AL is a medical emergency. So if you get like chains back and they're abnormal, these patients usually look very sick. And this is something in which you need to move quickly. I mean, in the days when we started to try to do transplants on patients with AL amyloid, the median time to death was 56 days. Now, these are really advanced AL patients, as we saw in the CURS. So you measure light chains and it's abnormal. You need to have a clock in your head, as Martha Grogan would say. And you need to get that person in and move as quickly as you can, whether it's a fat pad first. And if it's negative, then ART biopsy. TTR is a very indolent disease. The other thing, just epidemiologically, is that TTR is the tail that's going to wag the dog. It is going to be, as we heard, I bet 95% of all cardiac amyloid we see in the future, just given the epidemiology who's getting amyloid and aging. So if you do this enough, you get a real good flavor for what people have. But I would just say, if you think they have AL, call all your friends, call them quickly. Your hematologist, get consults and do not dog, right? I would just echo the following. I think if we walk away from anything Dr. Hussain highlighted in this morning's talk is AL amyloid is a heme emergency. So from a cardiologist's perspective, I hope that each of you think of this as a STEMI. Time is light chain, just like time is myocardium. And I would never want to treat these patients blindly. You heard from Dr. McPhail this morning, 25% to 40% of individuals with TTR amyloid are going to have some kind of MGUS. And just because they have an MGUS, they might have AL amyloid. They can have Waldenstroms. They can have TTR. So I had a patient who I, for sure, thought had AL amyloid. Fat pad was negative. He went for a bone marrow and turns out he had Waldenstroms, but didn't fit his cardiac picture. So ultimately, he got a cardiac biopsy and turns out he has TTR amyloid. So his Waldenstroms is now remission and he's on to famine. Interestingly, his ejection fraction remodeled when from 20% to 65. I'm thinking this was some light chain circulating toxicity. I don't know. But I think that we have potential to cause more harm than good if we're treating an MGUS blindly. I think many of us on this stage and this audience have seen individuals being treated with chemotherapy for TTR amyloid because they had that background MGUS. So really, thanks to our colleague, Dr. Dahlgren and colleagues at Mayo in 2009. We developed this technology you heard about this morning with MassSpec. So I think tissue is an issue. And to stress to each of you in the room, where do I go? You go wherever you can get the fastest result. Like, who can help you the quickest? As Dr. Maurer said, you call all your friends. Fat pad yield is somewhat low for TTR amyloid, but it doesn't mean they don't have TTR. And the biopsy of the bone marrow, too, might not show TTR or AL amyloid. So you ultimately do have to go to the organ that is problematic. And I think in this day and age, cardiac biopsy is relatively safe. There is about a 1 to 5% risk of perforation, but an experienced hands. This can be done and should be done. All right. That's wonderful. I think we should break for lunch. We'll be back at 12.45 for our keynote address.