 Good morning everybody. I'm Michael Castro. I'm an internist in Phoenix, Arizona. Been here for about 25 years, original from Puerto Rico. I lead the, as program director, I lead the Brasso Health Network internal medicine residency program, which I think it helps me recognizing cardiac amyloidosis and other amyloidosis and teach my residents about it. And so we are all aware of these disease. Really, really excited to be here. I've seen the faculty and what Dr. Jeff have put together. I'm really, really happy about it. It is my pleasure to introduce Dr. Chris Vijay. He's a man of many talents. He's my mentor. He has challenged me intellectually through the years. And I'm really, really happy to see him here. Because I know he's passionate about disease process and identifying ways to help people in whatever ways are possible. He's a heart failure specialist, clinical professor of medicine at University of Arizona. And without further ado, Dr. Chris Vijay. He does have 200 clinical trials and more than 100 publications as well. And I know he's humble about it, but I wanted to brag about him. Thank you, thank you. Is this working now? Yes, no? Yes? Oh, he's moving, okay. Okay, thank you. Thank you for that introduction. Thank you everyone for attending this meeting. So my charge today is to really articulate with compelling clarity those red flags, those things, signs and symptoms that we can detect earlier perhaps and then maybe make an impact on the therapeutic strategies. And why are we here? We are here because amyloid doses is making an impact, right? So we know that we had some kind of an erroneous belief in the past that, hey, we can't do anything about amyloid because once you diagnose it, we're just giving them the death sentence and there isn't anything we can do. But that has changed because of newer mechanisms out there and newer therapeutic strategies that's available and so many in the pipeline. And secondly, we always believe that we need to send these patients out for a biopsy, an endomyocardial biopic, to a specialty center. And that is changing because of newer modalities in imaging and we can detect noninvasively with higher sensitivity and specificity. And then thirdly, we have hot failure patients who now are being detected, primarily those who have half-path or hot failure with preserved rejection tractory. Now, realizing that many of these patients may well have amyloid doses and maybe we ought to be thinking about it and that's my talk again. And talking about all of this amyloid doses and the subtypes and what is the patient journey like and then what is the role of the subspecial and then we'll summarize with the case study. So as you see, amyloid doses is aggregate of proteins getting folded into shapes and then they get multiplicated into copies and then they stick and then they form fibrils and get deposited in multiple organs. And we thought that this was like starched so they called it amyloid initially. And then they said, oh, maybe it's more like fat. And then now we know that it's more like albumin or more like pre-albumin. And there are so many different proteins that are featured in different disease states that may well be amyloid. As you see over here in this slide, from Alzheimer's to Parkinson's to encephalopathy to the even prolactinomas and some of the cancers like the thyroid cancer, even atherosclerotic disease and patients with ApoA1 may well have diffused atherosclerotic disease, serum amyloid A, endometar arthritis. The finished amyloidosis is called the lattice-corneal dystrophy or gelsilin is the amyloid protein that is upregulated. And then there's so many. And all of them essentially constitute just about 5% or so. And then the other 95% is the two big ones that we're gonna talk about. The AL, which is the light chain amyloidosis and then the ATTR. So in the US, as you see in this slide, the amyloidosis is not uncommon, about 4,500 new cases are diagnosed every year and about 50 to 80 years of age is where their presentation occurs and is caused by this bone marrow disorder. The plasma cells, as you see in this slide, actually form the immunoglobulins and then you know the immunoglobulins consist of four proteins. They're light chains, two of them and then they're copine lambda, which is very important. And then the two heavy chains and there's so many other heavy chain diseases. And we know that even some patients with multiple myeloma, about 15 to 20% of them become amyloidosis. They may be the AL one and then the Walden-Stromes macroglobulinemia and the treatment strategy is totally different for AL. That's why we need to be quickly finding out figuring out if the suspect amyloidosis is it AL first and then eliminate it completely so that now we go this direction, completely dichotomized and because there are treatment strategies are totally different because for AL there is stem cell transplantation, bone marrow transplant chemotherapy with the zoomibs and beyond. So ATTR is really a protein again that's mutated from chromosome 18q12.1. It's been called what is called the Corino de Andrade's disease endemic in northern Portugal in a town called the V.R.D. Conde. It's along the way of the Santiago, the pilgrimage, the Camino de Santiago of many of you who are Catholics will know about it. And then there is a Skellefte town called Goldtown in North Sweden where 1.5% of the population already have amyloidosis and present in super centennials over 110 years of age. Again, it's a tetramer that dissociates to monomer and then misfolds and aggregates and gets deposited, right? So as you see in the slide, there are so many different ways of mutation. Some of them are pure neuropathy, some of them are mixed and then some of them are pure cardiomyopathy. The talk that we're gonna talk about mainly is the ATTR amyloidosis as you see. We said it's about AL and ATTR constitute almost 95% of the population. So ATTR is the again deposition as we talked about is it's a liver produces trans tyritin and it's a transport protein that actually carries cyroxine also the retinine is retinol protein which is the vitamin A. And so the trans tyritin exists in the serum in a soluble tetramer form. And this in amyloidosis becomes unstable, becomes dissociated, becomes multiple monomers and then they now aggregate and then they form amyloid fibrils and they get deposited. If it comes into the heart, it is now cardiac amyloidosis. And as you see in this picture, this is how it looks in our topsy amyloid heart very thick and muscle. And once it's diagnosed in untreated patients have immediate survival somewhere around two to 3.5 years. But again, it varies based on is it AL or ATTR and is it mutant or is it wild type? So what are the different types? The wild type and the mutant or the hereditary. So as you see over here in the slide, the wild type is again idiopathic, you know occurs in white men mostly, 60 years of age. The cardiac arrhythmia is a very common like atrial fibrillation. They can present with carpal tunnel, lumbar spinal stenosis, neurological. Whereas the hereditary one, there are multiple more than 120 known mutations, more both men and women can get it. And as you see the Afro-American population has a very unique mutation called the V122i, which stands for the valine in position 122 is replaced by isoleucine, so the V122i. In Ireland, in a town called Donegal in Northern Ireland, there is a very high genetic mutation called the T60a. And so yeah, so we need to be thinking about when you see Afro-American population and they have what failure, FF, and he has the question, could this be amyloid? Could this be cardiac amyloid? So again, we'll go through that in a little bit more detail. So the genetic mutation, as you mentioned, three to 4% of African-American population is thought to have the V121i mutation. And again, in one retrospective study, the African-American with ADTR had high rates of heart failure, 93%. And 47% had carpal tunnel syndrome. And when you look at the patient's journey, by the time they actually get detected to have amyloid doses, it's about 1.3 to 7.2 years. And if you look at it, they start off with symptoms, they're non-cardiac, and then they go to the primary care, and then the cardiology, and then they see another cardiologist, almost 30 to 40% of the time, they got to see somebody else with a second opinion, and then they've seen multiple specialties. They even come to the pharmacy with different kinds of medications that the pharmacist has an opportunity to ask, oh my God, could this be amyloid? They're carpal tunnel, they're on narcotics, they're also having heart failure, they got discharge, they're on lasix, and oh, the pharmacist is good actually, he says, oh my God, ask your doctor, your cardiology, whether you could have amyloid. So testing, diagnosed, by the time they get there, it's a trap. So hidden in plain sight. So this is a very powerful slide. So think about hidden in plain sight. The H stands for the half path, 16% have ATTR, of heart failure with preserver rejection fraction. I is intolerance to many of the standard medication we use, A is a RB, beta blocker, they can't take it, the blood pressure is low, the side effect profile. D is for discordant on the EKG, many of them have low-voltage EKG, and yet they have a thickened ventricle in the echocardiogram. And that's the, and the D stands for dysrhythmia, the E stands for the echo abnormalities with LVH, aortic stenosis. Think amyloidosis in a younger person, and orbit thickness by atrial enlargement, primary hypertension, some pericardial effusion that you cannot really figure out why they're having pericardial effusion, they're negative for ANA, and suddenly they have pericardial effusion for no obvious reason. And then the N stands for all the non-cardiac, which is on the other side of the slide, they can present with carpal tunnel, spontaneous bicep stendent rupture. Even statins can cause that, benbedoic acid can cause that. But then when they come with spontaneously, without really getting any weight lifting done, and they get spontaneous bicep stendent ruptures, think ATTR. There are multiple arthroplasties, the lumbar spinal stenosis, GI, peripheral, autonomic nervous system. They have all kinds of orthostatic blood pressure drops, and they're not able to tolerate many of the medications as well, and some neuropathy. So if you have many of this confluence of symptoms, start thinking, oh my God, suddenly you might have an epiphany. Oh, this could be amyloid. Let me go and dig a little bit deeper. And they have persistent elevation in NTPRO BNP, or troponin, or both. It's a prognostic marker. The Mayo has a criteria, and UK has a criteria based on these biomarkers that they can actually have a prognosis, which can be worse if both of them are significantly elevated to maybe just one and a half to two years in their longevity. The lifespan is decreased significantly, because persistent elevation in the biomarkers. Again, functional class, like EKG, and even cardiac magnetic resonance imaging. We can dig a little bit deeper as with both Bob and Beetal. We talk about that too. This is the EKG where there is a significant drop in the QRS voltage, but then again, the QRS voltage can vary, and only about 20% of ATTR cardiomyopathy have a low voltage QRS. So don't keep looking only for the low voltage QRS. If it's not there, don't assume that, oh, this cannot be amyloid. It could still be because even an AL amyloid dose is only about 60% have a low voltage QRS in the anterior. They can have pseudo infarct pattern. They can have AFIP. They can have AV block at an earlier age requiring a pacemaker for no obvious reason. Start thinking about it. And Bob will go through the echo finding, as you see over here, the cherry on top with the global longitudinal imaging with apical sparing. He'll go deeply into that. And cardiac MRI as well as the accumulation of delayed washout of the exogenous late gadolinium enhancement can occur. Increased extracellular volume can be seen in the second row there and an increased native T1 signal for both AL and ATTR, which can be detected before the presence of the late gadolinium enhancement, which is a marker of increased fibrosis. And so screenings. If one finds symptoms and signs is a bowel that are suspicious for ATTR, then yes, in hot failure, please do the screening for amyloidus. Consider screening even if they're not in hot failure, but they have all of this little thing, little signs and symptoms and you start thinking, maybe I should detect earlier. Why? Because earlier you detect, put them on therapy earlier, perhaps you can change the trajectory of their prognosis and their disease state and their quality of life and cardiovascular mortality, which will be discussed in detail again. So how do you rule out AL? Again, starts doing serum-free light chain assay, the Kappa-Lamda ratio, do the serum protein electrophoresis, but with immunofixation, because immunofixation is a lot more sensitive and specific or more than 95%. Same thing with urine immunofixation. And then once you know that it is not AL amyloidosis, then we go beyond and ask the question, oh, could this be ATTR amyloidosis? So what is the algorithm? Well, does the patient have a history? Does the EKG look like? I could be low voltage. Do you have you ruled out hypertrophic cardiomyopathy, constrictive pericarditis? They all can mimic amyloidosis, sarcoidosis, cardiac MRI, consider that is suspicious. Again, do the blood testing, urine testing, if positive, then go ahead and send them to hematologist. If negative, then start thinking, should I do a PYP scan? If PYC positive, then ask the question, or is it ATTRCM, do we do genetic testing? And then there's a treatment strategy. And that's defined over here in this algorithm, as you see from the top to the bottom, it may be a little bit tiny, but you'll have the slide kit with you. So essentially talks about the same thing. I just put it in words, but this is in a flowchart format, exactly talking about the same thing that we just mentioned. And in terms of the multiple subspecialties are actually involved and should be involved in detecting and managing ATTR from beyond cardiologists. Again, orthopedics should be thinking about it. Nuclear cardiologists, genetic counselors involved, neurologists ought to be thinking of their autonomic dysfunction, no obvious reason they can find that is very obvious. GGI, again, hematology, pathology, multiple different subspecialties, and each of them have a role to play, as you see from recognition to early clues, to knowledge about the ATTR itself, and that's why we are here. Hey, let's talk about amyloidosis again and again to increase the awareness, understand many of the symptomatology and recognize and provide consultation and support and work together. So let's summarize it with a case study. So a 66-year-old African-American male recently discharged from the hospital with half-past, sees PCP as follow-up, five days, has had the angiogram, cardiologists say it's all good, you don't have any coronary disease, so they don't want to follow up many times because they don't have any more procedures to do, and then suddenly the other patient has had third-degree AB block a few years ago, has a dual chamber pacemaker, carpal tunnel syndrome surgery, underwent TAVR for aortic stenosis, no bicuspid aortic valve, on multiple medications, not tolerating blood pressure, dizziness, or precious low. The BNP is a little high, creatinine is borderline high, LVH is present, and you can actually put each of them in a separate silo and essentially take care of those individual signs and symptoms and disease states and not put them all together in one box and look at what comes out from a confluence of this disease state process, and could this be ATTR is a question that you need to be asking. So what do you call an eight-foot creature weighing five tons with a large proboscis used as a vestigial appendage with two large tusks, two large ears, and gray in color, irregular in shape, rough, and if it is the opposite, small, wide, soft, smooth, regular, and round, then I would have to call it aspirin, right? So the elephant in the room. That's what we are talking about today. You have these confluence of symptoms. Can you quickly ask the question, am I seeing this elephant in the room? And clearly early detection, prevention, prevention, prevention. We do too much at the secondary and tertiary care level. We ought to be doing primary and primordial. What is primordial? Not even allowing them to have these risk factors, such as blood pressure, diabetes, obesity, dyslipidemia, and all of that, we are talking about primordial because too much has been done in late-stage disease with treatment strategies, as you see the bottom heavy model of cardiovascular care, and truly we got to be addressing it here in this action framework for a comprehensive public health strategy to do it earlier in the prevention and make this a social environmental condition, make that favorable, make the behavioral patterns and promote health at the population. George posted a beautiful job in discussing all of this strategy that we are talking about and through this department of future health, perhaps we can address all of these and then do it at an earlier. And I believe that we certainly can with knowledge gain, we can provide inspirational transformational message filled with credibility, humility, and the foundation based on empathy. So yes, Aldous Huxley said, the rung of a ladder was never meant to rest upon, but only to hold a man's foot long enough to enable him to put the other somewhat higher again, epitomizing that sense of hope. Thank you for your attention, as I say in the Tibetan Buddhism Jalei.