All right, thank you so much for inviting me to be part of this exciting session today. I'm going to be, thank you, oh, I'm going to be kicking things off here with a few questions on recognizing the suspect, if they will load. All right, so question number one, a 72-year-old white man with a history of atrial fibrillation, bilateral carpal tunnel, and lumbar spinal stenosis presents with gradually progressive LVH and a septum that is now 15 millimeters and new symptoms of HFPAF. This is most suspicious for which of the following? Now the answers on your phone are going to be in a different order than I'm about to read them, or they might be, so pay attention when you choose. Is this most suspicious for AL amyloidosis, wild-type ATTR amyloidosis, hereditary or variant ATTR amyloidosis, or giant cell myocarditis? All right, so 67% of people chose the right answer there, and here's our leader board with a couple of people tied for first place. All right, let's split things up a little. Next question. A 55-year-old woman with a five-year history of CIDP, or chronic inflammatory demyelinating polyneuropathy, refractory to treatment is referred for new AFib. Her echo shows normal biventricular size and function, mild concentric LVH with a septum of 11 millimeters, and biatrial enlargement. This is most suspicious for which of the following? Once again, pay attention to the answer order. Is this most suspicious for AL amyloidosis, wild-type ATTR amyloidosis, hereditary ATTR amyloidosis, or giant selenohicarditis? All right, plurality chose hereditary ATTR amyloidosis, and we have Meg pulling into the lead. Next question, please. A 65-year-old man with a history of hypertension is hospitalized with new heart failure. He has an ejection fraction of 40%, mild LV wall thickening, walls of 12 millimeters, and an antiprobian P of 30,000. He's had recurrent syncopal events in the past three months and describes severe orthostatic symptoms. He also has nephrotic range proteinuria, macroglossia, and severe anorexia. This is most suspicious for which of the following? Paying attention to the answer order, is it AL amyloidosis, wild-type ATTR, hereditary ATTR, or giant selenohicarditis? All right, 69% called it AL. Let's see the leaderboard. Is Meg going to hang on to it? Yes, she's still in first place. Who's going to dethrone Meg? She's going to walk away with this trophy if you guys don't get with the program. All right, next question, please. Which of the following ethnic groups is least associated with variant or hereditary ATTR? Greek, Portuguese, Irish, or Haitian? All right, that's a good spread there, 36% though correctly chose Greek. And let's see the leaderboard. Oh, Meg. Number. What is that? That's not even a number. That's a square parenthesis. Oh, is it a J? I need my eyes checked. All right. Okay. Jay is in the first, in lead. All right. Which of the following valvular abnormalities is considered a red flag for ATTR amyloidosis? Once again, paying attention to the order of traces, mitral stenosis, aortic stenosis, aortic regurgitation, or tricuspid regurgitation. All right, so two-thirds of you correctly chose aortic stenosis. You can see the leaderboard one last time, and then we'll get going here. Jay is holding on. All right. With that, we can get started with the talk, and hopefully you'll all understand why the answers that were chosen were the correct ones. So just to not belabor the point too much, but I just wanted to talk really quickly about the pathobiology of AL amyloidosis. Many of you will be aware that this is typically related to a plasma cell dyscrasia, where abnormal free light chains are generated by the plasma cells that can then aggregate into amyloid fibrils that can deposit in pretty much any tissue outside of the central nervous system in the body. And they can cause problems due to fibril deposition impairing organ function, as well as through direct tissue toxicity, primarily when we're speaking about cardiac amyloidosis. And so the manifestations of AL amyloidosis go beyond the heart and include renal disease, including nephrotic syndrome, soft tissue and skin manifestations like periorbital purpura, GI involvement, including macroglossia, and so forth. Whereas with transthyretin amyloidosis, which of course we understand is much more common, the pathophysiology is related to production of either normal, wild-type, or hereditary, or mutant, transthyretin protein in the liver. Transthyretin of course is a carrier protein that carries vitamin A and thyroid hormone around the body, and typically does that in a tetrameric form. But the tetramer can break down into dimers, which can then break down into monomers, and it's the monomers that cause the problem. They can misfold into amyloid fibrils and deposit primarily in the heart, in the myocardium, in the peripheral and autonomic nervous systems, and of course in the sort of tendons and ligaments and soft tissues as well. And this misfolding can occur due to aging and wild-type disease, or due to a gene mutation that predisposes to it, invariant or hereditary disease. But in all cases, it is a nonspecific presentation. And it's because of this nonspecific presentation that misdiagnosis is so common. Surveys have revealed that a majority of patients wait far too long to be diagnosed. In one survey, only 35% of wild-type patients and 17% of hereditary patients were diagnosed within a year of symptom onset. 17% of ATTR respondents visited five different physicians before they received the correct diagnosis. And in a similar survey, over 75% of AL patients had to visit three or more physicians before they received the correct diagnosis. Now with increased awareness and good disease-modifying therapy and so forth, the disease is being diagnosed more often. This is data from the National Amyloidosis Center in the UK, where you can see that with progressive time periods, there are a greater number of patients who are being diagnosed with amyloidosis, with ATTR specifically here. And that importantly, those patients as they're being diagnosed are being diagnosed at progressively earlier stages of the disease. So a greater portion of patients are now being diagnosed in so-called stage one, next stage one. And associated with that, we're seeing improved prognosis. So it's really important that we identify these patients early while they still have early-stage disease so that we can have the opportunity to institute treatments that you'll hear about later and ultimately improve their long-term outcomes. So how do we recognize it? Well, one of the things that we need to keep in mind is the epidemiology of the common genotypes, including wild type. This is a selection of the different gene mutations that can lead to hereditary ATTR amyloidosis. And I put stars next to the most common ones. Certainly the most common one that we see here in North America is the V122i or V142i mutation that's present in three to four percent of African-Americans. The penetrance varies and is, to be honest, not completely understood. But we do know that the incidence of this disease increases with age and is more common in men than women. Onset is typically greater than 65 years old. And these patients predominantly present with a cardiac phenotype. The T60 or T80A, they're a different nomenclature. You'll see it both ways. The updated one would be T80A mutation is present in one percent of patients from County Donegal in Ireland. This is the Irish genotype. This has greater than 90 percent penetrance. It has a mixed phenotype and has onset typically after age 50. The V30M or V50M mutation is an interesting one. There's an early onset phenotype of this that occurs primarily in patients in northern Portugal and to a lesser extent northern Sweden. This has a very high penetrance, approaching 100 percent. Onset at a younger age, typically less than 50, and this is predominantly a polyneuropathy phenotype. Interestingly, patients who live outside of these endemic regions can have the exact same mutation but have a more mixed phenotype with onset after 50 years of age. And of course, it's important to talk about the wild type genotype, which is no mutation at all. Prevalence estimates vary. It's really unclear how common this disease is because it's so underdiagnosed, but we do know that it is not inherited. It increases with age and is more common in men than women and has a predominantly cardiac phenotype. So how can we identify these patients? There are the cardiac manifestations, which are well described, heart failure, arrhythmias, conduction system disease, and so forth, and then there are the extracardiac manifestations. Some of these manifestations are unique to AL amyloidosis, including the periorbital purpura that we talked about earlier, as well as the macroglossia. Some of them are more specific to ATTR, things like spinal stenosis and some of the ocular manifestations that are seen in hereditary ATTR. And then there are some manifestations that are sort of common to both. Both AL and ATTR can present with polyneuropathy. They can present with kidney disease, although the protein area is more prevalent or more prominent in AL. And they can all have GI manifestations. So there are a number of lists that have been published, similar to the one I just showed you. But this AHA scientific statement was published about five years ago now, and it highlights some of the red flags in ATTR cardiomyopathy. And again, there are the traditional cardiac clues, including the heart failure that we talked about, conduction system disease, unexplained LV wall thickening, as well as intolerance to heart failure or antihypertensive medications due to hypotension. And then there's the non-cardiac clues that are so important to identify patients with ATTR cardiomyopathy, including polyneuropathy, autonomic dysfunction, and the orthopedic stuff like carpal tunnel syndrome, spinal stenosis, spontaneous tendon rupture, and other orthopedic injuries. Ethnic background is, of course, an important red flag. Here it's listed as black race, but members of any of the high-risk ethnic groups that I've described should be considered. And finally, even in the absence of belonging to a particular ethnic group, a family history of either cardiomyopathy or polyneuropathy should be a red flag. Similarly, the ESC put out a guideline on cardiac hemolytosis, and they also listed a series of red flags, the majority of which with the check marks here in the last slide that I showed you. But it's important here to note that they also comment on aortic stenosis. They talk about proteinuria and skin bruising, which are, again, seen more in AL amyloidosis, and then some of the important imaging findings, including subendocardial or transmural late gadolinium enhancement, or increased extracellular volume fraction on MRI, or reduced longitudinal strain with apical sparing on echocardiogram. Finally, I just want to draw your attention to the sex differences in ATTR cardiomyopathy. Many of the standards that have been published that we think about, like a 12-millimeter thick septum, are based on our experience in predominantly men. And that's because this is a disease more of men than women. But we need to remember that women can also get this disease, but that when they do present, they tend to have more advanced NYHA class, but their walls will not be as thick, because women don't have walls as thick as men in the normal situation either. And so we should be suspicious of this disease in women at lesser degrees of septal thickening than we would be in men. So keep that in mind. So in conclusion, cardiac amyloidosis is an underdiagnosed cause of heart failure, arrhythmia, and death, especially in older men in certain ethnic populations. Its nonspecific presentation presents challenges in disease detection. Cardiac and non-cardiac red flags can help identify patients to screen, but remember that women may present a little differently. And it's really important that through increased awareness, we can see earlier diagnosis, more diagnosis, so that we can ultimately improve outcomes for this patient population. Thank you.

cardiac amyloidosis

ATTR amyloidosis

diagnostic challenges

genetic predispositions

underdiagnosed populations