 And as we move forward, we're going to have Dr. Nishant Shah. He's going to talk about the role of imaging for amyloid. He's from Providence VA Medical Center, associate professor of medicine at Brown University, director of nuclear cardiology, his lifespan health system. And he's going to tell us about the role of imaging. He's traveled all the way from Rhode Island. So two things, right? So while you're traveling, about 15 cases of amyloid doses have already been diagnosed. That's right. And number two, if I had traveled the same time and I went west, I would be in Hawaii by now. But thank you for coming and to share your knowledge and wealth of knowledge. And really appreciate the role of imaging for amyloid. Go ahead. Well, thank you all. Thank you, Sinesh, for the invitation to come here and the organizers. It's awesome, as Julie said, to see a full room of folks interested in amyloid. This hasn't always been the case, so it's really nice to see this. So I'm going to talk a little bit about the role of imaging for TTR cardiomyopathy. My one disclosure is that I do receive grant funding and honoraria from Pfizer. As you heard from Julie, they are the manufacturer of Tefamidas. So really, the outline for today is just two things. One is that I want to emphasize some important nuances in the current expert-recommended non-invasive imaging-based algorithm for diagnosing TTR cardiomyopathy. And then highlight for you some recent data that actually Sinesh highlighted a little bit in his first talk that may soon prompt some significant changes to that algorithm. So just as a reminder, we've heard about this already this morning from Alberta. The pathobiology from a cardiac standpoint is really that when you get deposition of the fibrils into the myocardium that results in biventricular thickening, bi-atrial dilatation, mitral and tricuspid valve thickening. And then when you look on polarized light microscopy, you get the characteristic apple-green birefringence pattern. So why is that important? Well, so it's just one set of things that we look at. So from a cardiac perspective, Alberta already showed you this. We see all of those changes in the heart, but then there's other things that go with it. So there's atrial fibrillation. There's brady arrhythmias, conduction abnormalities. And then the presence of a pacemaker suggests that maybe the patient had those things in the past and maybe have already been treated for it. But as Alberta already pointed out, there are multiple other red flag clinical signs that we should be looking out for in musculoskeletal. As Alberta mentioned, especially bilateral carpal tunnel syndrome, ruptured biceps tendon is another really important one. And again, the point, as Alberta made, is that many of those things are not going to come to cardiology. They're going to end up in orthopedics. They're going to end up in neurology. The polyneuropathy here that's part of the clinical syndrome is, again, often present for sometimes years and treated by neurology without actually thinking about the fact that there may be cardiac involvement. And then as Alberta mentioned, autonomic dysfunction, things like somebody who had high blood pressure in the past was able to tolerate medications. And then you're sort of peeling them off over time. Alberta touched on this. This is the current diagnostic algorithm. And it's a little bit. So this is now from 2019. We're 2024 now. As Alberta mentioned, on the left-hand side, it's heart failure or the presence of any of those red flag signs or symptoms that we just talked about. Now, in the old days, in 2019, it was an increased wall thickness of greater than or equal to 1.4 centimeters. As Alberta mentioned, that's now gone down to 1.2 centimeters. And part of the reason for that is is that we recognize that these older numbers meant that patients were actually further along in their disease course. And as Julie mentioned, time is really important. By the time that somebody gets to 1.4 centimeters, they've already had the disease for quite some time. And now, with all of these new therapies that Julie talked about, we really should be treating these patients earlier. And so now that's 1.2 centimeters. We're looking for men over the age of 65 or women over the age of 70, particularly with respect to wild-type TTR. But I'm going to show you a little bit of data that I think challenges much of this algorithm at this point. So what's the role of imaging? As Alberta already told you, echocardiography is often the sort of gateway to figuring out that a patient has amyloid. Hopefully, that changes in the future. And Vinod hopefully will talk later today about how we might use some automated mechanisms to find patients before they actually have the signs even on echo. But as Alberta mentioned, you can see here on the left-hand side, essentially, you've got your thickened LV. One of the other things that I've seen in clinical practice and I pay attention to is, particularly if you have a thickened LV, but especially in the presence of a pericardial effusion that you can't otherwise explain, that tends to be a fairly high suspicion for me, at least, for amyloid. Alberta also mentioned that you can see mitral and aortic valve thickening. And then sometimes even the interatrial septum can be thickened as well. And then this is the 555 rule that Alberta already mentioned where you have an S prime, E prime, and A prime, all less than 5 centimeters per second. Now, with respect to the apical sparing pattern that Alberta mentioned, that is true that it's associated with amyloid. But I want to emphasize that there's actually a paper that came out last week from a European consortium that says that, actually, this pattern is present in a lot of other LV hypertrophy diseases. And so while you think amyloid while seeing this, it isn't actually as pathodynamic as we used to think. And so certainly think amyloid, but amyloid isn't the only diagnosis, but certainly something that we should pay attention to. I want to touch a little bit on cardiac MRI because I think this is becoming much more common outside of just academic medical centers. So cardiac MRI has some interesting findings as well that can point you towards amyloid. So what I want to point out here is that as amyloid progresses, and so this is early disease, this is late disease, there's certain clues on MRI. So there's something called T1 mapping. As you can see early in the disease, there's sort of a lower time for T1 mapping. And then as you progress in the disease, that time tends to prolong. As time progresses, you start to see a little bit more scarring in the myocardium. And then as the disease progresses, you essentially have this extracellular volume map tends to get worse over time. So here early in the disease, the extracellular volume is 39%. Here late in the disease, it's 62%. You can also, as a result of sort of getting more scarring over time, you can actually have a reduction in perfusion that you also see on MRI. The reason I bring all of this up is that MRI is a quantitative tool that we can use not only to help diagnose the disease, but we can also see the progression of the disease. And more importantly, as Julie mentioned, as we get therapies like these monoclonal antibodies that may be able to pull fibrils out of the myocardium, MRI right now is actually potentially the best mechanism that we have to quantitate reversal of the disease process as we get some of these treatments that have that capability. One last thing that I'll show you is, is that on the inversion scout images, you can see that in a control patient, essentially the myocardium nulls first and then the blood pool nulls later, the sort of classic finding with amyloid, and this is fairly pathodemonic, though not completely so, is that because of the deposition of the fibrils, actually the myocardium nulls first and then the blood pool nulls later. So this kind of reversed nulling pattern is very sort of typical in cardiac amyloidosis when visualized by MRI. So this is the algorithm that you've seen now a couple of times from Alberta and from Sinesh earlier today. I just wanna emphasize, because I think we have to keep doing this over and over to make sure that we all do this right, is that after you sort of have a clinical suspicion either from ECG, ECCO, et cetera, you really need to rule out ale amyloidosis and that's with all of the testing that Alberta already talked about, doing immunofixation electrophoresis of the serum in the urine and then doing a quantitative Kappa and Lambda from the serum. I do wanna point out, and I think Alberta touched on this a little bit, patients with chronic kidney disease have an abnormal Kappa and so you will have a ratio that is potentially elevated but normal for that patient and so there are different cutoffs in those patients than there are in patients that don't have chronic kidney disease. I will say also the same thing that Alberta said that in clinical practice, although in the guideline it says to do this first, you can do it simultaneously with the nuclear imaging that we're gonna talk about in a second. I do wanna point out something because this is really, really important. The guidelines have changed with respect to what constitutes a positive PYP study and we're gonna talk about it. I don't know if you guys caught it but in Sudesh's first slides, it used to talk about an HCL ratio in addition to the semi-quantitative grading. That HCL ratio in these newest guidelines has gone away and I'm gonna talk a little bit about why that's the case. I also want you to understand and we'll talk about this a little bit that just because you have a positive or a negative PYP study or HDP study, here in the United States, we don't use the other agent but if it's PYP or HDP, just because you have a positive or negative study does not mean that the patient either does or does not have amyloid. It's very important to put it in the context of the AL amyloidosis workup. So we'll move forward. So this is just a little bit about the bone scintigraphy, we call it cardiac bone scintigraphy. Again, here in the United States, we're using primarily PYP at most sites. I've actually moved over to HDP and the reason for that is that HDP tends to clear the blood pool faster than PYP and so you can image sooner and I've found at least anecdotally and others have as well that HDP tends to, there tends to be a better contrast between the blood pool and the myocardium in patients specifically with chronic kidney disease and or low EF or heart failure with reduced ejection fraction. So again, for these bone tracers, you inject about 20 to 25 millicuries. For PYP, you're imaging at about two and a half to three hours. I have reduced my imaging time for HDP to about one and a half or two hours and the reason for that is that there's at least a suggestion now that when you use HDP that in addition to clearing the blood pool, it may actually clear the myocardium quicker as well and if you image it three hours with HDP, you might actually be missing disease in patients, especially early on in the disease course that may not have as much radio tracer activity. I wanna be very clear right now that the ASNIC or American Society of Nuclear Cardiology Guidelines have gone away from using planar only to diagnose patients. And the problem as you can probably see here is that in planar only imaging, when you have uptake, it's not totally clear from planar imaging whether you're just imaging the blood pool or if the uptake is actually in the myocardium. The only way to truly do that is to use spectimaging, which is really what we need to use to confirm that the uptake is myocardial and not within the blood pool. And we still use currently right now this semi-quantitative grading from zero to grade zero, one, two, or three based on the uptake in the myocardium on spectimaging relative to bone uptake. And so spect is really mandatory to confirm the myocardial uptake. The one thing that we still can use planar for is that, and there are some labs that are doing this, that if you image at one hour after the injection and there is nothing at all lit up, meaning you don't see any signal at all, it can confirm the absence of any uptake. And so you can use it to rule out at least uptake but you can't use it to confirm that there is in fact uptake. The other thing that some labs are doing, we're not doing this in Providence, but some labs are doing whole body imaging. And the reason that some folks do that is that as you can see here, sometimes you get uptake in the shoulder or in the hip girdle. And if you do see that then there's sometimes suggestion that this is not just a cardiac issue, but it may in fact be a systemic problem. Planar based heart to contralateral ratio again has a very limited role at this point. This is how we calculate it. You basically put a region of interest over the left side of the chest within the myocardium and then you do sort of a contralateral region of interest on the other side. Essentially you're looking for a ratio of about one as being sort of normal if there's no uptake. The current American Society of Nuclear Cardiology guidelines say that you only use the HCL ratio when you have semi-quantitative grading of one. In other words, you shouldn't use it in grade zero when there's no uptake and you shouldn't use it when there's grade two or grade three uptake because that is just a positive study irrespective of what the heart to contralateral ratio is. And in that scenario only with grade one, a heart to contralateral ratio of greater than 1.3 at three hours or greater than 1.5 at one hour should be suggestive. And so essentially the point being here is, is that the heart to contralateral ratio should really only be used to help you differentiate what would otherwise be a fairly equivocal study. This is what we're doing in Providence and I encourage anyone here who's talking with their nuclear medicine folks or their cardiologists who are doing this to really use few specs CT. It's an extra layer to confirm that what you're seeing on spec is actually within the myocardium. If you don't do this, there are scenarios where you might believe that there's activity even on spec that is myocardial when in fact it's somewhere else particularly when you have other things that are nearby like the ribs that, for example, a rib fracture also causes uptake and if your rib is right next to the LVA packs you may or may not be able to tell the difference on spec between where exactly the uptake is. And so CT helps to more definitively confirm myocardial uptake. I just want to say that after a positive study it's really, really important to do genetic testing as Alberta said earlier. Why is this really important? It's because it has implications for both prognosis and treatment. As Julie said, there are other agents that are available besides defamidus if the patient actually has hereditary TTR and if they, let's say, have neuropathy in addition to their cardiac manifestations. And if somebody has hereditary ATTR then you're going to also consider screening their family members. This is just a quick slide to show you the different and there's far more than this at this point but these are some of the common genes that are implicated in hereditary TTR just to know that they're grouped basically by those that are predominantly neurologic, those that are predominantly cardiac and those that have a mixed phenotype. The other important point here is that patients with homozygous genetic abnormalities tend to present at younger ages than those folks who present with wild type TTR. So just some quick illustrative cases. 66 year old gentleman with half-path LVEF of 55%, a wall thickness of 1.6 centimeters, a global longitudinal strain of negative 11%, which as Alberta said is abnormal and has apical sparing. PYP shows grade three uptake that spec confirm and genetic testing is negative for a TTR mutation. So by show of hands, how many people based on what I told you so far think that this patient has TTR amylidosis? Raise them high, raise them high. Okay, all right. So this is actually AL amylidosis. This is not TTR. The piece of information that I didn't give you was the Capita-Lambda ratio in the immunofixation electrophoresis. So as you can see on the bottom here, the Capa-Free Light Chain was 2.383, a little bit elevated. The Lambda was markedly elevated at 41.8 and I will say that clinically, an elevated Lambda is always, always, always abnormal. Like I said, Capa can potentially be abnormal in the setting of chronic kidney disease, but if you have an elevated Lambda, it's always abnormal. And so the ratio was low and then the electrophoresis showed IgG Lambda monoclonal protein. So to make the point, AL amylidosis rule out is critical for making the diagnosis and you shouldn't just go by imaging or by the clinical picture alone. So second illustrative case, 68 year old male with neuropathy has a wall thickness of 1.7 and EF that's a little bit low, global longitudinal strain that's abnormal and apical sparing. MRI shows elevated T1 and ECV and then you've got the apical sparing pattern on echo. However, as you see in panel B, there is absolutely no uptake in the myocardium on PYP imaging. So the question again, show of hands, does this patient have TTR amylidosis, show of hands? All right, nobody, okay. So this patient actually does have TTR amylidosis, okay? And so even after a negative PYP or HDP study, if your clinical suspicion is high, you have to think about other ways of potentially diagnosing the disease, specifically endomyocardial biopsy plus or minus genetic testing. And this requires clinician knowledge and this is all of you in the room, you're here to learn. You have to have a high suspicion. So in this case, this patient had the P62 Lou variant, which is a specific hereditary variant that is known with studies that have been published now to have, it doesn't light up on cardiac bone scintigraphy. And so you just have to have a high enough suspicion to be able to test this patient genetically and or get a myocardial biopsy. Okay, so just real quickly, some newer data, so this showed you this already. Just the point being that when you systematically screen a population, as they did in this Mayo Clinic study, that if you just use diagnosis alone from just clinical suspicion, it's 1.3%, but if you systematically screen the same population, you get a prevalence of 6.3%. So this is a humongous jump and this is amongst inpatients and outpatients. So the point being that this disease is much, much more prevalent than we actually think that it is. And I would argue that it's actually not a rare disease. In fact, it's a disease that I think is pretty common. I wanna point out this important study from the Jackson Heart Study. Again, about 3,000 self-identified black adults, they genotyped all of them. And those patients that had this specific hereditary mutation of TTR, the V122 mutation. What they found was is that these patients often didn't have LV remodeling, but they had chronic myocardial injury, meaning elevated troponins, and then had an increased risk later on in life of heart failure hospitalization. So, and this was true even if they were heterozygous, not homozygous for the mutation. So the point being that even heterozygous carriers of the mutation don't have anything on imaging and still have worse outcomes than other folks. And so the first question is, is this true for other mutations of TTR? And also, what does this mean in terms of our algorithm? So just some implications for screening and diagnosis. I told you that you have the potential to miss hereditary ATTR, which if you use the criteria of 65 years for men and 70 for women, you're gonna end up screening too late. If you get the wall thickness at 1.4, that's too late in the disease course. So what we're really talking about is heart failure, red flag symptoms, and that's a humongous population. So Vinod is gonna talk with you about, essentially, how do we automate looking at the medical record to make sure that we find these patients early? And then I would argue that, as Sandesh talked about and posed the question earlier, should we be doing genetic testing potentially earlier on in the process, maybe when we're ruling out AL-emolydosis? And then just one last thing is that we've got spectro-CT quantization that correlates with the semi-quantitative grading. This is just another way for us to potentially, sort of in the nuclear world, match what MRI is doing and maybe have nuclear be a way that we could also monitor treatment response. And this is work that's been done by my colleagues, Sharmila Dorval and Sarah Cuddy at The Brigham. So some concluding thoughts. The current non-invasive imaging-based algorithm for the diagnosis of TTR must be followed carefully as we just showed with those cases to avoid false positives and false negatives. Imaging will soon transition from semi-quantitative to quantitative assessment, whether it's nuclear or MRI, and doing so paves the way for assessment of response to therapies that Julie just talked about. And newer data suggests that wider, more systematic screening is needed and it's possible with AI and automation to identify patients earlier in the disease course, such that maybe imaging hopefully will take a backseat. I hate saying that as an imager, but hopefully imaging takes a backseat to some other testing that we may have to identify these patients earlier in the disease. Thank you so much for your time. Appreciate it. Thank you.