Hello, and welcome everyone. Good afternoon. This is the ASNIC webinar on Optimizing the Diagnosis of ATTRCM Updates in Imaging and Best Practices. I'm Saurabh Malhotra, the chair of this program. I'm an imaging cardiologist at Cook County Health in Chicago, and it's an honor to be joined by three eminent imagers, Dr. Chidam Akinjolu, who is an associate professor of medical imaging at University of Western Ontario, Dr. Vaheel Jaber from Cleveland Clinic, where he's the professor of medicine, and Phao Chobran, endowed chair in cardiovascular medicine, and Dr. Prem Soman from University of Pittsburgh. Dr. Soman is the professor of medicine, associate chair in the division of cardiology, and the Richard Caligiuri chair in amyloidosis and heart failure. These are the learning objectives. You all have access to this in the ASNIC LMS online. And I want to highlight that this program is supported by an unrestricted educational grant from Pfizer. These are the disclosures of the faculty members. So we have a robust agenda today. We're going to have three sessions. First one, Technetium 99m Labeled Cardiac Imaging Traces by Dr. Soman, evolving from planar to spec, why and what you need to do from Dr. Jaber, and then clinical cases on interpretation reporting and how to use the different traces. And this will be shared by Dr. Akinjolu and myself. This will be followed by a 10-minute Q&A. Please put your questions in the Q&A box. We will answer as many as possible during this meeting. You will have access to the webinar recording for about three months on the CLAIM CME site, and no PDF of the presentations will be provided. You must complete the post-test and program evaluation online to receive your CME and the conclusion of the course. And this link will be emailed to you at the conclusion of the webinar. Please be sure to use hashtag CVNuke and hashtag amyloidosis and tag at myasmic to share your experience on X. And a big shout out to our virtual moderator, Dr. Sami Abuzaid, for moderating this virtually. Thank you all for attending this webinar on Optimizing the Diagnosis of ATTRCM, Updates in Imaging and Best Practices. For additional cardiac amyloidosis resources, visit the Cardiac Amyloidosis Resource Center at asmic.org slash cardiacamyloidosis. We'll now stop sharing and invite Dr. Soman to kick off this webinar with his talk on Technetium 99m-labeled Cardiac Imaging Traces. Dr. Soman. Thank you, Saurabh, and good evening, everybody. These are my disclosures. So Technetium-labeled scintigraphy for ATTR amyloidosis is a simple test that has been absolutely transformative for the field of cardiac amyloidosis. It's simple because it is rest only and requires no patient preparation at all. It is very widely available and most importantly, very widely applicable. You can use it irrespective of patient's body habitus, atrial fibrillation, renal failure, cardiac devices, and so on and so forth. If you order a PYP scan, the patient is sure to get it. The test time is relatively short and the radiation dose is not greater than the background radiation in the United States. Now there were a number of prior studies that evaluated the use of Technetium-based scintigraphy in cardiac amyloidosis, but the study that taught us all about the extraordinary diagnostic accuracy of this test was a 2016 paper from Julian Gilmore at the National Amyloidosis Center in London. And in this paper, in this study, it's important to note that the agents that were tested were Technetium Pyrophosphate, DPD, and HMDP. So these are the three tracers that can be used for screening for cardiac amyloidosis. HMDP is also called HDP. DPD is only available in Europe. For us in the United States, it's either PYP or HMDP. Now what is really important to mention here is Technetium MDP, which is the most widely used bone tracer in the United States, is not sufficiently sensitive to be used as a screening agent for cardiac amyloidosis, and it should not be used for this purpose. Now in this study, Julian and others showed us the extraordinary diagnostic performance of this test, with a sensitivity of greater than 90% and a specificity approaching 100% if the test is performed in conjunction with biochemical studies to exclude a monoclonal gammapathy. And the positive predictive value of the test in this study was 98 to 100%. But note, however, that the prevalence of amyloidosis in this population was 70%, and we'll come back to this later. Now I want to talk about three things in the next 15 minutes, and these are three important steps that all of us doing technetium scintigraphy should follow to avoid diagnostic pitfalls. The first is that we should always screen for AL amyloidosis. Now talk about this. In 2025, the diagnosis of TTR amyloidosis should not be performed using just planar imaging. We should always perform SPECT. I will just touch upon this briefly, and Dr. Jaber is going to elaborate on this in his talk. And finally, if there is a discrepancy between what you're seeing on imaging and your clinical suspicion, always perform further testing to elucidate that situation. Now today we all know about the value of SPECT, and the primary purpose of doing SPECT is to localize the tracer to the myocardium. On the top panel here is a planar image that looks positive. On the bottom panel is a classically positive pyrophosphate scan. In that, it shows on the SPECT image diffused myocardial uptake of tracer. And the scan looks like this. This is a classically positive PYP scan. If I didn't tell you this is a PYP scan, it could be mistaken for a MIBI scan or a tetraphosmin scan. To teach this, I say a classically positive pyrophosphate scan looks like a normal myocardial perfusion scan. It does not look like this scan. Because this is a scan, it looks like a MAGA scan because the tracer is in the blood pool and not in the myocardium. And the primary purpose of the SPECT image is to distinguish localization of tracer in the blood pool from tracer in the myocardium. Now if you do a chest SPECT, this is an unreoriented image. So we don't reorient it into the traditional SPECT cardiac images. But here again on the transaxial images, when you see a complete horseshoe like this with the apical cap intact, this is myocardial uptake. Whereas when you see this type of an image, that's most likely blood pool. So this is in the transaxial image. Now Sourav Malhotra tried to look at predictors of persistent blood pool, which is the primary confounding factor in the interpretation of these scans. And interestingly, the parameters of left ventricular function and filling pressure on echo were not actually predictive of whether there would be persistence of blood pool on the pyrophosphate scan. So left atrial pressure, ejection fraction, global longitudinal strain, and stroke volume were not predictive. So it's difficult to see which patient will have persistence of blood pool and which patient will clear the blood pool effectively and quickly. This is work that Ahmed Mashri did when he was a fellow at UPMC, showing that if you perform planar and SPECT imaging, now this is really important, it is planar and SPECT imaging, then the 1R image is good enough. And in this cohort of about 250 patients, the diagnostic accuracy of 3R imaging was identical to 1R imaging. Now this is if planar and SPECT imaging are both performed. What is more, you can see here that the 1R image has had a slightly higher sensitivity compared to the 3R image, and the 3R image understandably had a slightly higher specificity compared to the 3R image. Now 1R imaging is particularly important when you use HMDP. There is some evidence that this tracer washes out earlier from the myocardium, and I think Dr. Malhotra is going to talk more about this, but this is his publication showing an excellent example of how if you wait for three hours, you may certainly change the grading, but you may also miss the diagnosis because of early washout of tracer when you use HMDP. Now as I said, the most classically positive PYP scan is one where there's diffuse uptake, but you can encounter atypical uptake patterns as is seen in this image. Now the top panel here is a thallium myocardial perfusion scan, and every alternate row is a pyrophosphate scan. Now you can see here that if I didn't turn on the myocardial contours, it would be quite difficult to say where the localization of the tracer is, whether it's in the myocardium or the blood pool. So we use SPECT. We don't have SPECT CT available for these scans. So when thallium was available, we used to inject a small dose of thallium if the pyrophosphate scan was equivocal, and then do a simultaneous dual isotope acquisition on a solid-state system. So the advantage of doing a simultaneous acquisition is that you can contour the myocardium on the perfusion scan and very accurately apply those contours to the PYP scan. And with those contours in place, you can see that the uptake of the tracer is in the myocardium, but it is fairly patchy. So this is a positive scan, but it's not a diffusely positive scan. Now what is interesting in this patient was that he had one of the most abnormal MRI scans that I've ever seen in amyloidosis with a very high ECV, and you can see here that there's almost transmural uptake of gadolinium, late gadolinium. And so this brings us to the question of what exactly PYP is picking up and what it binds to. And we are not quite sure as yet, and that's a topic for an entirely different conversation. Note here that the thallium scan excludes large areas of myocardial infarction, which is another situation where parts of the myocardium may not take up tracer. But this is a graphic example of how the MRI can be very abnormal, and sometimes the PYP is overly mildly abnormal. And again, I'm not going to elaborate on this, but I want to make the point that a grade one scan on a planar image is a truly equivocal scan because you simply don't know whether this is due to persistence of tracer in the blood pool. In contrast, when you do a SPECT image or a SPECT CT, if you have a SPECT CT, and that's a much better test than just a SPECT scan. But if you see mild uptake on SPECT or SPECT CT, that's not an equivocal scan. That's a definitely abnormal scan with mild uptake in the myocardium. And I think Dr. Jaber will talk more about this. We do not include the perigee planar grade or HCL ratios in our report. In fact, we don't even grade the SPECT uptake. We only say whether the SPECT shows myocardial uptake or not, and whether the image therefore is negative, positive, or non-diagnostic or equivocal. Now in terms of testing for L-amyloidosis, now here you can see a very positive scan in a patient with a mildly abnormal serum study. Here the free Kappa is normal. The free Lambda was mildly elevated, and the ratio was 0.21. I want to make a point here that when the Lambda subtype, when the Lambda free light chain is higher, is more elevated than the Kappa, that is always abnormal and cannot be explained by renal dysfunction or any other factor. And this needs to be evaluated more, either MGUS, multiple myeloma, or AL. And in this patient, the endomyocardial biopsy showed AL, and this is an unusual example of a very positive PYP scan in a patient with AL-amyloidosis. The way to exclude AL-amyloidosis is to screen for a monoclonal gammopathy, and you can see here that individual tests have a lower than optimal sensitivity. If you perform serum immunofixation and free light chains, you have a 97% sensitivity for AL, and if you add on urine immunofixation, and this can be done on a spot sample, if you add on urine, you increase the sensitivity slightly. So the optimal complement is serum free light chains and serum and urine immunofixation electrophoresis. And finally, here is an example of a patient who was a 68-year-old white man who presented with new heart failure symptoms and an injection fraction of 40%. He was referred for the evaluation of cardiac amyloidosis based on the presence of LBH on echocardiography. Now his pyrophosphate scan was negative and his serum and urine were negative for a paraprotein. And I had all this information with me and I was about to and I went into his room preparing to tell him that he does not have amyloidosis when on a physical exam I noticed that he had a ruptured bicep standard. This led to a cardiac biopsy and his heart was full of amyloid and this was one of those unusual mutations, the PA to folium mutation, that we now know is associated with a negative PYP scan. It seems to be based on the type of amyloid fibril. The more ubiquitous type of amyloid fibril, which is seen in the wild-type disease in most variant forms, is the type A fibril, which is composed of the full fibril plus the AC terminal fragment, as opposed to the type B fibril, which is prevalent in certain specific types of gene mutations. It's the full-length fibril alone and this may be associated with a negative PYP scan. So that brings us to the question of how does one exclude cardiac amyloidosis? What is the minimum complement of testing that you need to perform before you can say that a patient has no cardiac amyloidosis? We started off thinking that the combination of a negative pyrophosphate scan and serum and urine biochemical test to exclude a monoclonal gammopathy would be sufficient to exclude ATTR and AL amyloidosis. But based on the recent evidence indicating that the type of fibril may result in negative pyrophosphate scans in some patients with variant disease, we now routinely perform TTR gene sequencing and we've included that into the minimum complement of testing that's required to rule out cardiac amyloidosis. The clinical suspicion is still high and I cannot emphasize this enough. One has to do further testing. That's usually a myocardial biopsy to exclude the less common forms of amyloidosis such as apolipoprotein amyloidosis. In my last slide here, I want to talk about the situation where you have a positive pyrophosphate scan in a patient on hydroxychloroquine therapy. Now this is a challenging situation. I'll tell you that most patients who have a positive pyrophosphate scan and are on hydroxychloroquine still end up having ATTR amyloidosis on the biopsy. But occasionally this is a false positive scan because of chloroquine toxicity and PYP uptake because of chloroquine toxicity. Now the chloroquine toxicity has a very unique and has very unique findings on both light microscopy and electron microscopy and can be very accurately distinguished from TTR amyloidosis. But the challenge is that, you know, when you have this situation you almost have to biopsy the patient. The other unknown here is that we do not know when PYP stops becoming positive after hydroxychloroquine is stopped. So if they've had hydroxychloroquine six months ago and the PYP is positive, we don't know what the duration is where you can be sure that the positive PYP is due to TTR amyloidosis. So our clinical approach to the diagnosis of TTR has evolved. We've gone from an entirely biopsy-based diagnosis to non-invasive testing with a high diagnostic accuracy. And this has unmasked a high prevalence, a high community prevalence of this disease and increasing community testing. As I said, the accuracy data are based on populations with a very high prevalence of disease. And now there is this tension between early diagnosis and accurate diagnosis. And one really needs to be vigilant, particularly when the clinical diagnosis and the clinical findings and the imaging findings are discrepant. Thank you very much. Thank you, Dr. Soman, for that excellent start to this webinar. And now welcome Dr. Wael Jaber to talk about evolution from planar to SPECT, why and what you need to do. Dr. Jaber. Thank you so much for the invitation. And thank you, Dr. Malhotra. And thanks, Pram, for setting the stage. So my task is made easier by this clear presentation from Dr. Soman, telling us about how we stumbled almost on this tracer to make the diagnosis. And the idea is here is to take you down a little bit beyond where we are right now and try to show you some of our experience with doing this test. So I want to first start by covering some of the objectives of my talk. We go from screening, screening with high sensitivity and specificity, as Dr. Soman presented, prognostic value of some of the screening we do. Why do we do screening? And in general, any screening test has to be easy to use and universal in use. And we have to have some value proposition for the community when we're applying this test. The recent, most of my slides actually are guided or inspired by the recent ASNIC quality metric guidelines on this on this disease. And they move from calling this various names, bone tracer, this and that to now cardiac amyloid radionuclide imaging and CARI. And that's why I'm going to reference to throughout my talk. So this is one of the most recent basically flowcharts on how to approach these patients. I think Dr. Soman presented this very well with basically we have some suspicion, you rule out AL. And the next step usually for these patients is to move down the track of getting a nuclear scan or CARI scan. And then based on that, you can proceed to genetic testing, which we do universally at our institution. Now, in the past, the way we approach this disease, and this is, again, the way we stumbled on it before, is a disease that has two outcomes, or a screening test that has two outcomes. One outcome is positive, this is the disease is present, or an outcome where the disease is not present, which is negative. And that's why we'd like tests for screening to be very highly sensitive and very highly specific. Anything in the middle, it becomes confusing, and especially in an entity like this, where the downstream test will be a myocardial biopsy, which has its issues and complications. So is this a reliable screening test? Yes, if you talk about disease prevalence of 70%. So in most of the lessons we learned about the sensitivity and specificity of the screening test, actually was where in patients who presented to tertiary care centers with some symptoms of at least two, three, or even four myocardial classification heart failure. And you can see here, even in this population with very high prevalence of the disease, there was a significant number of patients who fell with this equivalent bucket, at around 5%. Now, I don't want to rehash this issue again and talk about it, but the sensitivity that's established right now for our screening modality, which is a technician pyrophosphate or di-pyrophosphate in Europe, is in the range of 97%. But again, it's very important to go back to your medical school days or to residency days and remember that sensitivity is always affected by the prevalence of the disease, and so is specificity. So we have to be careful with that. However, the current guidelines recommend strongly that we use SPECT or even SPECT-CT to differentiate or to improve the specificity of this test, to differentiate blood pool from myocardial uptake, and I will share some examples with you in the next few minutes. So this is a test that a few years ago we were in our—not early experiences, probably this is right before the pandemic—we were reading a stress test in the basement, and we stumbled on this test for a patient with suspected cardiac amyloid. And you can see here on the left-hand side, this is uptake, which you can probably grade as grade one on the planar images. But you can see, as Dr. Soman told you earlier, that we can localize this uptake very well with SPECT and even better with SPECT-CT, where you can see this uptake is not in the myocardium, but rather in the blood pool. Versus this patient, which has a similar grade of uptake, where you can see now the uptake is mostly in the myocardium, and again, it's not in the blood pool. And again, I agree fully with Prem on saying if you see this on SPECT or SPECT-CT, this kind of uptake in the myocardium, this is a positive test. We should not misconstrue this test as grade one or equivocal. Uptake in the myocardium is a positive test by SPECT-CT or SPECT. So I'll share with you a couple of cases to just highlight what we just talked about. This is a 67- year-old male, asymptomatic, history of hypertension and diabetes, presents with, you know, minimal symptoms, again, no symptoms, and he has a normal EKG with normal voltage. He has an echo with increased wall thickness with minimal apical sparing, normal troponins, normal NT-proBNP, and these are tests that I order or we order on most of our patients, if not all our patients at our institution. So a tech PYP scan was ordered on this patient. And here you can see the, at one hour and at three hours, at one hours on the left, at three hours on the right, you have a heart-to-contralateral ratio of 2.1 and then 1.7 at three hours. So this patient was treated for 18 months with tefamidus. He has still no symptoms. He presented actually to see me for blood pressure management. He was remarkably very hypertensive. And whenever I see that combination of patients with possible cardiac amyloid and persistent or resistant hypertension, I usually doubt the diagnosis. Usually patients when they develop ATTR amyloid or AL amyloid, you have a tendency to have a lower blood pressure. And even sometimes patients present to you to tell you that I was, I used to be on three or four blood pressure medications, now I'm on one or two. That's usually a light bulb should turn on and like, you know, alert you that there's something here that's not right. So I repeated the test on him and this is the test we did with a SPECT CT. And again, you can see that all this uptake that they saw on the, on the planar images was actually in the blood pool. There was no uptake whatsoever in the myocardium in this patient. So this patient again was treated with tefamidus for 18 months, asymptomatic, and you can see that the uptake was, of the blood pool was misconstrued on a planar images as cardiac uptake or myocardial uptake. And this is not an uncommon scenario. So what about sensitivity? So all historic data are from an era of patients where, again, we talked about with heart failure class two to four, specialized amyloid centers. This precedes also the aggressive genetic testing, aggressive screening that most of our centers right now follow, such as ours, where we do screening on most of our patients with aortic stenosis above certain age. Now we start screening patients with atrial fibrillation. We're screening patients before left atrial appendage occlusion devices. We screen patients with HEF-PEF of unexplained etiology. So we move to a different era right now of screening. So this is a 73-year-old male, history of dyspnea and exertion, spinal stenosis, hyperlipidemia, hypertension, bilateral carpal tunnel syndrome, septum of 1.7. He's on antihypertensive medications as well as atrovastatin. He has a normal physical exam and a blood pressure of 130 of 85 and a BMI of 37. So this is the algorithm we started adopting recently at our center. This comes from a group in Spain where they have a grading system and you have a scoring here for how likely you're going to have a scan that's positive. So you add a few things that we talk about all the time, like such as carpal tunnel, age above the age of 80, male gender, thickening of the septum rather than hypertrophy of the septum, and low QRS voltage. So if we apply this to this patient, you can see that he has three points for carpal tunnel, three points for male gender, one point for the septum, and the QRS is an issue because of his high BMI. So let's not give him that, but we'll try to apply this here. And you can see this this predictive model says that this patient has a likelihood between 86 of 100 percent of having a positive scan consistent with ATTR. So this is his planar image on this patient. Again, we do the same as Dr. Solman said earlier. We do planar images as well as SPECT images, SPECT CT on all these patients, and this is the heart to contralateral ratio here you see is 1.1. And when you do a SPECT CT on this patient, you can see this uptake right now here in the septum, you can see it here, and the short axis images all over here, and this is now a different diagnosis. On this, on the planar images, this patient does not have, the scan is not consistent with ATTR, versus on the right side now, we can see with this minimal uptake in the septum. And this is what we started noticing in all these patients, what we call early amyloid or screening patients with amyloid, that cohort, they have that kind of uptake. Another case, this is a 57 year old asymptomatic with family history of ATTR, comes for screening. This is, he has normal EKG, normal echo in labs. This is hard to contrast the ratio here of 0.9. You can barely see anything here. But when you do a SPECT CT on this patient, and you can see, again, uptake in the myocardium on the septum and lateral wall with the apical sparing pattern that we see with echocardiography. So why is it important to scan these patients or screen them earlier and screen them before they become symptomatic? This is a nice paper from the National Amyloid Center in the UK, again, showing that these patients who have ATTR confirmed by screening, who still are in stage 1A, meaning before they develop any symptoms and where their NT-proBNP is still normal, these patients have a very good life expectancy versus patients who are stage 1B, where they have no symptoms, but they still, now they have elevation of NT-proBNP, and you can see their prognosis travels along a different path. So it's very important to detect these patients earlier and screen them earlier. So my challenge to the community, and I talk about this all the time, is planar TEC-PYP, or whatever tracer you use, is an insensitive test in asymptomatic patients and in gene-positive patients who are at risk. And therefore, in most of these patients, SPECT or SPECT CT even should be used to screen for these patients. And in a world where we still use disease stabilizers before all the other medications are introduced, I think we need to stabilize the disease as early as possible, preferably while asymptomatic and before they have any imaging or biochemical progression. Best is stage 1A. Now, a small, short, mini-tutorial from the ASNIC guideline about this. This is a very important paper. I think right now my fellows who want to read with me, I refer them to it all the time and tell them, please review this before you start reading so they don't ask me all the questions that are covered in this paper. The interpretation here has moved from relying on planar to relying on SPECT rather than planar images. We do not report degradation anymore. As Dr. Solman said, we just report it whether it's consistent or inconsistent. Be cognizant of potential effects of imaging normalization. Again, this can be addressed by using SPECT or SPECT-CT. You can perform delayed imaging in case of persistent blood pool. We do not do that in general because we image at three hours. And SPECT-CT fusion images, as per ASNIC guidelines, is the preferred method to diagnose these patients. As far as the process of diagnosing these patients, again, after ruling out AL, monoclonal gammopathy, we, at our center, we used to three hours. Other centers use one hour. I don't think there is a big difference in your sensitivity or specificity for this diagnosis. I know the issues would wash out right now at three hours. We're thinking of moving to one hour. But with SPECT-CT, I think you can avoid most of these issues. And finally, it's very important when you're sending a message from a screening test which acts as a diagnostic test, is to be clear in your conclusion. So we report them as suggestive or not suggestive, basically positive, binary, or negative. It's rare for us to have a test that's equivocal because we know that that's gonna lead to biopsies and misdiagnosis. Of course, we will have some instances once a month or once every other month where we have a test that is equivocal. But again, the localization by SPECT-CT avoids all these issues. We have a lot of tests and tools at our disposal, but I think we fortunately have one of the best, which is a great screening test as well as a great diagnostic test if used properly. Thank you. Thank you, Dr. Jaber for that very excellent overview of SPECT imaging and the state-of-the-art in CARI. Now we're gonna move on to a further discussion around these aspects using some case examples. And I'm gonna go first, followed by Dr. Panjoli. These are my disclosures. So Dr. Jaber and Dr. Soman have already talked about the excellent sensitivity and specificity of syntagraphy with bone abtracers. And this is just a different representation of the same data, 100% specificity for grade two and three PYP outbreak. Flight chain disease has been ruled out, but also a 99% sensitivity. And I mentioned PYP at the bottom, but actually the data is pooled data from PYP, HMDP, and DPD. We do want to highlight, and my focus for my portion of the talk is going to be highlighting differences between the two traces that are available in the U.S., PYP and HMDP or HDP. And this has become more relevant because of the shortage that we experienced in 2024 that had actually prevented several sites that I know of from doing imaging for amyloidosis. And we're experiencing another shortage this year which may continue to, at least till May, but also likely beyond. And it's very important to know that there is an alternative, similar specificity in some regards, in my opinion, a better tracer. I'm gonna show some examples of why I think of HMDP to be that as compared to PYP. And to talk about some nuances and some differences between PYP and HMDP and highlight the fact that they should not be treated in an equivalent manner. And there are some specifics about these tracers that we need to talk about. So there are differences in pharmacokinetics of these different bone marrow tracers. This is taken from an editorial in GNC published in 2022 showing the key differences and similarities between these bone tracers, PYP, DPD, and HMDP. Specifically, I want to highlight the long clearance half-life of PYP from blood pool and the soft tissue of about 380 minutes, just about four hours, a little over four hours. For DPD, a much shorter clearance half-life of 100 minutes and for HMDP, which mirrors clearance of MDP of about 144 minutes. So even though they are bone marrow tracers, we use them for amyloidosis imaging. They have good specificity, again, in a population of biopsy-proven amyloid with a prevalence of 70%. These tracers have significant differences in their pharmacokinetics. And we often may not think about this. In cardiology practice, we are imaging these tracers, maybe thinking that these are cardiac tracers, similar to how we image perfusion, but that's not the case. These are bone tracers, and we need to be respectful of that and their individual pharmacokinetics and peculiarities. So I want to highlight, starting off with PYP, this is a very old work done in animal models by Krishnamurthy and colleagues, a seminal work done by them in the 1970s, depicting the clearance of PYP from the blood pool, and essentially shows that at one hour, and I have highlighted these time points and three hours, there's a similar, there's a definite decline in blood pool activity at three hours, but it's not exponentially different than at one hour. And Dr. Soman has already shared with us that their analysis did not find any differences from a diagnostic perspective using SPECT, whether patients are imaged at one hour and three hour, and that has been our clinical experience for the longest time, and others have seen this as well. And this is likely because of the long half-life of PYP, whether you do at one hour imaging or three hour imaging, if there is myocardial uptake, you're likely to see a myocardial uptake at both time points. So this is a very important characteristic of PYP, which is both important for one hour and three hour imaging, but also detrimental in some aspects, because the blood pool activity may also persist at three hours. So this is an example from one of our patients. On the left are the one hour images. This was classified as visual grade three on 10-hour images, HCL ratio 1.33, but no myocardial uptake or blood pool activity, and similar findings, slightly lower visual grade of two, but again, intense blood pool activity at three hours because of the long clearance half-life. In contrast, HMDP has a much shorter clearance half-life from both blood pool and soft tissue. This is a figure taken from a chapter called Bone, from radiopharmaceuticals and nucleopharmacy and nuclear medicine. This is not in the cardiac literature because of course, these are bone traces. I'm marking a three-hour time point here and highlighting the differences in the percent dose in blood and soft tissue for PYP, which is similar to polyphosphate, which is about 10% at three hours and much lower than that for HDP at the three-hour interval. This is an example from one of our patients when we first started doing HMDP or HDP imaging over two years ago, we did both one-hour and three-hour scans. This is a one-hour scan showing diffuse uptake and this was reconstructed in a cardiofocal pattern. However, repeat imaging at three hours looked much less exciting, and it's very likely that this could have been called that this could have been called as equivocal or possibly negative because the tracer uptake is not as marked as it was at one hour. So three-hour imaging with HDP may result in false negative study. This is the same example that Dr. Soman initially alluded to a one-hour HDP scan. This was done as a SPECT CT, shows grade three diffuse uptake, even the RV is lighting up in this case, but repeat imaging at three hours shows that the SPECT there is a significantly reduced activity in the myocardium and concomitantly increased activity in the bones, which is the property of these tracers. Now, this brings us to the point that when we are reporting these studies, we must report the type of tracer that was used and the timing of imaging at which the images were acquired. There is a relative myocardial washout at three hours for HDP as I showed from its clearance curves. And thus it is possible that if you're reporting HDP images at three hours, you're likely to report either a lower visual grade or possibly a complete washout of the tracer from the myocardium. This brings me to the next case, which was just recently imaged. This is a SPECT CT, which is oriented in a four-chamber, two-chamber and a short-axis orientation, one-hour HDP SPECT CT, showing a very focal uptake in the infraceptor region. This is co-registered with CT, and this is why the SPECT CT becomes so important as we diagnose patients at an earlier stage with the lower burden of myocardial disease. However, if this patient was imaged at three hours, which he was, you see that that focal tracer uptake that one noticed at one hour with HDP imaging is now completely gone at three hours. And thus we would have called this patient as being negative, which would have been incorrect in this regard. And we would have missed diagnosis of early focal disease in this patient. Now, we know we have studied this patient very well. This patient was sent for a cardiac MRI because of the focal findings that showed focal thickening of his interventricular septum marked with the asterisk here, the focal elevation of the myocardial native T1, and then focal LGE in the septum and also in the basal lateral wall, which corresponds exactly to that area of tracer uptake on HDP imaging. And this patient has a known PS7TR mutation and had a biopsy that was positive for TTR amyloid from his glaucoma in the eye. This is an example of a patient done in 2023, one hour imaging on the left shows marked tracer uptake on planar images. The spect reconstruction here essentially doesn't conform to typical myocardial boundaries and looks more like a MAGA scan. And this patient had intense blood pool activity. We brought this patient back two months later for HDP imaging, much reduced tracer uptake activity on planar. And again, the blood pool that was so intense for PYP has now gone away. We then sequentially studied these patients, our experience with HDP and PYP. We've switched over to HDP for the last two years since that case I just showed. And we compared the patients who had underwent PYP scintigraphy before that time point and after that. And we found that significant blood pool activity is present in about 15% of patients with a negative spec and only about one to 2% of those with HDP have significant blood pool activity, which is again, pointing towards the differences in washout of these tracers. Please refer to the ASNIC interpretation reporting statement on scintigraphy with bone marrow tracers for further specifics. Dr. Akinjola is going to touch on these things. I just want to highlight that just like ruling out or diagnosing TTR amyloid has several components, scintigraphy with bone marrow tracers, PYP and HDP has several components, including planar, a cardiofocal reconstruction, and also a spec or a chest reconstruction if you acquire in a wide field of view pattern. And Dr. Akinjola is going to touch on these more. Do not use planar images to determine myocardial tracer uptake. This is an example of visual score two, no myocardial tracer uptake, intense blood pool activity, and a myocardial tracer uptake on spec as being zero. So just again, to highlight the fact that a visual score on planar image does not necessarily mean that you will have the same visual score on spec and you should not be interchangeably using planar visual scores or spec visual scores because this is going to result in false findings and reporting. Thank you, and I'm going to hand it over to Dr. Akinjola to talk about other specifics about imaging. Thank you, Dr. Malhotra. Can everybody see my screen? Yes, you do need to put it into full screen. Oh, okay, perfect. All right, thank you. So it has been a great review. And I think some of the cases I will show are maybe overlapping. I can maybe add some technical points. These are my disclosures. So here's a story of two different patients with planar two-dimensional imaging, which show similar heart to contralateral ratios and somewhat similar looking planars. However, when we do the full chest SPECT images on these patients, just like the previous presenters have shown, we do see actually significant difference. One of these patients have positive scan with clear identification of the myocardial borders, and the other patient has persistent blood pool activity. This is a SPECT performed 90 minutes post-injection with the full chest field of view and the landmarks that you can see because they're bone-seeking agent. You have your spine, ribs, and sternum. And it makes the whole world difference when on the planar images, it could have been interpreted as equivocal if we were to rely on planar images only. And here's a cardiofocal reconstruction where some practices perform. And here's your landmarks on the cardiofocal reconstruction, maybe the above the kidneys on the left hemithorax. And as long as the tracer activity is prominent and diffuse, probably this is an easy way to find the heart, orient yourself, and eventually see the slices. It may not be as easy when there is blood pool activity or when there is low-grade uptake or focal uptake. However, when you do the SPECT CT, you can clearly see with the hybrid fusion images nicely oriented with the landmarks that the tracer again is in the myocardium versus blood pool and also you can identify the bilateral small pleural effusions in this patient. So one point is to actually perform the grading on the pool chest SPECT images, not on the planar images, and they are not interchangeable. As you can see, even when there is low-grade, like grade one uptake, as long as the activity is within the myocardium, this is a positive scan. Of course, as long as you rule out plasma disc disease. And this is actually examples of HMDP SPECT, but the same rule goes for the pyrophosphate scan, full chest reconstruction and grading the myocardial uptake on the full chest images comparing the ribs. Here's another example. This is a 61-year-old female with family history of known mutation, amyloid peroneuropathy. And initially she has been seen by a neurologist in 2020 and sent for a pyrophosphate scan and then referred for a cardiologist who worked her up again in 2021. And both of these years she was asymptomatic. In 2022, she developed mild orthostasis and we scanned her for the third time. All these three planar images are unremarkably similar. Here's your landmarks in your SPECT CT. When we do the fusion imaging, you can actually see exactly where you are, even if there is no or trivial uptake within the thoracic cavity, as long as you have your landmarks, such as your spine, your ribs, and your sternum. Even when there is focal and small uptake anywhere in the chest cavity, you can see where it corresponds when you do your full registration. And in this patient in 2021, although when she was still asymptomatic, we did see a very minor focal uptake. And maybe I can show you this little trick. I'm sure most, maybe all vendors have this capability of obliquing the images when you'd like to see your images on a regular short axis, as if you're viewing a cardiac scan. And what you do is as soon as you click on this oblique button, this line appears on the transaxial image. And then you just manually rotate the line to become parallel to the septal wall. And when you do that, your anterior images on the regular SPECT-CT becomes your short axis images, as if you're looking at the myocardial scan. And here in this patient, we have derived these SPECT-CT short axis images, and you can see and comfortably actually say that this activity corresponds to the septal wall, although very low grade. This is the third scan of the patient when she developed orthostasis, and you can see the septal uptake as a crescent and more prominent, although still focal. You might notice the CT is a little different on the third scan, because in the first two, we applied ACER to further reduce the CT dose, which is usually without ACER is two millisieverts. With ACER, with the smart scan, you can lower it down to one millisievert, which adds, which totals to five millisieverts on top of the pyrophosphate scan. Just for comparison, when you're doing cardiofocal and there have been studies performing thallium images, thallium, two millicuries of thallium itself adds 17 millisieverts of dose to the patient. So when you have low dose CT capability, this is the way to go. Also, this is a recent study where Roth and Gilmore evaluated over 3,000 patients who underwent DPD or HMDP scans for amyloidosis. And they have found that actually 98% of the patients with only grade one uptake on SPECT, as long as it's in the myocardium, and ruled out monoclonal gomopathy, 98% of these patients did have TTR cardiac amyloidosis. So grade one uptake is still, as long as it's in the myocardium, counts as a positive scan. And one more example, just to emphasize what else you can see on 3D imaging. This is an 83-year-old patient with multiple red flags for cardiac amyloidosis. Here's his planar images. Although you can see it looks quite abnormal, there is something wrong on the contralateral side, and you might want to move your hand or you might want to move your hand a little bit. Here's the contralateral side, and you might want to move your ROI up or down, but again, it's futile. Maybe you can just do a three-dimensional imaging and figure out what else is going on. So here, this patient turns out has a moderate to large size right-sided pleural effusion with partial collapse of the right lung, which adds counts to the other side. So that's why it's so important to have this anatomic map plus finding out what else is happening in the patient. Here's the slices. And again, you can derive the cardiac short axis images. So where are the counts on the planar image coming from? So are they coming from blood pool activity? Are they coming from extracardiac structures? Are they coming from, again, blood pool, but it's on the right heart chambers? Or sometimes the heart chambers are so enlarged or there's so many other pathologies that the left ventricle is in a place where you can't really derive a proper conclusion. So over the years, we have identified various distribution patterns on the SPECT CT images. And diffuse images with grade two or three is still the most common pattern that we see. However, there are other patterns like focal, focal on diffuse where there's septal predominance, there's diffuse low grade. This is, again, there's an example of maybe grade one. And again, diffuse with apical sparing. These are all the different patterns. And again, you can just review them in short axis slices. So in order to optimize the diagnosis of TTR cardiac amyloidosis, we have a very highly accurate test, but it's important to rule out AL amyloidosis in all cases. Grade one uptake is abnormal and can be early TTR. Blood pool may persist at three hours with pyrophosphate scan as Dr. Malhotra alluded to this very nice washout curve. And greater myocardial HDP washout at three hours. Maybe imaging these patients at one hour is a better option. And PYP and HDP are similar, but not the same. That's why consider one hour imaging in HDP. Planar imaging is not a diagnostic standard anymore. And planar and visual SPECT scores are not interchangeable. SPECT must be performed in all cases. Strong consideration for SPECT CT, which improves diagnostic confidence. And a bit out of scope, we have been getting referrals for patients suspected of cardiac amyloidosis with aortic stenosis. We've been actually doing calcium scoring on these patients too on our low dose scan. And so American Society of Cardiology, again, this has been shown before, but has quality metrics for imaging and reporting, which is really helpful. Lab studies to rule out plasma cell dyscrasia should be performed in all patients. Interpretation should be based on SPECT. Reports should include sufficient technical details to allow proper interpretation of the study findings. So you should include the tracer used, the dose of the tracer, imaging time and parameters. And conclusion should be clear and unambiguous to guide clinical management. So this way we can introduce quality improvement initiatives and which will ultimately improve patient outcomes. So with that, thank you. Hope I'm on time. Thank you, Dr. Akinjolu. I now invite Dr. Soman and Dr. Jaber to come back online. We are at the top of the hour, but I'll just have a few questions to the panel. And this is to all of you. I know, Dr. Soman, you mentioned that you don't use the visual scoring, and I know some labs are doing that. Any advantage of doing that while in treatment? And especially if you think about maybe the need for sequential imaging in the future, would that be something of value from a drug efficacy or a prognostic perspective? Fine. So the reason to move from that is to move away from the diagnostic uncertainty, which can be generated from these numbers. I think, especially with SPECT, because you can have lesions outside the myocardium that can impact at least the visual estimation of the uptakes, it can be an issue. And we have patients, as Prem showed in the MRI, we have patients with very advanced amyloid where the tracer uptake by MRI, very advanced, clinically very advanced where tracer uptake is minimal. And those patients, by SPECT, and those patients should be considered positive. As far as the issue of treatment and prognosis, to my knowledge, short of absolute quantification going forward, I think relying on the visual uptake is misleading to follow these patients. So maybe in SPECT we will have a solution for that. But I think right now with the current tracers we have and the machines we have, I think for the general community, it's just probably best to avoid the numbers. Cheetah, many thoughts from you? Yes, so we have been still doing planar images, but not for diagnostic purposes. I think when you're just starting, it's important to do planar to see where you are in your orientation. Full chest reconstruction, I would strongly emphasize, especially again, when your eyes are not that experienced, finding your way within that focal cardiac area is difficult. And for SPECT-CT, it's great for localization, anatomic map. We have done few cases with repeat images after treatment, one year and two years after treatment. It's just, we have to, I think, find out a way to see how they correlate with the patient outcomes. We do not know yet. We still actually do not know how pyrophosphate localizes in the myocardium and what is the mechanism that actually we see less pyrophosphate uptake after treatment. We still don't know that. Dr. Soman, we all showed cases where we have done chest reconstruction, transaxial pattern. Any closing remarks to the audience as to what they could do to be able to develop that kind of a capability in their labs so that instead of just relying on cardiofocal reconstruction, which most cardiology practices do for perfusion imaging, that we have a wider ability to do a more chest or a transaxial reconstruction, just like a CT scan. So all SPECT, especially on traditional gamma cameras, is acquired as a chest SPECT, right? And when the myocardium shows tracer, whether it's perfusion or whether it's PYP, you then reorient the images to what we are used to, correct? The problem with PYP is, at least with the traditional gamma camera, you don't know whether it's going to be positive or not. And if it's not positive, you don't know where the myocardium is. So there's nothing to reorient. So we always start with, I mean, in the traditional gamma cameras, you can only do a chest acquisition and reconstruction and then reorient if you see tracer in the myocardium. And I'll just make one quick comment. That's the problem with the cardiofocal cameras. You don't know whether the myocardium will take up tracer and then it becomes very difficult to reconstruct the image. Would there be a need for cardiology practices to maybe consider either acquiring or reconstructing, of course, their images or acquiring maybe a software that allows for a transaxial reconstruction, even though the images are acquired, but they may not have the capability to perform a reconstruction in a transaxial fashion. You know, when... So, you know, the camera is going to acquire the images in the long axis of the body, correct? And when you acquire a chest spect, the image you get is a transaxial slice. And then along the long axis of the transaxial slice, you can then reorient it into the images that cardiologists are familiar to. And I mean, I think, you know, because we're all trying to see whether it's positive or negative, as opposed to the cardiac perfusion images where you want to look at anterior wall, inferior wall, apex, you want to correlate it with coronary territories. So that's why we do this orientation. And that 17-segment modeling is what we are used to. But for PYP, I don't think that's important. You know, you just need to be able to identify the myocardium. And if you have SPECT-CT, I think that's the most sensitive method to detect very mild uptake. That's the beauty of SPECT-CT, because you can reorient. Usually, you know, the challenge is when there is some uptake, is it the blood pool that belongs to LV and RV cavity, or is it actually the wall? Because usually they both appear as a linear uptake sometimes. But when you have the SPECT-CT, you eliminate that question. Correct. Wael, any final thoughts from you, Wael? Another thing to pay attention to coming down the line is, you know, especially if you decided to do these studies with SPECT-CT, look at the atria. There is a very big body of literature that's gonna be developing over the next few years about the correlation with the prediction of atrial fibrillation in these patients. So we, right now, we started reporting the left atrial uptake and right atrial uptake, even RV uptake in these patients. But the atria is probably a focus that we'll probably be interacting with another group, our electrophysiology colleagues, to probably inform the likelihood of developing atrial fibrillation in these patients. Yeah, we have a mini-series actually published in 2023, just 10 to 12 patients that we have looked. And there was quite an impressive atrial roof uptake in patients with persistent atrial fibrillation. But again, like more studies needed. So thank you, everybody. With that, I would like to close this webinar. I'm thankful to the faculty and very grateful for the exceptional talks. And then, of course, thank you to the audience for joining us this evening. Thank you so much.

ATTRCM

transthyretin cardiac amyloidosis

Technetium-99m scintigraphy

SPECT imaging

PYP radiotracer

AL amyloidosis

genetic testing

atrial fibrillation

ASNIC guidelines

early diagnosis