Welcome, everybody. Thank you for ASNIC for inviting me to give this talk. I'm Ed Miller from Yale, and I'm going to be talking about cardiac sarcoid PET imaging and clinical data. Here are my disclosures, none of which are really relevant to this presentation. So our learning objectives for this talk are threefold. I want you to understand the optimal patient preparation for FDG PET imaging for cardiac sarcoidosis. We're going to describe the various methodologies for interpreting FDG PET for cardiac sarcoidosis, compare and contrast existing methodologies and perhaps potentially some novel methodologies for interpretation of FDG PET. And we're going to use and discuss the use of FDG PET for the diagnosis, prognosis and response to treatment of patients with cardiac sarcoidosis. So to talk about the clinical roles for F18 FDG PET and cardiac sarcoidosis, we really focus on two areas, diagnosis and treatment. And in diagnosis, we're looking at the identification of extracardiac sarcoidosis because that identification of extracardiac disease is so important to our understanding of the likelihood of cardiac disease in the patient. We're going to understand that there are different FDG and myocardial perfusion imaging patterns for the identification of cardiac sarcoidosis on imaging with our PET scans. We're going to look to define extracardiac sarcoidosis and how we do that on imaging, particularly in the evaluation of acute avian autoblock. From a treatment perspective, we're going to use FDG PET to identify those patients that need immunosuppression, in particular those with the positive FDG study or those with, contrasting those with a negative study in the setting of a prior CMR with late gadolinium enhancement, as well as talk about the use of FDG PET to titrate immunosuppression. Here are some examples, and we'll go over these examples and what they mean later in this talk. I'd like to highlight two sets of guidelines that are now a couple of years old, but still very relevant. The first is the SNMI ASNIC expert consensus document on the role of PET-CT in cardiac sarcoidosis detection, monitoring, and therapy. The chief author on that is Panethia Chariot-Dataweek. The second is the EANM EACVI ASNIC guidelines on procedural imaging of imaging, a statement on imaging and cardiac sarcoidosis. This includes PET, but also includes other methodologies for the identification of cardiac sarcoidosis. Much of the talk, much of the detail that I'm going to be highlighting in this talk comes from these guidelines in some form. So taking a step back to let us understand where cardiac sarcoidosis is in the epidemiology of the disease, this study looked at hospitalization rates from the national inpatient sample and the prevalence of cardiovascular manifestations and outcomes associated with sarcoidosis in the United States. And what you can see here is that over the course of the past decade or so, the rates of hospitalization for sarcoidosis appear to be increasing and for factors that we don't quite understand, but could be due to things such as detection bias. Nonetheless, we see that in those patients who have sarcoidosis and are admitted, the prevalence of cardiovascular manifestations of sarcoidosis are quite significant. And they can include heart failure, arrhythmias, conduction disease, and pulmonary hypertension and an ischemic cardiomyopathy. So it highlights the major clinical problem that cardiac sarcoidosis represents in patients who have sarcoidosis. Now, not every patient that has sarcoidosis has cardiac disease. In fact, cardiac disease is clinically evident in only approximately 20% of our patients with sarcoidosis. While the reports on subclinical involvement by imaging or other ways of detection vary depending on the definition, we do think that a significant percentage of our patients with sarcoidosis have some degree of cardiac involvement either clinically or subclinically. When we talk about the problems that occur from patients with sarcoidosis, a major cause of death in patients with sarcoidosis is cardiac involvement, up to 70%. Unfortunately, the antemortem diagnosis can be challenging, symptoms can be nonspecific or absent. And so screening for cardiac sarcoidosis, understanding the risk of an individual patient with sarcoidosis for cardiac involvement is really important for the practicing cardiologist. Now turning our attention to FDG PET for cardiac sarcoidosis, I want to focus on patient preparation and interpretation of the exam. With FDG PET imaging for cardiac sarcoidosis, the methodology relies on the ability to manipulate myocardial substrate utilization in order to reduce endogenous glucose uptake so that we can identify inflammatory disease, areas of myocardial inflammation, myocardial infiltrates, inflammatory infiltrates in the myocardium through the use of FDG. To manipulate the myocardial substrate utilization, we can use a couple of different methodologies. One of the most common methodologies is a prolonged fast following a low-carbohydrate diet over 12 hours. This is relatively simple, realizing that you have to do a lot of patient education, as I'll point out, in order to ensure the patient follows the appropriate diet and follows the strict fasting protocol for over 12 hours. When a practical issue with this dietary preparation is that labs might want to schedule their studies for the late morning rather than the afternoon so that patients can begin their fast after dinner the night before but still have a prolonged period of fasting. So, for example, in our laboratory, we tell patients to stop eating after 6 p.m. the night before and then schedule our FDG exams for approximately 9 a.m. the following morning. This reliably gives us 15 hours of dedicated fasting, most of which is occurring while the patients are sleeping, enhances compliance. As you're undergoing the fasting protocol, though, watch for things that have sugar in them or glucose in them that one might not realize. In inpatients, this can be quite challenging. For example, IV medications that include dextrose, 5% dextrose, such as IV magnesium or IV amiodarone. Other preparations try to shift substrate metabolism using high-fat, low-carbohydrate diets with a shorter fasting period. This can be relatively complicated and has a slight bit more variability with risks of standardization depending on the particular social or cultural milieu of the patient and what their dietary standards may be. As you can see here, this is an example from a Japanese publication showing their high-fat, low-carbohydrate diet, which would certainly be significantly different than what would be consumed by a normal American diet. Another option to increase myocardial free fatty acid uptake and reduce myocardial glucose utilization is intravenous heparin. The data on IV heparin prior to FDG pedigree for inflammation is quite mixed, but some laboratories use heparin, realizing that there is a balance of efficacy versus risk in giving somebody systemic anticoagulation and all the issues that might go along with that in terms of monitoring and patient assessment risk. Here are some examples of patient instructions that we give our patients at Yale. We provide these very detailed instructions and go over them with the patients by our laboratory nurses or staff, emailing these instructions, mailing these instructions, ensuring that the patients have the ability to understand what we're asking them to do. So, we want them 24 hours before the exam to eat a high-fat, low-carbohydrate diet. We want them to eat particularly low-carbohydrate foods, particularly unsweetened, non-breaded foods, and not eat foods containing carbohydrates and sugars, focusing out also on things like liquids that may contain sugar or artificial sweeteners. So, artificial sweeteners, most of which, while not sugar, do lead to endogenous insulin release should be avoided. And then we're very strict at emphasizing that after dinner the night before the test, we want them to fast until the test is finished the next day, drinking only clear water. We also give all of our patients a food diary, so that when they come in for the exam, we can have some idea in greater detail about what they ate the night before, so we can understand and interpret the exam in that context. So, that's our patient preparation. Let's talk about now moving into interpretation. There are two main imaging patterns of FDG PET imaging for cardiac sarcoidosis. They include a complete nulling of myocardial glucose uptake, as shown here, where you're seeing an inverse image where the outline in the purple areas is actually the myocardium, and the only thing we're seeing here is blood pool. Conversely, this is an abnormal study of FDG PET where we're showing areas of focal FDG uptake throughout the anterior apical portions of the myocardium in the basal lateral wall. You'll also notice that in these examples, we're showing concomitant myocardial perfusion imaging. It's important to add myocardial perfusion imaging to our imaging protocol, usually through PET, but SPECT is appropriate as well. It can be utilized. In order to look for areas of myocardial scar, as you can see in this example, you see an infralateral perfusion defect consistent with a prior area of myocardial inflammation potentially, and consistent with an area of scar adjacent to an area of FDG uptake. So, I'm showing you these images displayed in a conventional myocardial perfusion imaging display format, realizing that as we're going through this, I'm going to advocate for a different approach to our interpretation. The reason that we might need to use different interpretive strategies for FDG PET than what we use for myocardial perfusion imaging is the difference between myocardial perfusion imaging as a cold spot technique, and FDG PET imaging as a hot spot imaging technique. So, with FDG PET imaging, excuse me, with perfusion imaging, we're looking at a cold spot, or we're looking at relative differences in the perfusion uptake, and we're looking at to define areas or absence of counts. In FDG PET imaging, we actually want to display our FDG image in absolute terms, so we can understand the intensity of the hot spot in absolute terms, rather than in relative terms. Here's a nice example of how SUV scale images or non-normalized images can be useful. So, you see on the left here in panel A, this is a traditional myocardial perfusion imaging display format, where we have short axis images of perfusion on top in the first row and in the third row, and then the FDG images below. Alternatively, we like to use a fused hybrid imaging display, where we have the PET CT images overlaid on each other, and the images displayed in intensity of zero to seven grams per ml SUVs. This is a relatively arbitrary scale, and zero to five or zero to seven are commonly used scales, but it allows us to ensure that we're not dealing with normalization artifact or scaling artifacts that can occur. In addition, on the myocardial perfusion display, you see these focal areas of FDG, which might be difficult to anatomically localize without the concomitant fused PET CT image. So, we advocate for the use of fused FDG PET imaging using an SUV scale for interpretive approaches. The methodologies that can be used to interpret FDG PET imaging for cardiac sarcoidosis include those visual scales, where we're using normalized, we call angle-corrected, or myocardial perfusion imaging display patterns, with the classic pattern of focal myocardial uptake of FDG being consistent with active cardiac sarcoidosis, realizing that diffuse or focal undiffuse myocardial FDG uptake have also been reported in cardiac sarcoidosis exams. The problems with this approach include studies with mild uptake, displaying focal uptake in areas where it might be difficult to do a reconstruction without the CT overlay, more importantly, understanding extracardiac uptake, which can be an important surrogate to our understanding of the total burden of disease, and then obviously, any visual display scheme where images are normalized, quantifying change in terms of progression or response to treatment will not be possible. We think that the absolute intensity of F18 FDG uptake is probably important, and so using semi-quantitative tools based on standardized uptake values, where we're correcting for the decay correction of FDG as a percentage of the measured activity in the patient's weight, and we can display and report semi-quantitative approaches such as SUV max, or the maximal intensity SUV pixel in the image, the mean intensity of SUVs, the total SUVs. We can display our terms, our images relative to heart-to-blood flow, or as a percentage of variance, or the volume of abnormal FDGs, the volume and intensity of abnormal FDGs, such as cardiac metabolic volume or cardiac metabolic activity, etc., and increasingly, the field will be moving towards dynamic or K1 measurements of FDG uptake to hopefully differentiate areas of nonspecific myocardial uptake from areas of true inflammation. Here's one approach that we've advocated for using SUV thresholded interpretation from a hybrid imaging display system where we're looking at the axial image of the heart. You can see that we've created a volume of interest around the myocardium, and we've defined certain areas. We've defined the LV blood pool. We use this as a marker of intensity of the image, and then we create isocontours of the volume of abnormal FDG uptake based on the LV blood pool value and identification of cardiac SUV max here as well. So, now that we've gone through preparation and interpretation, let's talk about some clinical cases where we can use FDG PET imaging. The first is in the diagnosis of cardiac sarcoidosis, and particularly the identification of extracardiac sarcoidosis, and moving towards the concept of probabilistic diagnosis in our approach to our patients. So, why is it important to understand sarcoidosis in a diagnostic perspective? It's because sarcoidosis is a systemic disease. So, when we're looking for cardiac sarcoidosis, it's important to identify areas of systemic sarcoidosis. We need to understand that the chest x-ray or chest CT can identify thoracic involvement, whether it's pulmonary parenchymal or media-style lymph nodes in approximately 80 to 90 percent of our patients. But don't just stop there. A good skin exam looking for lupus perneo, keloids, tattoos, erythema nodosum can point us to areas that our dermatology colleagues can biopsy. Ophthalmologic evaluation can identify 25 percent of our patients that have ocular involvement, including conjunctival involvement, and laboratory data, such as alterations in calcium and vitamin D metabolism, urine calcium, or markers of inflammation, such as the ACE level, but more importantly, cardiac disease, probably soluble interleukin-2 receptor levels that have been associated with cardiac involvement. So, here's a nice case of how we can use FDG PET imaging to define extracardiac disease. This is a 75-year-old man who had a history of pulmonary emboli and presented with chest pain and new conduction disease, a new right bundle and left anterior fascicular block, which in isolation may not be indicative of sarcoidosis, but certainly is a common imaging pattern that we see in patients with cardiac disease. He had mildly depressed left ventricular systolic function and echocardiography and underwent a negative left heart catheterization. CMR was what was obtained, cardiac MRI, which showed some late gadolinium enhancement and mild left ventricular systolic dysfunction. He had no known systemic sarcoidosis at this point, so we're dealing at that point with a patient who has conduction disease, LD dysfunction, and some abnormal MRI findings, but again, no systemic sarcoidosis to tie everything together. So, here's the fused PET-CT image. The PET will be in red, and obviously the CT is in gray, and I'll play it for you here as a movie. What we can see as we're going through the axial image are areas of multifocal cardiac FDG optics shown here in yellow in the septum and the lateral wall as I scroll through, some degree in the left ventricular free wall as well, but more importantly, look at the subcarinal lymph nodes there, metabolically active, and in the bilateral hilo. So, this patient had multifocal cardiac FDG uptake, including the infraceptal lateral walls. He was found to have pulmonary nodules, which we can also see slightly on this, I apologize for the quality of this image, subcarinal FDG avid lymph nodes, and an elevated soluble IL-2R level. He subsequently underwent endobronchial ultrasound guided biopsy of these lymph nodes, was found to have non-caseating granulomas consistent with sarcoidosis, again, tying in and unifying the diagnosis that the patient now has systemic sarcoidosis, a classic imaging pattern in CMR and FDG PET, as well as conduction disease consistent with sarcoidosis. Data out of Finland have validated the use of FDG PET to identify areas of biopsy. They used gadolinium-enhanced MRI and FDG PET imaging to target biopsies, whether it's cardiac or extracardiac, including mediastinal lymph node biopsies, to areas of FDG uptake, and found that that increased the diagnostic yield to identify patients with sarcoidosis. And so, not just understanding the cardiac involvement, but also understanding extracardiac involvement is very important for our patients. Using imaging studies together, such as in this case, is also very important. And this is a wonderful approach advocated by the group of Brigham Women's, Dr. Vita and colleagues here at Cirque Imaging in 2018, where they use various imaging patterns to understand the probabilistic likelihood of a patient having cardiac sarcoidosis. It's very rare that we're able to identify with 100% certainty that a patient has the disease, but we can use a combination of MRI likelihood and PET likelihood to identify patients that have either low likelihood of cardiac sarcoidosis or very high likelihood, or somewhere in between, of having the disease. That's based on these imaging patterns, such as the one I showed you, where you have multiple areas of focal FDG and areas of abnormal light gadolinium enhancement together can be used to create a probabilistic diagnostic framework that can be useful for our clinical understanding and treatment of our patients. Another great use of FDG PET imaging for CS is the evaluation of acute AV block. Here's a nice case example of a patient presented with complete heart block. He's a 45 year old man who two years ago had new unexplained complete heart block. At that point, line testing and genetic testing were negative and a CMR in the interim was obtained, which showed faint anterior light gadolinium enhancement, but normal systolic function. Now, however, he's presenting back with mild left ventricular systolic dysfunction. And the question is, is there a unifying way, was something missed? And is there a unifying condition for his diagnosis? Here again, from a fused axial, fused FDG and PET image, you see really one of the most classic FDG PET scans I've ever seen for cardiac sarcoidosis. Starting in the liver, see multiple areas of focal FDG uptake throughout the hepatic parenchyma. And then as you get into the myocardium, you see very intense left atrial and RV free wall FDG uptake, very intense septal FDG uptake, multiple areas in the lateral wall. And also, again, these areas of focal mediastinal and hilar lymph nodes that are FDG avid. So this patient, again, underwent endobronchial ultrasound kind of biopsy of those lymph nodes to diagnose non-caseating granulomatous inflammation consistent with pulmonary sarcoidosis and unify our diagnostic approach to this patient, who then subsequently was treated with corticosteroids and methotrexate for his cardiac disease. One of the interesting concepts as well, as we combine cardiac MRI and FDG PET imaging, is that the different areas of different anatomic regions of myocardial involvement, whether it's delayed enhancement, increased two-way signal or FDG uptake, can define different patterns of disease. So septal predominant abnormalities, particularly in FDG uptake, identify those patients who have complete heart block, which makes sense in the area of the AV node. And those patients who are primarily arrhythmogenic, for example, who don't have complete heart block or have non-specific left ventricular dysfunction, they predominantly have areas of scar formation in areas of the septum, inferior wall, etc. So the clinical presentation goes along with our imaging features, and we can use our imaging features to understand how a particular patient might clinically present. Our last series of case vignettes will be focused on defining treatment response using FDG PET. So we know from, again, from the Brigham group in a seminal paper from 2014 from Blankstein and colleagues, where they looked retrospectively at the Boston experience, and they identified that the combination of abnormal perfusion on myocardial perfusion imaging at the time of FDG PET imaging, a combination of these two abnormalities, was associated with a higher risk of death in ventricular tachycardia. This puts into the concept that we can use FDG PET imaging as a prognostic tool. Further data has shown that patients who we identify as having abnormal FDG or then treated with immunosuppression and have a reduction in the FDG signal, have an improvement in their ejection fraction measured by echocardiography. So said more simply, responders on FDG improve their heart function with immunosuppression. And here's a nice example from our lab. So again, an axial fused image, 0.7 grams per ml scale, and you see that there is marked, again, areas of abnormal FDG uptake throughout the myocardium and the metastinal and pulmonary parenchymal lymph nodes. This patient was treated with a combination immunosuppression. You see that the hepatic parenchymal disease and the cardiac disease nearly completely resolved. I can tell you this is not a scaling error, right? You see that the scale here is 0 to 7 grams per ml in both sets of imaging. And we've measured semi-quantitatively SUV values, 11.9 SUV max in the before prednisone image and 2.6 SUV max nearing normal in the after prednisone image. And our group has shown previously that we can look at multiple markers of treatment response, and this is looking at patients who underwent a baseline exam that were treated, and then their treatment was reduced or tapered for surveillance. We can see that things like cardiometabolic activity or cardiometabolic volume and SUV max all respond to treatment to various degrees. We also can see here that there is some rebound in the FDG signal after we reduce our therapy. So, what's the data to even show that therapy is useful? We're waiting for prospective data on that trial called the CASM-RCT trial, amongst others. The CASM-RCT trial led by David Burney and colleagues out of Canada is enrolling patients currently to identify, hopefully be able to provide us further evidence that immunosuppressive treatment in patients with cardiac sarcoidosis is useful. But the best data we have to date are case series, and this is summarized in a meta-analysis several years ago where a group out of Canada evaluated the use of steroids and found a beneficial signal on systolic function and VT in patients who are treated with corticosteroids. How about the use of corticosteroids plus other immunosuppressive drugs? There are some data that suggest that the combination is better than one alone, although in other studies out of Europe that data has not been reproduced. So, in summary, I utilized this treatment algorithm to some degree with some modifications in individual patients. If we suspect cardiac sarcoidosis, we're going to identify extracardiac disease either by CT chest, skin exam or derm exam, eye exam, metabolic testing, inflammatory testing. We would generally start in patients who are screening to start with imaging with cardiac MRI. In those patients who can't get MRI or a high clinical suspicion persists despite inconclusive MRI, or those patients with an acute heart block, I will start with FGG-PET as our first imaging tool. If FGG-PET is negative in those patients, I think that there's no indication for immunosuppression and those patients should be followed and look for scar predominant features either with CMR or other tools. And those patients who do have active inflammation in FGG-PET, in many cases those patients should be treated with immunosuppressants. In an FGG-guided approach to treatment, we'll use FGG-positivity as a gatekeeper for the initiation of immunosuppression. It's commonly using prednisone, although the combination of prednisone plus methotrexate or methotrexate alone are certainly reasonable options depending on the patient's clinical scenario. We need to understand on patients we treat with immunosuppression, we need to be mindful and prevent immunosuppressive side effects in the case of prednisone, osteoporosis, PCP, prophylaxis, etc. And we will repeat the FGG-PET image on treatment in our institution. So we'll understand with the same prep, FGG dose and incubation time, has there been a quantitative reduction in the myocardial FGG? If there is, then in many cases we'll start to taper our immunosuppression. If there's not or clinical scenarios lead us to want to increase immunosuppression further, we will consider repeating the image after increasing the immunosuppression. So in summary, our FGG-PET imaging is useful for cardiac sarcoidosis, but the patient preparation requires strict attention to detail, patient and laboratory education. When we're interpreting these exams, an SUV-scaled image review may be beneficial for interpreting FGG-PET for cardiac sarcoidosis, particularly because it improves specificity and identifies extracardiac areas of FGG uptake. In treatment response, FGG-PET has high utility in the diagnostic evaluation, as well as determining the necessity for and the titration of immunosuppressive therapy. So thank you very much. This is our laboratory at Yale prior to COVID. Hopefully we'll be getting back here and all together in the near future. Thank you for your attention, and thank you again for ASNIC and the PET Council for putting this together.

FDG PET imaging

cardiac sarcoidosis

patient preparation

interpretation methodologies

extracardiac sarcoidosis

acute AV block