Hello, my name is Marcelo Di Carli, and I am going to cover the clinical advantages of PET over SPECT myocardial perfusion imaging as part of this webinar series. Here are my disclosures, nothing to do with the presentation, and here's where we start. We start with the testing options and where does PET fit in and where nuclear cardiology actually fits in. The latest chest pain guidelines have agreed in reviewing the evidence that there's really not much value of testing in patients who are at the very low end of the risk spectrum. Conversely, when patients are very high risk, there is most of the patients actually will undergo to coronary angiography, and the discussion that we're having today is what happens of patients in the middle of these clinical risk spectrum. Nuclear cardiology used to be performed in patients who were in the boundary of the low to intermediate risk, but over time, we have seen that nuclear cardiology studies are actually performed in intermediate high risk patients, and why is that? Because there are other options that are either less expensive or more effective at ruling out disease that are very cost effective, for example, cardiac CT. Coronary CT angiography is now taking the place that used to be dominated by myocardial perfusion imaging in the past, and you can see that nuclear cardiology studies are now being pushed to be done in patients who are much higher clinical risk, and we will discuss what are the challenges with pushing SPECT in doing patients who are much higher risk. The other interesting phenomenon that we need to cover is that coronary disease, the epidemiology of the disease has changed, and what we have seen over the past few years is that most of the angiograms that we perform for patients who have chest pain actually don't show any obstructive coronary disease. Take for example this large data set from the NCDR registry showing that two-thirds of the patients that were referred to coronary angiography for chest pain actually did not have obstructive coronary disease, and this is a phenomenon that is not just a U.S. phenomenon. This has been documented worldwide in multiple registries. Here is a well-known registry from Scandinavia showing that over a period of approximately 10 years, there's been an increase in the prevalence of non-obstructive coronary disease here depicted in blue, both in men and in women, and you can see that the trends are the same for both men and women, but the proportion of patients without obstructive disease, despite the fact that they have chest pain, is much higher in women than in men, and the other thing that these registries have shown is that the absence of coronary obstruction does not necessarily identify low risk on those individuals. So most of our patients will have some combination of atherosclerosis in the epicardial coronary arteries, and then they will have also downstream problems in the small vasculature of the heart, what we call the microvasculature. And so the interplay between the large and the small vessels of the heart will actually define what is now known as ENOCA, which is one of the most prevalent conditions associated with coronary artery disease, and you can see that ENOCA is associated with many of the common cardiometabolic risk factors that are risk factors for coronary disease. So when you look at this interesting review published three years ago, it really showed that the phenomenon of the combination of diffuse non-obstructive atherosclerosis with microvascular disease affects the vast majority of the clinical presentations for the disease that we have clinically, from the obstructive presentations to patients who have non-obstructive disease, heart failure, Takotsubo, et cetera. Now, the epidemiology has changed. We no longer are looking for just the obstructive stenosis. We're looking for the combination of the hemodynamic effects of non-obstructive disease and microvascular disease. Now, this diffuse process of atherosclerosis affects the ability of the myocardium to increase flow, and that presents some distinct challenges for SPECT imaging because we don't quantify flow, we look at flow in one area versus another area. So when we have all the areas with flow relatively reduced, we limit our ability to pick up coronary artery disease. Here's one example. This is a physician in our hospital who has a known history of coronary disease. At a prior PCI, he presented with recurring chest pain, and he underwent an exercise system, maybe a SPECT study, and you can see that during stress, he developed angina, and he developed ST segment changes, as you can see here in the electrocardiogram, but the myocardial perfusion study was pretty normal. There were no perfusion abnormalities. Of course, we had lots of concern about this patient, so he was brought back for a myocardial perfusion study with PET, and you can now see that he has clear abnormalities here involving the inferior and infralateral wall, and his flows are homogeneously reduced. They're worse in the area where the perfusion defect is, but they're not normal even in the LAD coronary artery, and so this, in part, explains why there's an additional challenge to SPECT imaging because we no longer have the ability to pick out the most severe area because everything is homogeneously reduced. The angiogram, of course, showed a critical stenosis here in the right coronary artery that was actually stented. So is this a one-off? No, this is actually a phenomenon that we're now beginning to recognize as nuclear perfusion imaging is pushed to doing more high-risk patients. This is a recent study published in 2022, and the uniqueness of this study is that there were 322 patients who underwent a single stress test, and they were injected with both the cystimib and the rubidium, so we were comparing the performance of both SPECT and PET under the same condition of stress. And of the 322 patients, there were 94 patients that, by PET, they had severe myocardial ischemia. Now, interestingly, on the SPECT study of those individuals, 18% showed no evidence of ischemia, and another 23% showed mild ischemia. So approximately 40% of the patients with no or mild ischemia on SPECT had severe ischemia by PET. So by using better perfusion agents with PET and by quantifying the flow, we're better able to identify areas of abnormalities where SPECT is actually more challenged. Ultimately, when we perform a study, we not only want to make a diagnosis, we want to assess the patient's risk that ultimately we think will guide patient management. So what are the tools that PET uses to doing this? Well, we look at perfusion the same way we look at perfusion with SPECT imaging, except that the perfusion tracers we use with SPECT imaging, with PET imaging, have better physiologic characteristics than those used with SPECT. We also look at ventricular function, but in difference with SPECT, we look at ventricular function at rest and during peak stress as opposed to post-stress, which gives us an additional element to assess the presence of ischemia. Every patient or most of the PET cameras are coupled with a CT scanner, so we get for free the ability to look at the extent of calcified atherosclerosis, as you can see here on the slide, and the actual unique element of PET is the ability to quantify flow pretty seamlessly to assess the presence of diffuse coronary disease and microvascular disease. We look at flow at rest, we look at flow during stress, and then we look at the ratio of stress over rest, which we call the coronary flow reserve. Now is this a research tool? Well, it used to be a research tool, but the latest guidelines, both the Chespin guidelines and now, more specifically, the chronic CAD guidelines, suggest that if you have coronary disease and the patient's symptoms have changed, they specifically mention PET over SPECT if available at your site. And if you do a PET scan, the expectation is that we will quantify myocardial blood flow, because now clinicians recognize that there is incremental value in the quantification of myocardial perfusion. So when we quantify flow, what we look at is the hemodynamic effects of focal stenosis, diffuse atherosclerosis, and ultimately also microvascular dysfunction on myocardial perfusion. And we quantify these at rest, as I mentioned, during peak hyperemia, and then the ratio of the two, which we call the myocardial or coronary flow reserve. Here's one example of how that is applied clinically. This is a 68-year-old male with hypertension, diabetes, presented with atypical angina, and you can see that the myocardial perfusion study is clearly abnormal. There's a small to medium-sized perfusion defect in the lateral wall showing reversibility shown here on the polar map. But when you quantify the flow, there's a different picture. Not only do we see a reduced flow in the circumflex territory, which is the area where the defect is, but we also see abnormal flow augmentation in the LAD and in the RCA coronary artery. And the reason for that is that patient has high-risk coronary artery disease, indicating that when you have balanced reduction in flow, even with PET, you will pick out only the most severe, least-denosed territory, and when you quantify flow, you bring up the sensitivity of the study to pick up coronary disease in areas that were visually normal. This has been proven to be a very accurate approach. The PACIFIC trial did a comparative effectiveness of PET, SPECT, and CT, including CT-FFR, and shown that it is the most accurate approach for detection of flow-limiting coronary disease, as defined by a stenosis greater than 50% that has an abnormal FFR. So the ultimate gold standard for flow-limiting disease. The other interesting aspect with PET is that missing balanced ischemia, even when you don't quantify flow, is pretty rare. And you can see here in this very large cohort of patients with both PET and coronary angiography that there was only about 3% of patients that had severe three-vessel disease or left main disease who actually had completely normal perfusion, no evidence of perfusion defects. Now, the advantage of PET is that when you add the response of the ejection fraction to stress and you quantify the flow, you essentially don't miss, or it's very rare that you would miss a patient with high-risk coronary artery disease. So there's evidence for that. Now, we talked a lot about diffuse atherosclerosis and microvascular disease, and this is, you know, comprised two-thirds of our patients that don't have obstructive coronary disease. And you can see that both men and women, the prevalence of this problem is very high. This is a cohort of 1,200 patients without obstructive disease, and you can see that 50% of men and women will have abnormal microvascular function, indicating the presence of microvascular disease. And when it's present, both men and women have much higher clinical risk. In terms of risk stratification, there's plenty of data now from multiple labs using different cameras, using different tracers, and showing consistently that when you add flow on top of the routine semi-quantitative analysis of the images, we gain risk stratification. We're better separating the very high and the very low-risk patients among high-risk populations. And we combine both the flow reserve and the stress flow to get these distinct groups of patients that have very different clinical risk that allows us to identify or to delineate how to manage those individuals in terms of further management or further evaluation, and ultimately, which are the patients that may need revascularization. One last point is that the integration of the flow quantification on the perfusion pad allows us to reclassify patients. And here is one example of that. These are two diabetic patients that have either chest pain or dyspnea, and both have normal myocardial perfusion, no evidence of perfusion abnormalities. And the question is, which of the two is higher risk? Based on these data, we would suggest that both are equally low risk. So once I show you now the flow data, you can see that this patient has normal augmentation of flow, normal coronary flow reserve, whereas the patient on the bottom has a blunted increase in flow and a reduced coronary flow reserve. And now with this data, we can clearly identify that this patient is actually higher risk than this individual. And where's the data to show you that? Remember this. This is a comparison of patients with and without diabetes. In this case, you have all diabetics without known coronary disease. These are patients with relatively reduced flow reserve, and these are patients with relatively preserved flow reserve. And you can see that there is a clear distinction in the risk of cardiac mortality between these two. And when you compare these patients, for example, to patients who do not have diabetes but do have prior revascularization of myocardial infarction, you realize that the flow reserve becomes our CAD risk equivalent marker that we have adjudicated to diabetes. You can see that when the flow reserve is relatively preserved, those patients look similar to patients who don't have CAD or diabetes. So it's a very powerful tool that we can use to risk reclassify our patients. Ultimately, can we use these to guide management? Well, we don't have randomized clinical trials, but the data suggests that maybe the flow reserve as our marker of ischemia will be a critical measure that we will use in the future to decide which patients need revascularization to improve their symptoms and perhaps even to improve their outcomes. So the data we have so far comes from this large study from Kansas City showing that indeed in propensity match cohorts, you can see that myocardial flow reserve, very reduced flow reserve, has an advantage with revascularization compared to medical therapy. But that will have to be confirmed in randomized trials. So in conclusion, we're witnessing a very dramatic change in both clinical and angiographic presentations for coronary disease, which are associated with the surge of cardiometabolic disease. The predominant anatomic phenotype is going to be one that combines diffuse non-obstructive coronary disease in large vessels and both structural and functional abnormalities in the small vessels of the heart. Quantitative PET offers improved accuracy for the evaluation of the entire spectrum of CAD presentations. That is, both the obstructive phenotype of coronary disease and the more prevalent non-obstructive disease and microvascular disease phenotype that we have been discussing. Flow quantification also improves risk stratification for CAD, as I mentioned. And we are witnessing a transition to flow-based quantification of myocardial ischemia for the evaluation of chronic disease and hopefully in the future for making decisions regarding revascularization. Thank you very much for your attention.

PET

SPECT

myocardial perfusion imaging

coronary artery disease

microvascular disease

risk stratification