Good morning, everyone. My name is Dr. Krishna Patel. I'm a cardiac imager based out of Mount Sinai Health System in New York City. And today we're going to talk about how we can use myocardial blood flow quantitation on stress-fed MPI to identify different phenotypes of ischemic heart disease, namely obstructive epicardial coronary artery disease and coronary microvascular dysfunction. I have no disclosures relevant to the content of this talk. So let's first talk about why this is important, right? Why are we talking about it? Traditionally, we've always focused our diagnostic testing for ischemic heart disease on diagnosing patients who have obstructive epicardial coronary artery disease. However, we have data from multiple centers across many continents, including this one, which is an analysis from the ACC and CDR database, which show that as many as half of all women and a third of all men who do undergo diagnostic coronary angiography for symptoms of stable angina do not have any evidence of obstructive coronary artery disease. And then that this is not a benign condition, that even these patients who have supposedly normal coronary arteries or diffuse non-obstructive coronary artery disease on angiograms and have symptoms, they had higher rates of adverse cardiac events compared to a reference population. And typically, the cause of these symptoms as well as ischemia among these patients with non-obstructive disease are related to a combination of diffuse non-obstructive epicardial atherosclerotic disease as well as coronary microvascular dysfunction, which refers to structural and functional abnormalities of the microcirculation, both of which make up the predominantly the larger phenotype of ischemic heart disease among adults. So traditionally, when we talk about myocardial perfusion imaging, we are referring to diagnosing obstructive coronary artery disease by looking at perfusion uptake, relative perfusion uptake. It's based on the concept that any area of myocardium which is subtended by a vessel which has significant obstructive coronary disease will have less perfusion, that is less tracer uptake compared to a region which does not have significant obstructive disease which we take as normal. So we look at this relative decrease in tracer uptake. This initially occurs at stress. We look at a relative decrease in tracer uptake in one region compared to a normal region to identify areas of ischemia or reversible perfusion defect on MPI. We do this both with SPECT-MPI as well as SPECT-MPI, but with SPECT, we have a lot of other information that we get which can help us identify the other phenotypes of ischemic heart disease in addition to just obstructive coronary artery disease. Now this includes LVEF assessment at SPECT, particularly with rubidium tracer, which is the predominant tracer that we use currently, we are able to measure wall motion and LVEF function at peak stress versus with SPECT where we measure it at about 30 to 60 minutes post-stress. So the wall motion abnormalities at peak stress and the drop in LVEF with stress that we get with SPECT also provides additional information which is helpful for diagnosis and prognosis. Majority of the stress PET that we do are done on PET CT scanners. So majority of the times we end up getting a coronary calcium assessment, either using a gated calcium score or if a gated calcium score is not performed, we always have a low-dose chest CT scan for attenuation correction where we can look at it to identify calcified atherosclerosis. Now this can help us identify subclinical calcified atherosclerosis, which does not result in perfusion abnormalities. But perhaps the most important information that we do get from a stress PET study in particular is the ability to non-invasively quantify the actual amount of blood flow that is reaching the myocardium at stress, at rest, and measure something called the myocardial fluorescence, which I'll talk about in a minute. So when we look at the schematic of coronary circulation and look at the different metrics, physiologic metrics that are available to us to assess the significance of disease, measures such as FFR or fractional flow reserve, they measure the pressure drop across an epicardial stenotic lesion. So it helps assess the severity of an epicardial focal stenosis, whereas myocardial flow reserve or coronary flow reserve, what we measure on PET, this is the ratio of stress myocardial flow to rest myocardial flow. PET assesses the hemodynamic effect of coronary disease throughout the entire coronary circulation, including the epicardium and microvasculature on myocardial perfusion. So myocardial flow reserve can help us diagnose disease in the microvasculature as well as disease epicardially. With PET, we typically, with flow assessment, we get three pieces of data. We get the absolute myocardial flow at rest. We get absolute myocardial flow at stress in the 17 LV segments, and then we get flow reserve, which is stress divided by rest myocardial flow. So before we go on and look at examples, let's talk about what are normal myocardial blood flow values. It's important to note that absolute values of myocardial blood flow may differ slightly between different software that we use for quantifying these flows. However, the ratio or the myocardial flow reserve is comparable across different software. Rest myocardial flow typically ranges between 0.6 to 1.2 mL per minute per gram of myocardial tissue, and normally it's proportional to the resting rate pressure product, so it's proportional to the myocardial work that our heart does at rest, which is the product of resting heart rate and resting systolic blood pressure. So among patients who have either tachycardia or resting hypertension, when they have an elevated high or high resting rate pressure product, they may have higher values of rest myocardial flow, and it's also typically higher among women and obese patients. The values of stress myocardial flow and myocardial flow reserve varies with age and sex. Typically it's higher in 2.5 to 3 range in younger individuals, and as patient age it kind of falls, and it's lower in females. But as a general rule of thumb, stress myocardial flow normally is generally greater than 1.8 to 2 mL per minute per gram of myocardial tissue, and myocardial flow reserve of 2 or greater is considered low risk among patients, symptomatic patients who present with chest pain. So let's look at examples. This is a perfusion scan, a PET scan of a 67-year-old male with CKD hypertension who presents with often on atypical chest pain. You can see here, so stress images are on top, rest are on bottom, and you can see that there is a small reversible perfusion defect predominantly at the base and the mid-inferior region in the right coronary artery territory. And when we look at the flows in this patient, the myocardial flow reserve, let's focus on the flow reserve, is decreased in the RCA territory, so it's less than 2. It's decreased in the RCA territory, and the myocardial flow reserve is normal, greater than 2 in NAD and circumflex territory. Stress flows are kind of mildly to moderately reduced in all three coronary territories, which represents diffuse non-obstructive atherosclerosis, which we'll get to in a minute. But when you see this type of pattern, where there is regional reduction in myocardial flow reserve, along with a perfusion defect in that same region, and the flow reserve is normal in other territories, that pattern is suggestive of single vessel obstructive coronary artery disease, which is what was confirmed on this patient. Compared to this, let's look at this other patient, who also has multiple cardiometabolic risk factors and is presenting with exoskeletal dyspnea. Again, this patient also has a reversible perfusion defect in the kind of just basal inferior region, as you can kind of see here. But when you look at the flows for this patient, this patient has a diffuse global reduction in stress flows, as well as flow reserve, in all three coronary territories, not only in RCA, but also in the LAD and circumflex territories. So when you see this pattern of abnormal perfusion with a global myocardial flow reserve reduction, there is concern for multi-vessel involvement, multi-vessel obstructive epicardial disease. In this patient, he also had multi-vessel coronary artery calcification, and a drop in EF on stress, both of which are, again, high-risk markers, which suggest the presence of significant multi-vessel disease, which is what was confirmed on this patient, who was then referred for bypass surgery. The one concern that we have with perfusion imaging, especially with SPECT, is when there is a multi-vessel high-risk obstructive epicardial C and E, because there will be reduction in flow in all or majority of the heart, we might not be able to identify high-risk disease while just looking at relative tracer uptake or the perfusion images, something that a phenomenon called balanced ischemia. We looked at this. Typically, the rate of balanced ischemia, where you would have completely normal perfusion, we're talking about relative perfusion, completely normal perfusion, and the patient has high-risk multi-vessel obstructive disease on PET, is very low. It's about 3%. And even among those patients where the perfusion was completely normal, all of those patients, the other high-risk markers that we talked about, the myocardial flow reserve and the LVEF reserve, they help pick up high-risk disease among those patients. So we don't really miss balanced ischemia on PET, and the rate of balanced ischemia on normal perfusion is quite rare. So typically, if the patient has any obstructive epicardial coronary artery disease, in 97% of the patients, you will see some sort of a perfusion abnormality along with reduction in myocardial flows, which will point you towards obstructive epicardial disease. Now let's look at another example. This is a patient where, again, stress is on top, the rest is on bottom, has this kind of mild, small, reversible perfusion effect in the anterior region, in the diagonal territory, otherwise normal perfusion. And when you look at the flows, the rest flows are okay in this patient. The stress flows, especially in that LAD, the anterior region, which has the perfusion effect, are mildly decreased, but the flow reserve in that territory is normal. So when you see this type of pattern, then you should think about whether or not this patient has diffused non-obstructive epicardial CAD or not. And there are other things on the flow that can help us differentiate between obstructive and non-obstructive disease. So what other information can we use to help us identify whether that perfusion defect that we're seeing, is that from obstructive CAD or non-obstructive CAD? So we can use something called a relative flow reserve. What a relative flow reserve is, is it's the ratio of stress myocardial flow in the affected vascular territory. So in that region, it is the ratio of stress flow in the LAD, divided by the normal reference area. So whatever the normal stress flow is in the other region. It typically can be calculated in patients who are single or two-vessel disease, because you need some normal reference area. And invasive RFR was first validated against this metric of PET-RFR. So you kind of interpret it in a similar manner. So if the PET relative flow reserve RFR is more than 0.8, then that's non-obstructive. The other thing that you can also look at is you can look at this kind of ratio gradient from base to apex. So we can look at this. So gradient from base to apex, if it's a kind of slow gradual decrease versus a sudden drop, that's also suggestive of non-obstructive diffused disease versus obstructive CAD. So in this particular instance, the RFR was 0.9, suggestive of non-obstructive disease. So this is basically we're doing 1.6 divided by 1.8, non-obstructive disease. And also the gradient also suggested non-obstructive disease, which is what was confirmed on this gap. So flows in this case help us differentiate obstructive from non-obstructive coronary artery disease. And when you see this pattern of mildly reduced stress flows with a normal myocardial flow reserve and non-obstructive gradient base to apex gradient with RFR more than 0.7, then that's suggestive of diffused non-obstructive CAD. Now let's take another example. This is a young male, 55-year-old, who is very obese, BMI of 40, and is presenting with exertional dyspnea. The relative perfusion, you'll all agree, is normal. In this case, we don't see any relative perfusion abnormalities. When we look at the gated coronary calcium score, we don't really see any coronary calcium in any of the coronary arteries. And then when we look at the flows, the rest flows are okay, but the stress flows are moderate to severely reduced in all coronary territories. And so is the flow reserve. The flow reserve is also reduced, less than 2 is abnormal, especially in a young male. The flow reserve typically is in like the 2.5 range, so this is quite abnormal. The flow reserve 1.7 in a young male. So when you see this, there are two possibilities, right? This could be from significant obstructive epicardial disease, or this could be from microvascular disease. So when you see something like this, the first thing we need is some sort of an anatomic assessment. Given that there is no coronary calcification on this patient, the likelihood of this patient having significant high-risk multivessel disease or balanced ischemia is less. However, given that the patient is young, it might still be possible. So the next step would be to do some sort of an anatomic assessment to make sure that we're not missing any high-risk epicardial obstructive coronary artery disease. So in this patient, a coronary CTA showed mild non-obstructive atherosclerosis in all coronary arteries, did not show any obstructive CNE. So in this setting, knowing the anatomy, as well as this PET, helps us diagnose microvascular dysfunction in this patient. So the decrease in flow reserve and stress flows among this in this patient, and the symptoms are likely secondary to a microvascular disease. So microvascular disease refers to abnormalities in the structure or function of these small microcirculatory vessels, which make up the predominant resistance of the coronary circulation. This results in impaired vasodilation, which is what we're picking up using the stress PET with slow quantitation. It's important to note that microvascular dysfunction is the predominant endotype. It occurs in about 2 thirds of all patients with ENOCA or ANOCA. And the non-invasive estimation of myocardial flow reserve or coronary flow reserve is important and critical for diagnosing coronary microvascular disease as the cause of ENOCA. Majority of the patient, it coexists with some form of epicardial atherosclerosis. And the other important thing to keep in mind is you need some sort of an anatomic assessment either with a coronary CTA or with an angiogram to exclude that this low CFR or myocardial flow reserve is from epicardial disease before you make the diagnosis of microvascular disease. And the treatment is focused on risk factor control, and statin as well as ACE are in beta-blocker or calcium channel. So in summary, you can use, we can combine the relative perfusion assessment along with flow assess, quantitative flow assessment and coronary calcium information that we get with PET to differentiate different phenotypes of ischemic heart disease among our patients. Majority of the PET is performed with CT attenuation correction scan or a gated calcium score scan on a PET CT scanner, which can help us identify subclinical calcified atherosclerosis and start treatment for that. And but quantitative flow assessment is critical to differentiating the different phenotypes. Obstructive epicardial disease, most of the time, they present with a relative perfusion effect. It might be mild. It might be subtle, but it will be there in 97% of the cases. And then you can use myocardial flow reserve and LDF reserve to help delineate the extent of involvement, confirm that there is obstructive epicardial disease in single vessel versus multi-vessel involvement for among these patients. And that balanced ischemia and completely normal perfusion is rare, but can occur in about 3% of the cases. But in those cases as well, the myocardial flow reserve as well as the LDF reserve will help you pick up the high-risk disease. So you won't miss anything. PET relative flow reserve is akin to FFR. It is the ratio of stress myocardial flow in the affected territory by the normal territory, and it can help you differentiate obstructive versus non-obstructive epicardial CAD in the region of perfusion effect. That coronary microvascular dysfunction is diagnosed by a decrease in myocardial flow reserve. Typically, we use myocardial flow reserve of two or less than two as the cutoff. But the diagnosis is made in conjunction with some form of an anatomic assessment to exclude significant obstructive CAD. And then when you see this pattern of reduced myocardial flow reserve in the absence of a significant obstructive CAD, that is typically from coronary microvascular dysfunction. Thank you.

myocardial blood flow

stress-PET MPI

ischemic heart disease

coronary microvascular dysfunction

myocardial flow reserve

non-invasive PET