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Dr. Kendal Williams (Host): Welcome to the Penn Primary Care podcast. I'm your host, Dr. Kendal Williams. Cardiac stress testing and imaging has changed in leaps and bounds in the last decade or so, and even beyond that. For someone like me who trained late '90s, early 2000s, there's been a lot of changes, not only in stress testing, but certainly in CT imaging and MRI, which was almost never used for cardiac imaging when I was in training, is now commonly used for both ischemia evaluations as well as structural evaluations of the heart. So, this is an area I've actually been eager to have someone on the podcast to discuss. And thankfully, our guest tonight agreed to come on.

So, Dr. Mahesh Vidula is an Assistant Professor of Clinical Medicine in the Division of Cardiology here at Penn. He has an expertise in all of those modalities: CT, MRI, sort of the native stress testing that's used and so forth, and really an expert in that area. So, Mahesh, thanks for coming on.

Dr. Mahesh Vidula: Thank you very much for the invitation. Very excited to be here today.

Host: I was reflecting on your resume a little bit, and it seemed like you kind of built into this field with the training you had. I saw you went to MIT and studied biological engineering, right? And then, did you always know you wanted to do this kind of work or...?

Dr. Mahesh Vidula: No. Actually, I studied biological engineering at MIT. And when I came to medical school, I thought I was going to be an orthopedic surgeon. Then, I did my rotation in surgery as my very first rotation in medical school, as a third year of student. And I realized that I enjoyed it, but I didn't love it as much as I thought I would. And so, I kept an open mind reflected back on what I really enjoyed during the first two years, realized I loved cardiology.

And when I became a cardiology fellow, again, I thought I was going to do interventional cardiology before I started fellowship. Then, I started here as a first-year fellow and became introduced to the really wonderful world of imaging where you really get a chance to see all the most interesting cases of all the different specialties of cardiology. And that really fascinated me. And for that reason, I decided to do some advanced training in cardiac imaging and craft the career that I have today.

Host: It's terrific. This is a really exciting area. I mean, we're able to learn so much about the heart now through interventional imaging. And then, we still can't do catheterizations through imaging. But we can get a ton of information and know exactly where to go. So, you and I are going to build throughout this podcast and talk about, especially when we get to stress testing, some of the older things and then build into the various nuclear imaging and so forth.

But I wanted to start with coronary calcium scores, just a non-contrast CT of the chest. I have to admit, when I went back into primary care five years ago, this was not something I knew much about. I mean, I thought it was potentially valuable. I actually thought it was a little overrated, which is interesting, because it's turned out to be the complete opposite. I use it all the time. I find it very valuable. But of course, with non-contrast CT imaging, we're basically trying to answer the question, does this person have any plaque at all, right? So, it works well in my environment, which is really primary prevention. But I imagine it works in your environment as well as you're evaluating patients, right?

Dr. Mahesh Vidula: That's exactly right. So, I think that coronary calcium scores are exceptionally helpful for the risk stratification of patients. So when you're meeting somebody who is asymptomatic, has some traditional risk factors for cardiovascular disease, has an ASCVD score that is in that range where you know they could potentially benefit from a statin or not. And these patients may not want to start a statin or may want more evidence that they are somebody who may benefit from a statin. And that's where coronary calcium score in my practice, I use, and that's probably similar to your cohort of patients as well in the primary prevention space. However, in those patients who are presenting to us with chest pain, whether it's in the emergency room or it's in the inpatient services, having a coronary calcium score or looking at their non-gated chest CTs, that will also show calcium is a very helpful tool to have, because it again adds to their risk stratification.

Now, in my mind, then I'll say, if I see calcium on these scans, I'll say that these patients are at higher risk for having a true cardiac event that needs to be investigated further, or they may need additional testing in some capacity. So again, in both situations, I use it as a risk stratification tool.

Host: From a pure imaging standpoint, is there much difference between a CT of the chest done for other reasons, for instance, followup on a pulmonary nodule or just a CT of chest done, not so much a CTA, but just a routine non-con and a coronary calcium score CT, is there a difference between those? They seem to provide virtually identical information.

Dr. Mahesh Vidula: The main difference of those two is that a CT that is done for a coronary calcium score is gated by ECG for the motion of the heart. And so, that allows us to have more accurate quantification of the calcification in the coronary arteries. If you take a CT of a chest done for a different reason, you can still get a sense of whether or not there is calcification, but sometimes there can be motion of the coronary arteries, specifically the right coronary arteries are the most susceptible to motion, and that can be tough to see. But you can definitely get the same out of information. If your question is whether or not this patient has coronary calcification, you'll get that information from both scans, but you'll get it with a higher degree of accuracy with the coronary calcium score because of the gating.

Host: One issue that comes up all the time for me, and I really need to learn just to read a CT and pick out coronary calcium, which I know I had a radiologist as a patient came in and said, "I can teach you in five minutes." And we had this conversation, but I actually don't know how to do that. I didn't train in the time when we read CTs. But I often do look back at reports of CTs to the chest when I'm kind of trying to decide. And my thinking is if they don't mention it, it's probably not there. But I don't know if there's any standardization of that. I'm sure you're just looking at the CT images yourself. But I'm curious, do you happen to know if there is a standard in the radiological community to report it if it's there?

Dr. Mahesh Vidula: I think it's now growing. It's now moving in that direction. So, talking with my radiology colleagues, at this point, they're most likely looking at the CT of the chest if it's just done for a different reason and commenting on coronary calcifications that are seen in the heart. However, that might have happened to a lower degree in CTs done several years ago, or even, let's say more than five years ago.

So, that's why I do think it's important for us always, if you're able to pull up the imaging, to review the primary data and going to the bone window and sectra in the window that pops up when you click show images and just dragging your cursor through the heart will be able to show you the degree of coronary calcification.

Host: Yeah, I probably should watch a YouTube video and learn it in the five minutes. And yeah, I think I plan to do that. It comes up a lot. So, we talked about a fair amount of coronary calcium scores with Dan Soffer and others in preventive cardiology. So, I'm not going to go into too much detail. But those were sort of imaging aspects I wanted to ask you about because we're increasingly using them. And so, the other thing that happens to us in primary care is a patient comes in and has some symptoms that we think may be referable to the coronary arteries. And so, we want engage the patient in further testing to see if those symptoms potentially are due to blockages.

Before we get into stress testing, I was going to do this a little later, but I actually want to talk about coronary CTA. So, that's coronary CT angiogram. This has been I think one of the main growth areas in cardiology. I love tests that I can order myself that don't have a lot of delay associated with them, don't require a cardiologist to be present, and I can get a ton of information. And the ability to image the coronary arteries in real time, to me has been a remarkable advance. And I know based on studies like the PROMISE study, which was out of Britain, I believe, this is actually becoming somewhat normative, at least outside of the states in evaluation of patients who potentially have ischemia and are presenting with chest pain. With that intro, any thoughts?

Dr. Mahesh Vidula: Yeah, no, I completely agree. I think that this is a fantastic tool for the evaluation of coronary disease. As you mentioned, it's now growing here. Our program at Penn is growing. We're only getting more volume in the coronary CT program, which is great. And I think understanding when to use it and the value of it is really critical. And I'm happy to go into that by the way, just as an aside.

And so, the way that I think about coronary CT is that first thinking about what is the information that I'll get from this test that I may not be able to get from other tests. And thinking about, again, more broadly when I'm seeing a patient, what is the right test for this patient who is sitting in front of me , since we have just so many different tests now to look at.

And what the coronary CT will tell you-- and to first distinguish this from a cardiac calcium score is that the coronary CT involves the use of contrast. And so, when we give now contrast to the patient, we're able to see the actual vessels in the heart and then not only see the amount of calcified plaque, but also get a sense of any noncalcified plaque, which is something that happens very commonly in our patients with coronary disease.

And so, being able to give that estimate of any of a degree of stenosis based on the degree of noncalcified in calcified plaque, being able to tell if vessels are patent. And also give a sense of the overall amount of plaque is a very powerful tool of coronary CT and can help you answer that question whether or not this patient has an obstructive stenosis that needs to be looked into further, that may be the cause of their symptoms.

We also have a tool now called fractional flow reserve that can be performed as a post-processing tool on these coronary CTs. And what that actually tells you is whether this lesion that is seen visually on the coronary CT may be hemodynamically significant or not based on the fractional flow reserve or FFR value.

Host: Just to highlight, I think, why that's important, because coronary CTs show you the anatomy, right? And we've always distinguished between sort of functional tests that give us dynamic information about whether ischemia is actually happening versus just showing the anatomy. We're going to talk about stress testing. Stress testing value, I think, was for functional evaluation. But now, with FFR, we're kind of getting that with coronary CT as well, at least to some degree, right?

Dr. Mahesh Vidula: Exactly. And the coronary CT will give you information about the amount of plaque and how the vessels look. And that will really help guide medical therapy even if the patient does not have an obstructive stenosis that needs to be looked in to further, if you know that they have some amount of mild non-obstructive plaque, that can lead to changes in their medical therapy, intensifying through lipid-lowering therapy, et cetera.

Host: We're not used to as sort of internist reading, imaging and getting degrees of stenosis. I mean, as cardiologists, you're doing it all the time because you used to do diagnostic caths. I mean, we would get those reports and look at them, but we weren't often making decisions about them. Now, we potentially are, because we can get a test on our own that doesn't require a cardiology consult. And we can look at that imaging and make a decision.

Now, just to go over this, you know, the original studies for CTA in the emergency department showed that, as long as you had a less than 50% in all arteries, you could be discharged from the emergency department safely. Those were the original studies. But it turns out that there's a little bit more to that, right? I think generally a plaque that is over 70% is a candidate for being actively ischemic. But the PROMISE study, which I referenced earlier, taught me one thing that was very interesting, at least the reviews on the PROMISE study. And that is that that group from 40-70% are just as at higher risk in some ways, not necessarily in the immediate, but if you look a year down the road. And so, we're getting info about those folks. And those folks will be missed on stress testing, we're going to talk about in a bit, right? So, that's why these tests are valuable also for us in primary care.

Dr. Mahesh Vidula: Exactly. I think it really helps for your risk stratification and understanding what degree of coronary disease these patients may have. However, it's also important to understand that these tests do come with some limitations. For example, patients with high heart rates at the time of the scan may have poor image quality. And that's because again, we're gating these images at the time of acquisition to their EKG and trying to acquire these images according to their EKG. And so, if their patients are very tachycardic, then what we shoot for is a heart rate around the 60 to 70 range, though the patients above that heart rate may have lower quality scans that may not be as diagnostic.

Furthermore, patients with a lot of calcification may also have scans that are more difficult to interpret because calcification causes artifact on these scans. It's hard to say really, truly what the degree of stenosis is sometimes in areas where there's a lot of calcification. So, those areas can be overestimated. So, I think thinking about the right candidates are patients who you think may not have a load of intermediate risk, probability of having coronary calcification or coronary disease, patients who are able to tolerate these scans, patients who you're okay to give contrast to as well as to expose to the radiation, which isn't much radiation, but still it is radiation that patients are getting exposed to. So, thinking about all those factors in mind when thinking about whether this is the right test for this patient.

Host: Does the regularity of the rhythm make a difference? If somebody has rate-controlled AFib or maybe a lot of PVCs, is that going to impact whether you can get a test?

Dr. Mahesh Vidula: So if they have a lot of activity, it's more challenging. They can still potentially go for it. And we might be able to do things at the scanner to get the right images. But it is much more challenging when patients do not have a regular rhythm. So if they have a very fast AFib, then they're not a candidate for it. But if they have more rate-controlled slower rate AFib, then yeah, those patients could be a candidate for it. And we also give metoprolol for patients who are presenting for the scans so that they can then be a better candidate for the scan and so that the heart rate is lower at the time of the study.

Host: I've ordered these now a few times, and I ordered them at Radner and they always ask me to send metoprolol down to the pharmacy for the patient to pick up so they have it in hand. And then, I guess it should also be said, my understanding is they're also given nitroglycerin during the test. So, there are two medications involved in this test.

Dr. Mahesh Vidula: Exactly. The nitroglycerin, the goal of that is to actually vasodilate the artery so that we can get better and higher quality images, and also run these FFR post-processing algorithms to get that FFR information as well.

Host: My understanding of the guidelines and to some degree the evidence so far is that the evidence for CTA is primarily in the ED population. but patients who are presenting to our practices with chest pain, it's a little less clear. I think the guidelines still recommend, and you may be able to correct me on this, Mahesh, but we recommend proceeding with stress testing first as the first modality, although there may be some variation there. The AHA chest pain guidelines came out a few years ago, and I think they may have mentioned it. Maybe you can correct me on all of this.

Dr. Mahesh Vidula: Sure, no problem. Yeah. The 2021 ACC/AHA guidelines for the evaluation of patients with chest pain is a great resource. I highly recommend it for the listeners that just going through the tables and some of the recommendations is very useful. But in those patients, you can have patients who are presenting with stable chest pain who you think might be in that low to intermediate risk category. So, just like you don't think that they have a ton of calcification in their arteries, so then that could prohibit the accurate interpretation of the scan. Those patients are great candidates for getting a coronary CT. If your question is, does this patient have an obstructive lesion that is causing their symptoms, it will really provide that anatomic visualization of the coronary arteries well.

Host: You're absolutely right. I actually reviewed those guidelines for another talk I gave. And you're right, they do actually recommend coronary CT. Every time I order it, I feel like I'm doing something a little bit devious because I'm going against guidelines. But I just reviewed them and you're right, it is that way. So, let's talk about stress testing, because the standard thing that we all grew up on is to do stress tests.

Before we, go into the details of each individual stress tests, one of the difficulties with stress tests is that you're not finding out does the patient have coronary disease, you're actually only finding out do they have a degree of stenosis that is symptomatic, and is causing ischemia with exertion or even without. And so, it's not quite the comprehensiveness of a CTA, right?

Dr. Mahesh Vidula: Yes, to a degree. So, the one thing I would say is that on nuclear studies, which we'll get into, such as SPECT or PET, we at Penn here use attenuation correction, which is a form of improving our image quality by acquiring a CT at the time of the scan, and then using computer algorithms to reprocess the images of the nuclear scan to correct for artifacts and things like that.

But on these attenuation corrections CTs, we are able to first get a visual estimate of coronary calcification, which we do include in our reports in terms of whether the patient has a small degree of calcification, a moderate degree, or a large degree of coronary calcification.

In addition, in our nuclear lab at the main hospital, at the hospital of the University of Pennsylvania, we have started doing coronary calcium scores in patients who are undergoing these stress tests who meet certain criteria. We don't do them in patients where the clinical utility might be low. But in patients who meet our criteria, we will give the ordering provider a coronary calcification score as well, which will quantify the degree of calcified plaque.

So, we'll do it in two ways, in visual as well as this quantification in some cases. But right now, it's the only stress test modality that will allow us to give you that type of information. And you're correct that with stress testing where we are not able to give an assessment of noncalcified plaque that may be non-obstructive and causing issues we can clearly see on the stress test.

Host: Or from a primary care perspective may cause issues down the line and we want to know about it for the long term. Let's go back to the non-imaging stress test later, because we'll pin those with stress echo, but we brought up myocardial perfusion imaging, and I want to stick with that for a second. So, this is where it gets confusing for folks. And you just mentioned now that you're adding a CT into nuclear imaging, and maybe we can just sort of sort this out for folks, right?

The first aspect is when you're talking about one of these tests is what is the analog, if you will, that you're using to highlight ischemic areas or to highlight blood flow, right? So there's sestamibi, which is, I think technetium-99. There's rubidium, and then there's some ammonia analogs and so forth that are used. And then, there's PET. Can you just help us with this? And then, of course, we'll get to the non-exercise aspects where you actually use chemical stress tests. We'll get to those in a bit. But just for sort of the nuclear imaging aspect, can you help us sort through PETs, SPECTs and then the various analogs that are used?

Dr. Mahesh Vidula: Of course. Happy to. So first, let me define SPECT and PET, because it's just a lot of acronyms to start. So, SPECT is single photon emission computef tomography, and PET is positron emission tomography. And so, these are two modalities that are looking at myocardial perfusion. And so, what we're doing in these scans is that we're first acquiring rest images. So, you know, the patient gets an IV and we're injecting a radiotracer that goes into the myocardium. And again, we are able to actually see whether the myocardium is being perfused or not. And the whole heart will light up on the rest images, if there is no evidence of infarct, so a prior myocardial infarction that would've caused scar. In those areas of scar, there is no uptake of this radiotracer. But then, we then do a stress agent then at that point.

So for SPECT, we're able to exercise patients or we're able to give a pharmacologic stressor. And the pharmacologic stressor that is typically used is called regadenoson, which is an adenosine type agent. And the basic concept here is that the regadenoson is a coronary vasodilator, so it dilates the coronary arteries. And then, we inject the radiotracer. And then, now we're looking at the myocardial perfusion when the coronaries have been dilated. So, thinking back to kind of medical school of physiology in those areas that where there's an obstructive lesion, those areas that are distal to that stenosis are already maximally vasodilated. So, those areas get relatively less blood flow than the areas that do not have an obstructive lesion. And so, then we compare the perfusion of the heart at rest compared to stress. So at rest, we're looking for areas of infarct, and then we're comparing or we're hoping to see a normal myocardium. And then, on the stress images, then we look to see are there any areas that were being perfused at rest that are now not being perfused with stress. And then, those, we then try to correlate with the coronary territory to give a suggestion of, "Hey, I think that there is a coronary stenosis in this territory based on this myocardial perfusion scan."

SPECT is the more commonly used modality across the United States. And that's because it started earlier, and it also costs less than top-rated PET scanner. And SPECT has the advantage of being exercise and pharmacologic. But it is at risk for artifacts. It is highly susceptible to artifacts, which is why have to do some sort of artifact correction, which is traditionally in a lot of places that use CT, but some places don't use attenuation correction. And so, that can lead to more false positive or just inaccurate studies. But here, we use CT attenuation correction to help us distinguish areas of artifact versus areas of true ischemia.

And then, PET is a newer perfusion modality. And it is not as susceptible to artifacts. It actually gives us very nice image quality, especially in patients who are high BMI, which is the population that is traditionally approved for by insurance to get this study. But we have beautiful images with PET. We're also able to offer PET to quantify myocardial blood flow so that we can give you a sense of what the coronary flow reserve is, which can help with patients who may not have disease in the epicardial arteries, but may have disease in the microvasculature. And so, that's a helpful tool.

But the issue with PET right now is that we can only do pharmacologic stress with it because that radiotracer rubidium that we use for PET has a very short half-life. But one thing that's very exciting that is coming out potentially soon is that a tracer that has a longer half-life for which we will be able to do exercise for PET, which I think will be helpful when we can get into that when we talk more about the value of exercise. But the disadvantage of that tracer is that we'll be unable to give you quantification of the flow reserve. So, it's very interesting, all of these modalities with these novel new advances, they come with some advantages, but some disadvantages. There's no one modality that'll give you all the information that you desire. I'll keep harping on this, but it's very important to think about what is the right test for the right patient.

Host: Yeah. You said a couple of things in there that I found interesting. One of them, I think you alluded the fact that PET's more expensive and you suggested that insurance will approve patients if they hit a certain BMI threshold, but it may be more difficult to get it if they're under that threshold. Is that fair, yep?

Dr. Mahesh Vidula: That's correct. I'll say it with a caveat, because these things are always changing. There are some insurance companies that are now approving it for lower BMI. But the safest thing traditionally is that for those high BMI, BMI greater than 38 is where it typically gets approved.

Host: I wanted to ask you about microvascular disease. I think in my training period, just had no way to evaluate microvascular disease, so nobody ever talked about it, right? It was sort of a mystical thing that everybody was-- coronaries are pretty normal, but he still seemed to have an ischemic event, and we don't really know why. Can you just educate us? We'll just take a few minutes as a side note here to just talk about microvascular disease, which you can instead, you can see better on PET. How common is that? What are the scenarios in which we are seeing that and so forth?

Dr. Mahesh Vidula: Yeah. So, I think it's pretty common probably in our patients. And so, basically, the concept goes back to that there's the perfusion of the myocardium is by these large vessels, the epicardial vessels, the ones that we typically talk about, the LAD, the circ, and the RCA and their branches. And these are the vessels that we can see on coronary CT when you send a patient for cath. These are the epicardial arteries that we see. However, there's this huge network of microvasculature that we can't see on cath or on coronary CT. But these small vessels are what are perfusing the myocardium and they're networking within another to provide blood flow and nutrients to the myocardium, deeper into the myocardium.

And so, what we found more and more in the last several years is that disease of these small arteries can cause symptoms of angina, can cause shortness of breath with exertion similar to epicardial disease, and they're also associated with worse outcomes in the overall patient population as well. And so, typically, microvascular disease is associated with cardiometabolic risk factors like diabetes, hypertension, hyperlipidemia, also coronary calcification is an association, and kidney disease. All these things can cause disease of the small vessels as well.

But again, these can cause similar symptoms in these patient populations. It's very difficult to treat because we don't have standardized treatments for these patients. Aside from trying to treat their overall cardiometabolic risk profile and then trying antianginals and seeing what works. But the very interesting thing I think about microvascular disease is that it has probably been underdiagnosed in our population. Because we typically talk about patients who are undergoing an EKG stress or an EKG stress along with an imaging modality, like an echo or a nuclear stress test. And sometimes we see that these patients are exercising and they have symptoms, they have ischemic EKG changes. But the perfusion that we see on the nuclear scan or the wall motion that we see on the echo, on the stress echo all look normal. And these have been regarded as false positive EKGs for years.

But there was a very nice study that came out, I think probably about a year or two at this point, that looked at patients with EKGs that were positive for ischemia on an exercise EKG test. And then, they took these patients to the cath lab, did invasive testing for microvascular disease. And what they found is that the majority of these patients had microvascular disease. So, these EKGs weren't false positive. They were telling us something. They were just the combination of the imaging with EKG showed that was no epicardial disease, but there was indeed microvascular disease in these patients.

And so, I think it is something very important for us to think about in our patients, because it helps, first of all, give them a diagnosis, that I think is important. And from there, then we can think about how to best treat them. And now, as it's being more and more recognized, it's getting more investment by the cardiology research community. And so, I'm hopeful that we'll have more treatments for it in the future.

Host: Now, that you're talking about it, it almost seems kind of obvious. I mean, when we think for instance about advanced diabetic complications, folks have retinopathy, they have neuropathy, they have nephropathy, which is really in all those organs and tracks together in those organs, meaning that they happen virtually at the same time. Because it's the microvascular, all of these are just being supplied by the same microvascular blood flow that is being affected. And of course, it makes perfect sense that the heart would be involved in that same process. And it's like, "Oh gosh, you know, of course, that would be the case." So, I assume that these are the same folks, the advanced diabetics. And as you said, the metabolic disease folks that you expect to have microvascular disease because we see it in other areas.

Dr. Mahesh Vidula: Yeah. A lot of them are, and some of them are surprised. They might not have as bad risk factors as you would expect, but they have all the criteria for it and going through an extensive evaluation yields as diagnosis. So, I think a large portion, those are risk factors for it, but you may have a patient who may not exactly fit that profile.

Host: And you can see that better on PET than you can on SPECT, right?

Dr. Mahesh Vidula: So, yeah, we can get a sense of it on PET, which we can't get a definite sense of on SPECT. And the reason is that, on PET, we're able to actually quantify the amount of blood that goes to the heart at rest and then compare it to stress. And so just thinking about this at a very basic level at rest, the blood flow to the heart should be lower than the blood flow to the heart at stress. When we give that vasodilator, there should be an augmentation of blood flow to the heart. And so, we actually are able to divide that ratio of the amount of blood at stress divided by rest and give a number called coronary flow reserve. And what we've seen in studies is that a coronary flow reserve less than two is associated with worse outcomes in the overall population.

And so, in a patient who has typical symptoms of angina or exertional dyspnea has normal perfusion on their PET, which suggests no epicardial disease, but they have a reduced coronary flow reserve, then those patients may have microvascular disease that could be explaining their symptoms. There are some caveats to think about. When you're looking at these reports, it's also important just take a look at the rest flow, because sometimes if the rest flow is high for some reason, such as hypertension, tachycardia, anemia, just overall high volume of blood in patients like our end-stage renal patients, those patients can have a reduced flow reserve, just because the rest flow is very high. But they may not have that typical microvascular angina-type phenotype. So, we can't just say that all patients with a low flow reserve have microvascular disease, we really have to put it in context with the overall clinical picture. And so, that's PET.

But for SPECT, we can get a suggestion of microvascular disease. So if you exercise a patient and they have EKG changes consistent with ischemia, but they have normal perfusion. One study looked at that patient population and looked at what if we did PETS on these patients? And they found that there was a high correlation of that finding of EKG changes with the normal SPECT perfusion with reduced coronary flow reserve on PET, suggesting that those patients might have microvascular disease as well.

Host: Before we leave this, I wanted to just talk about what we refer to as chemical stress test, using adenosine or some sort of vasodilator. I had a patient early in my career who came in with chest discomfort. And then, he had actually had AFib and so he was seeing a general cardiologist that I was working with. And he had a stress perfusion study that was normal. And so, we said, "Oh, you're fine." And then, he came in with this just right out of the textbooks typical story of angina. He said, "Doc, every day I get up and I walk two miles. The same trip, I do the same thing all the time." He said, "I used to be able to get up this hill in this amount of time." He was very diligent about this. He knew exactly his timing and everything else. And he said, you know, "Now, I get a mile in and I get chest discomfort. You know, it's very predictable. I have to slow down." It's the same tree that I pass every day. And I'm like, "Ah, you know, it really sounds anginal."

And so, what was happening in him, and I'm sure you probably have queued into this, is that because we had used a vasodilator, if you do have blockages in all your arteries, you're not going to get that differential that you need in order to illuminate an ischemic area, right? Everything is ischemic and so it all looks about the same. But maybe the newer imaging technology kind of eliminates that issue.

Dr. Mahesh Vidula: Yeah. So, that's a great question. So, I think this concept that you're talking about is what we call balanced ischemia, where there's ischemia in all these different territories. And so, everything and all these nuclear modalities are looking at relative perfusion. So if everything's down at both at rest and stress, then you may not think that there's a true defect. And that's why I think that it is and ultimately extremely important to go back to our pretest probability and think about: Who is the patient sitting in front of us? What is our pretest probability for disease? And if the stress test comes back negative, but you still have a high pretest probability, then thinking about an anatomic study, like a coronary CT or a cath is I think the next step.

And going back to your original question about some of these other modalities, PET is in theories should have a lower risk of balanced ischemia given the higher spatial resolution that we have. But there are some cases where that in the literature that have been published as well, where patients can have normal perfusion on both rest and stress and can have blockages in all three vessels. And so, I think in those patients, we have to carefully look at how much coronary calcification they have on the CT scan. And if they have a lot, then that's an increased risk factor. If they don't really have increase in their stress flow with the radiotracer, then that can also be a marker of balanced ischemia, so just like a low coronary flow reserve.

And the third thing is the ejection fraction of the heart should increase with stress. So if we don't see that, that's another high risk marker. So, these are all other high risk markers of a stress test. So even if you get one that's normal, you have these other high risk markers, those could be indicative of more significant ischemia that our stress test just can't see.

Host: I also wanted to talk to you about MRI technology, and I think there's a natural flow of this discussion into that because my understanding is cardiac MRIs kind of come in two forms, if you will, right? You have a cardiac MRI to look for infiltrates of the diseases like sarcoid or amyloid or maybe hemochromatosis or something. You're looking at the myocardium. I think about doing those when I'm working up a non-ischemic cardiomyopathy, or I'm trying to decide if somebody has sarcoid involving the heart, or I'm trying to figure out about trying scle rein amyloid or so forth. But then, you also have stress cardiac MRI, which I'm actually going to ask you about now. Where does that fit into everything we've talked about and when would you use that?

Dr. Mahesh Vidula: Yeah. So, I think that's a great question. And as you mentioned, cardiac MRI, is an exceptional tool for looking closely at the myocardium and specifically characterizing the tissue and getting a sense of what type of cardiomyopathy a patient may have is one big question. Another big question is if a patient has had evidence of myocardial injury on echo or on by labs, an elevated troponin, understanding where or what the mechanism of that injury is another powerful tool of MRI, because it can differentiate non-ischemic from ischemic injury.

And so with stress MRI, the way that that works is that we do it currently is all through regadenoson stress. So again, a pharmacologic vasodilator that the patient receives while they're on the scanner. And the basic workflow is that the patient will come in for their MRI. About 15 minutes, once we've taken the planning sequences, we'll then inject them with regadenoson. And what we're looking for on the stress MRI is again perfusion to the heart. So after we give the regadenoson, we then inject the gadolinium contrast agent. And then, we're looking as the gadolinium flows into the myocardium, are there any areas that where it looks like the myocardium is not being perfused? And then, we're able to compare these images to the later images where we look at the scar in the myocardium to get a sense of was there presence of any infarct in the resting myocardium.

The role that I see that I utilize in my practice for stress cardiac MRI isn't these patients who are presenting with a cardiomyopathy of unclear etiology, but I really think that it's low to intermediate risk for ischemia. I'm more interested in their cardiomyopathy and look in characterizing their cardiomyopathy using cardiac MRI. The reason I say this is because the evidence for first cardiac MRI is very strong. But at Penn, the protocols that we use are all qualitative perfusion. So, we're just looking at the images and we're seeing broadly: is there any areas of the myocardium that look like they're not being perfused? But we're not getting that quantitative estimate of blood flow to the heart that you can get with PET, as we're not getting a sense of coronary calcification, which you can get through other modalities as well. And so, for those reasons, I tend to use it in my clinical practice for those patients who are lower in intermediate risk of ischemia, but I'm more interested in the cardiomyopathy part of their evaluation.

Host: Yeah. So, it, fits within a cardiomyopathy evaluation primarily where you don't think it's ischemic, but you're not sure. And so, you're looking for the non-ischemic causes, but you're also potentially getting some information, some more general information about whether ischemia is present and causing it, including microvascular disease.

Dr. Mahesh Vidula: So, there are centers around the world where they're able to do quantitative perfusion to, again, quantify the blood flow at rest, and then with stress, and then give you a coronary flow reserve can give you a sense of microvascular disease. Here, we don't use those sequences yet. Eventually we hope to, but at this point, we don't. So, we cannot give an accurate sense of microvascular disease assessment using stress MRI at this time.

Host: So, the other issue that comes up, because everything we've talked about other than MRI involves radiation, right? The nuclear imaging involves radiation, the PET involves radiation, coronary CTs involve radiation, coronary calcium CTs involve radiation. I know that's a concern, in how much radiation we're giving patients. It's been a concern for probably 20 years. So, is that a concern for you, I suppose, is my question?

Dr. Mahesh Vidula: Yes, it is. So, this is radiation. As I also mentioned at the beginning, just thinking about the right test for the right patient is one of the big things that I think about, about whether I want to expose this patient to radiation, whether that's the right thing to do at this time. And as you mentioned, we have stress MRI as something that doesn't involve radiation, but does involve gadolinium, which is safe overall. But at this time, we don't know what the risks are for cumulative gadolinium exposure.

But then, this kind of branches actually very nicely into the other modality of using stress echo, which doesn't involve the use of radiation. So for patients who I am thinking about, young patients who don't want to be radiated at this time may have risks associated with early radiation, especially young women who I don't want to irradiate, exposed to radiation. Those patients, I think, about stress echo, as a very real possibility of evaluating their symptoms.

However, that being said, echo and MRI, again, don't give us that information about coronary calcification and about the amount of calcified plaque. So if the risks of radiation outweigh the benefits that I foresee, for example, I really foresee a shift in their treatment. I think that based on their pretest probability they would really benefit from it. Then, I think exposing to radiation is something reasonable to discuss with your patient. But if you're, again, having these patients who the story doesn't sound too convincing, the pretest probability is low, then thinking about these modalities that don't involve the use of radiation is very important and making sure that you don't choose the wrong test for those patients.

Host: * I think my singularly favorite tests in medicine is an echo for the value you get, right? I mean, it's an ultrasound. It doesn't have any radiation. It's not painful, it's not invasive, and it's incredibly useful in terms of the information you get, not just about the heart, but also about the lungs with pulmonary hypertension. My favorite test.

And now, we can do to some degree point-of-care ultrasound and at least get rough information on the heart. So, I love stress echoes, and I think that's usually my favorite test to send people for, because oftentimes I do not have any information about the person's, structure and function of the heart, the EF. And so, I feel like I'm getting two tests in one. And my impression is that the echo I get on the stress echo is not quite the same as the diagnostic echo I get, but probably better than a POCUS. But it's not quite as good. But it gives me some information. There's a read there. Is that right?

Dr. Mahesh Vidula: That's exactly right. So, our protocols stress echoes actually involve an abbreviated initial transthoracic, where essentially what we're doing is ruling out for any contraindications for the stress test, while also getting a sense of the left ventricular function, right ventricular function. But we also want to make sure that the patient that we know of have any severe valvular disease, want to make sure that we can get a sense of it. If there's any pericardial effusion or any other thing that would make us step back and say, "Hey, I'm not sure that we want to do a stress test on this patient right now." And so, if you do want to get a full transthoracic echo along with the stress echo, you have to order both tests. The one that comes with the stress echo is an abbreviated study.

Host: We haven't talked about exercise testing. But just to go over the protocol for a stress echo, somebody comes into the lab, they get an echo, and then they get-- I always wondered how these worked and actually reading about it before this podcast really helped me because I had always wondered, and I never bothered to read about it. And then, you have them exercise under the Bruce protocol, I think, which is a standardized protocol used for stress testing, both exercise, all forms of exercise stress testing, I assume, where you change the gradient and the speed of the treadmill, and you're trying to achieve a heart rate of over 85%. And that's the process. And then, when you've achieved that or if a patient has symptoms, you basically have them hop off the treadmill, lay down again, and do another echo. Is that basically how it's done?

Dr. Mahesh Vidula: That's exactly right. So, yeah, that's our protocol. We are, in some cases, like patients with valve disease or who meet other criteria, we are looking into doing the supine bicycle, which those patients then we can scan while they're on the bicycle at different levels of exercise. But right now, for most patients who are coming in for ischemia, they're getting the treadmill stress, the protocol that you very nicely described. The one issue though, as you can imagine, it does take time to get a patient off a treadmill and then onto the bed so that they can start being scanned. And so, there is some cases, and we'll mention this in the report where we don't catch the peak heart rate, the images at peak heart rate, because the patients, some of them have very robust heart rate recovery, their heart rate's already come down in a few minutes, in the short time that it takes to get them to the table. But that's exactly the protocol.

Host: That's the one thing I always wondered about, because I knew you had to get them at peak stress, and I'm like, "Well, how do they do that? They're still on the treadmill." So, you just have to get them off while they're still sort of at that same heart rate and get them on the table so you can look.

Dr. Mahesh Vidula: Yeah. And our sonographers are excellent. Our nurses are excellent. They do a really great job at making sure that this happens and the sonographers start scanning right away. But in very rare cases, sometimes the heart rate will slow down by the time that we're capturing the images.

Host: I guess we should say it's an older test, a dobutamine echo can achieve similar things that a stress test can for those who can't walk on a treadmill, right?

Dr. Mahesh Vidula: Exactly. And that is the test of choice here for our patients undergoing liver transplant evaluation. And the reason for that is the thought that there are most likely already maximally vasodilated from their liver disease. And so, increasing their heart rate and contractility with dobutamine echo, we'll be able to then give a sense of any major obstructive coronary disease.

Host: And I suppose it should be said, dobutamine works differently than the vasodilators we were talking about before, in that it's really just increasing contractility. It's not affecting the blood vessels themselves and creating a differential perfusion abnormality, rather it's just increasing contraction and simulating what happens when you exercise.

Dr. Mahesh Vidula: Exactly.

Host: So, I wrote down some of the sensitivities and specificities of these tests as we were sort of prepping for the podcast. And it was interesting, because stress echo had a sensitivity approximately 80%. Now, this is just reported in the article I was reading. So, you can correct these if they're not quite right.

Stress echo, about 80% sensitive; specificity was 84%. Myocardial perfusion imaging depended. SPECT was about 82% sensitive, 76% specific. PET was better, 89% and 91%. Coronary CT just for the anatomy is actually really valuable, and it has high specificity and high sensitivity of 89% and very high specificity. So, that makes it really good as a rule in test. So, we have sitting down there lonely is the stress testing, that just EKG stress testing, which has a sensitivity of 68% and a specificity of 77%. And so, should I still trust these tests, I guess, is my question?

Dr. Mahesh Vidula: So, that's a great question. Again, I think it's important to think about what this test is giving you. And what your question is. Sometimes you have a patient who has symptoms with exertion, who you might not think that they have coronary disease, but you might be wondering, "Hey, does their blood pressure go up when they're exercising that could be causing their symptoms?" Or are they unable to increase their heart rate when they're exercising? Or are they having any arrhythmias while they're exercising that could be caused of their symptoms. And for those patients, this is a great test because you're having them exercise under a supervised setting. They're getting an EKG, vitals monitoring the whole time, exercise stress test at that time. And you'll get all of that information, which is very important and can guide treatment in a lot of cases.

But if your question is, does this patient have obstructive coronary disease? Then, you have to go back to your pretest probability. So in those patients who have a high pretest probability, and you really think that they might have coronary disease that's causing their symptoms, having an exercise stress test with those types of sensitivity and specificity may not be enough to shift your decision-making. But in a patient with a lower pretest probability, that might be sufficient for your younger patients who are coming in with some vague symptoms, no real significant risk factors for coronary disease, but they're having exertional symptoms. You might want to do an exercise stress test to take ischemia, just, make it an even lower probability than what your pretest probability was, but also assess for all these different things, these hemodynamic changes and potential arrhythmias that could be occurring while they're exercising that could be the cause of their symptoms.

Host: The other patient population I think I use it for is the ones who have high coronary calcium scores. You just do routine testing and it's 458 or something like that. And they're not so active that you're confident-- you know, I had a guy got a coronary calcium score and he was cycling 200 miles a week. So, I was pretty sure that an exercise stress test wasn't going to help get any more information from him. But somebody who's not very active that you just kind of want to see are they having some exertional ischemia, that maybe they're just not active enough to bring out that we need to kind of tease out a little more. Is that right?

Dr. Mahesh Vidula: Yeah, I think it's a good thought. To be honest, if they were having symptoms with that sort of coronary calcium score, then I would go to a test with imaging to make sure that we're not missing something. But if they're not having symptoms, they feel okay, they might not be as active, but they feel okay, it could be test that you could consider. But I wouldn't give it too much confidence if your question is, "Do they have ischemia?" Because, you know, in those patients, sometimes they don't also exercise as much as they could on some of these exercise stress tests. And so, they may need another type of test, like a pharmacologic test to really assess whether or not they have ischemia.

Host: That's very helpful. I noticed when I do send patients to cardiology with higher calcium scores, they do end up doing ischemia testing. Not everybody, but oftentimes, and just the group of cardiologists I send folks to, especially if you're not sure how much it may be affecting them. So Mahesh, this is great. We're actually past our hour. I thought we would fill it up easy, because there's a lot of good questions here. And I have more, but I don't think we're going to be able to get to them. Any final thoughts on the sort of the spectrum of testing that's available to us now?

Dr. Mahesh Vidula: Yeah, I guess the biggest takeaway would be that we have all these different tests. They all come with risks, they all come with benefits, they all come with things that they can do, then the things that they can't do. And so, there's a lot at your disposal now. And so, I think that one thing that I would recommend that is, if you have a question about what is the right test for your patient, feel free to ask one of us. Just curbside, the cardiologist in your office, or sometimes I get a phone call to the nuclear lab directly about just somebody asking, "Hey, do you think is the best test for this patient and happy to help." And I know the cardiology teams are also happy to help in the hospital to try to figure out what is the best test for the patient, just so that you don't have to do too many tests. You don't have to do unnecessary tests. If you're able to pick, again, that right test for the right patient. And so, I think that's the biggest thing that I wanted to emphasize that we're happy to help.

Host: Yeah. This is really an exciting area. I'm sure you're thrilled to be in this area because there's a lot going on and getting more depth of information about cardiac ischemic disease, but also cardiomyopathies and so forth with advanced imaging. It's very exciting time. So, Mahesh, thanks so much for coming on. Really appreciate your time. This has been extremely informative. I'm sure everybody's going to find it as valuable as I have. So, I want to thank you for coming on. I want to thank the audience for listening, and please come again next time.