Melanie Cole, MS (Host): Welcome to AHN Med Talks, an informative resource for physicians across various specialties as we delve into the latest medical insights and best practices, ensuring you stay at the forefront of your field. I'm Melanie Cole and joining me today is Dr. Indu Poornima. She's the Medical Director of Nuclear Cardiology and the Director of the Section of Preventive Cardiology and Women's Heart Center at Allegheny Health Network. She's here today to highlight coronary microvascular disease for us. Dr. Poornima, thank you so much for being with us today. I'd like you to start by giving us a little overview of coronary microvascular disease and how it differs from what we think of as traditional coronary artery disease.

Indu Poornima, MD: Melanie, thank you for having me. I'm excited to talk about this topic. I'm quite passionate about heart disease in women and the different ways of diagnosing it, as well as some of the unique conditions that predominate in women. And certainly, microvascular dysfunction is one of those conditions. So, microvascular disease refers to the problem that occurs in the smallest arteries that supply the heart muscle. So, we all know that the coronary arteries are the large arteries that come out of the great vessels, specifically the aorta, and essentially supply the heart muscle. But what we call as epicardial coronary arteries then give way to multiple smaller branches and these are what are called as capillaries and arterioles. And when this part of the coronary system has a problem, that is what is referred to as coronary microvascular disease. This condition seems to be occurring in both men and women, but certainly occurs more commonly in women. At this time, we think that there are about 3 to 4 million people living with this condition of microvascular disease. it is otherwise labeled as ANOCA or INOCA. ANOCA is basically angina in the presence of normal coronary arteries. And INOCA is ischemia in the presence of normal coronary arteries. And this is important to understand that the way we diagnose this condition is to first make sure that the main epicardial coronary arteries, which are the large, what we call as large vessels that supply the myocardium, those do not have significant obstruction. So in the absence of significant obstruction in the epicardial vessels, when the patient continues to have ischemia and specifically angina, which is a symptom that they present with, that would be classified as coronary microvascular disease.

Melanie Cole, MS: This is such an interesting topic. And as you and I both know, vascular disease and heart disease in women always does present itself differently, and most of the studies when we were going through school were on men. So, I'd like you to tell us about the WISE trial, Dr. Poornima, and why this is so important for our discussion of coronary microvascular disease and specifically in women, because this is a trial about women.

Indu Poornima, MD: Absolutely. So, the WISE trial was one of the largest studies to actually enroll, first of all, a large percentage of women in the study population. And secondly, looked at this question of when you do not have significant obstructive disease, what exactly are the outcomes of these women? And these women were specifically selected from a population that came in obviously with chest pain or chest pain-like syndromes, meaning shortness of breath, which is the other common symptom that women present with, and it is otherwise called as an angina equivalent. And these women then underwent stress testing to show that definitely there were some abnormalities and subsequently had a cardiac catheterization. Now, a proportion of them also underwent what is called as an MRI stress test with assessment of coronary flow reserve. So, what this study showed was women can have abnormal stress tests and no significant obstruction in the coronary arteries and yet have adverse cardiovascular outcomes, which is quantified as MACE. This is basically a combination of different cardiovascular outcomes, including death, myocardial infarction, as well as hospitalization for angina. These women, the subset of women that underwent the cardiac MRI, it was also shown that these women have abnormal coronary vascular resistance, which likely is the mechanism by which these women continue to have these symptoms of angina, as well as poor outcomes. So, WISE was the first clinical trial, NIH-funded clinical trial, that first of all enrolled a large number of women and then brought to light that coronary microvascular disease is indeed something to be taken seriously and the absence of epicardial disease does not mean a benign prognosis.

Melanie Cole, MS: How does that fit in with diagnosis? What do we know now that we did not used to know about diagnosing microvascular disease? Because I think that's the crux of this podcast today. As many women are concerned about undiagnosed heart disease and it's so important. We see calcium scores and you mentioned a stress echo and the MRI. How are we diagnosing this?

Indu Poornima, MD: Yeah. So, the traditional sort of pathway that both men and women go through when they come in with angina symptoms is first of all an EKG and that will usually be followed by some form of stress testing. Now, these days we've gone to more anatomical evaluations such as a CT scan or a CT coronary angiogram. Calcium scores is a part of that evaluation. When a patient gets a CT coronary angiogram, they also get an assessment of the coronary calcium scores. In addition to that, there is something called PET stress testing, where the stress test is done with a vasodilator, but the imaging is with a PET camera. Now among all these tests, a PET stress test is the one that can actually assess what is called coronary flow reserve. So, coronary flow reserve is really the ability of those little small arteries or arterioles to vasodilate in response to a vasodilator. And the typical vasodilator that's used is either dipyridamole or regadenoson or adenosine, either of those. And with those stress agents, we look at the capacity of these arterioles to dilate by measuring the blood flow after stress as well as at rest and comparing the two. So, the ratio of the stress blood flow to the resting blood flow is what is called as coronary flow reserve, which is the ability, as I said, of these arterioles to dilate.

Now, the traditional forms of stress testing, which is nuclear imaging with a SPECT camera or stress echo typically are not able to identify these abnormalities or provide this information on the coronary flow reserve. The majority of the time, the abnormalities that are picked up on those pertain to the epicardial coronary disease. Now, having said that, a recent clinical trial called the ISCHEMIA trial showed that in both men and women with evidence of at least moderate to severe ischemia on the traditional stress test, which includes echo as well as nuclear imaging, about 13% of them did not have any obstructive disease. And these patients truly had ischemia. So, 13% of the patients that were enrolled in that large clinical trial actually were classified as ENOCA or ischemia with non-obstructive coronary arteries. Now, on the other hand, CT coronary angiogram gives you an assessment of the epicardial coronary vessels, but it does not really provide any physiological information regarding blood flow itself.

So, a couple points to pay attention to here are that when you have a patient with true anginal symptoms who gets any form of stress testing and the stress test is abnormal, and the patient goes on to either have a CT coronary angiogram or a cardiac catheterization, meaning an invasive coronary angiogram. And if significant epicardial disease is not noted there, that does not mean that the stress test is a false positive. It actually means that this patient may indeed have ischemia with normal coronary arteries or non-obstructive coronary arteries and therefore needs to be treated as such, which is a really important paradigm shift in how we approach results of stress testing. Similarly, if somebody comes in with classic chest pain, goes on to have a CT coronary angiogram, or again an invasive coronary angiogram, without a stress test preceding that, but ends up really showing no obstructive disease on those assessments, it does not mean that the patient does not have angina. It means that the patient needs further physiological assessments. And now, we are able to do some specialized forms of testing right in the cath Lab to assess this aspect what I talked about earlier, which is coronary flow reserve. So, coronary flow reserve, the two forms of assessments that can determine that are a PET stress or invasive coronary angiography with specialized physiological testing.

In addition, during that coronary angiogram, there can be some provocative testing done to look for entities such as coronary vasospasm, and that's by infusing a drug called acetylcholine. That is given right in the cath lab and the response to that, if the artery starts constricting in response to that, that tells you that the patient probably has epicardial or microvascular coronary spasm. So, the spectrum of patients that come in with angina and the possible diagnosis for that, which we used to think always had to be obstructive coronary disease, has really changed and we are really broadening the definition of what would be considered abnormal coronaries.

Melanie Cole, MS: So interesting. That was an excellent explanation, Dr. Poornima. So now, I'd like you to give us an overview of AHN's program. What sets it apart? Tell us about this testing that you were just discussing, how it's really beginning to learn how to best treat microvascular disease. Tell us about the program and your team.

Indu Poornima, MD: Yeah, definitely. Really excited about some of the changes in how we approach these patients. So as I said earlier, stress PET is an integral part of this assessment or diagnostic pathway, and similarly, the invasive coronary, physiological assessments. And we now have both of those available. We have been doing stress PET for many number of years. But the invasive assessment plan was actually missing. But we are now able to combine these two into a diagnostic pathway that provides a comprehensive assessment of patients, even those who do not have obstructive coronary artery disease. And we are able to figure out which one of these little buckets do they belong to, and therefore, how we can manage their treatment accordingly.

In addition, I think it is very important for these patients to actually have an answer. Previously, they were left sort of going from one doctor to the next, wondering why are they still having symptoms when they're being told that you do not have heart disease. So, I think it is going to be a huge step forward for patients in terms of a complete assessment of the coronary vascular system. And the integration of the non-invasive stress PET with the invasive coronary hemodynamic assessment, I think is one of the major steps forward in the management of these patients. Being able to offer both of these under one roof, I think we are really excited about that. We have a collaborative team that consists of non-invasive cardiologists, nuclear cardiologists, such as myself, and invasive cardiologists who are well-trained in the hemodynamic assessment of these patients.

Melanie Cole, MS: And with this multidisciplinary approach and team, Dr. Poornima, tell us a little bit about what we know now about treatment options, whether it's lifestyle modifications or medicational interventions. What are we doing now? If you do determine that a woman has microvascular disease, what can be done?

Indu Poornima, MD: Yeah. That's a very good question, because diagnosis is very exciting. But we obviously need to be able to treat the patient. I think, again, lots of ongoing studies in this area in terms of assessing different forms of treatments. But what we know now is essentially addressing some of the traditional cardiovascular risk factors such as hypertension, diabetes, obesity, go a long way in not only preventing coronary microvascular dysfunction, but also treating a patient who may have that. But in addition to that, there are some other forms of drugs that we typically use in these patients. And one of which is calcium channel blockers, in addition to beta blockers that are commonly used. So, if a patient falls into the bucket of coronary vasospasm, for example, rather than a beta blocker, a calcium channel blocker plus nitrates, both of which are vasodilators, may actually be more applicable. In addition, it has been shown that patients with coronary microvascular dysfunction actually benefit from being on an ACE or ARB. These are angiotensin receptor blockers or ACE inhibitors. And this group of drug has actually been studied in a clinical trial and shown to be superior. This traditional aspirin and statin, of course, is exceptionally important for these individuals because we do think endothelial dysfunction and inflammation are a part of this. But I have to say that lots more to be learned about how best to treat these patients. Cardiac rehabilitation may be helpful. But of course, we currently do not have guidelines or evidence supporting that yet. So as a corollary, we advise exercise on a regular regimen, weight loss, obesity reduction, all of those are also important aspects of treatment.

In addition to that, there may be some non-traditional almost supplements that may be useful, L-arginine, which is a nitric oxide donor, is a supplement, but it is useful in these patients who may actually have epicardial coronary dysfunction that is demonstrated on the invasive assessment. And if they do not respond to the calcium channel blockers and nitrates alone, they may benefit from L-arginine treatment as well.

Melanie Cole, MS: How do you know if they're benefiting, Dr. Poornima? How do you know if it's working for them? Are they getting less ischemia? Are they getting less angina? What are you noticing with your patients?

Indu Poornima, MD: So, there are several well-established, well-validated questionnaires, such as the Seattle Angina Questionnaire that can be used and that have been used in studies that have incorporated these patients? That is what we do in the clinical scenario as well, use some of these angina questionnaires to determine if indeed they are responding to treatments and if treatment needs to be escalated, et cetera.

Melanie Cole, MS: Well, wrap it up for us because this is just such a great topic and so important. I'd like you to give us your best advice for other providers that have not heard very much about coronary microvascular disease, primary care, people that are seeing patients and women coming in that are complaining of chest pain. What would you like them to take away, and when do you feel it's important that they refer?

Indu Poornima, MD: So, coronary microvascular dysfunction is an entity that needs to be considered in both men and women when they either present with a heart attack and there is no obstructive disease identified on any form of angiography, be it CT or invasive. It also should be considered, especially in women who come in with recurrent chest pain, do have symptoms that are very suggestive of angina with an abnormal stress test perhaps. And these women men should be referred for additional testing, such as a stress test or invasive assessment. And they should be actually evaluated in centers that have these multidisciplinary teams, such as the AHN where we are able to provide this comprehensive assessment and subsequent management. And again, I think, most important message to get across is that these patients not be told that this is not heart disease and, therefore, they are left to have adverse cardiovascular outcomes.

Melanie Cole, MS: Thank you so much, Dr. Poornima, for being with us and sharing your expertise on this topic. To learn more or to refer a patient, please call 844-MD-REFER, or you can visit ahn.org. Thank you so much for listening to this edition of AHN MedTalks with the Allegheny Health Network. Please always remember to subscribe, rate, and review this podcast and all the other AHN MedTalks podcasts. I'm Melanie Cole. Thanks so much for joining us today.