Melanie Cole (Host): Welcome to UAB MedCast. I'm Melanie Cole, and joining me today to highlight coronary microvascular disease, is Dr. Gretchen Wells. She's a Cardiologist, a Specialist in Cardiac Imaging, Cardiology, and a Professor of Medicine at UAB Medicine. Dr. Wells, thank you for being with us today. I'd like you to start by telling us about the WISE trial and why this is important for our discussion of coronary microvascular disease. Tell us about this trial.

Gretchen Wells, MD: Okay, first, Melanie, thank you for having me. This is indeed a very important topic for women, and we're going to find out later men as well. But going back to the WISE study, the Women's Ischemia Syndrome Evaluation, so it of course studied women. And what we learned from this study, is that about 50 percent of the women who underwent a cardiac catheterization for an appropriate indication, they were having true angina as determined by their cardiologist or they had abnormal stress test; one half of those patients did not have obstructive coronary disease. For years women had been told, you know, you're just crazy, anxious, whatever, or these stress tests are invalid, and they were written off. But once the technology was developed, it turned out that half of those women actually had coronary microvascular disease. So that was a real game changer in ischemic heart disease in women.

Host: Well, I can appreciate this trial for the simple fact that Framingham, all these studies of heart disease have always been done on men. And so it was really something that was under recognized and the awareness was not there. And still to this day, some women have to really talk to their doctors and beg them for tests and things when they're feeling these kinds of chest pain, because who knows what it could be.

Stress mimics all, there's a lot of things that we told that that's what this is. So I'd like you to speak specifically about coronary microvascular disease, how it's different from traditional coronary artery disease. Tell us a little bit about it.

Gretchen Wells, MD: What we know is that when we image the coronary arteries on a cardiac catheterization, you're seeing only about 5 percent of the circulation. Where the action really is, is not in the epicardial vessels that we see, but in the smaller vessels, in the arterioles, the pre-arterioles, and the capillaries, and so on. That is what determines the resistance to blood flow, not the epicardial vessels. I don't want to discount the importance there, but I want to emphasize the importance of the microcirculation.

Host: Then tell us any symptoms, risk factors associated with this, because I think that's going to be one of the key messages when providers are seeing women with various symptoms and assuming one thing, and maybe they do, as you said, have a normal stress test, a stress echo, something, and it comes out normal. Tell us a little bit about any symptoms that would warrant investigation into this.

Gretchen Wells, MD: Most of these women will actually have an abnormal stress echo or an abnormal stress nuclear study. It's just that the cardiac catheterization itself will not show evidence of obstructive disease. Now, you bring up a good point, Melanie, because more recent investigators are saying, ah, well, the stress tests were validated against epicardial disease. They've not been validated against microvascular disease. So that's a whole new area of investigation. In answer to the question regarding symptoms though, there's the exact same symptoms that people with epicardial disease get. Chest pressure or tightness, may or may not radiate to the jaw, to the arm. May or may not have associated nausea, shortness of breath, or so on. I always tell patients anything that's out of the normal, these symptoms should be investigated.

Host: Then what? What's the next step?

Gretchen Wells, MD: The next step, usually, we start with low tech investigations, a good history, looking at risk factors, looking at an EKG, and then making a decision about what the next testing should look like. If we find an abnormal EKG, we usually proceed directly to a cardiac catheterization. What we're trying to do now at UAB, if the cardiac catheterization shows non-obstructive disease, then we proceed directly to the microvascular testing, which is just simply adding another wire and testing for coronary flow reserve index of microcirculatory resistance; some terms that are relatively new to most providers, but are increasingly important and further investigation of ischemic heart disease.

Host: Well, tell us a little bit more. I'd like you to expand on that testing for a minute. Does it happen at the same time?

Gretchen Wells, MD: That is our goal. Usually, it does now. In the past, we had it set up to where they would have to return. And I would also add that many of our patients who are referred for microvascular testing have come from places where they've undergone two, three, four cardiac catheterizations and they've been repeatedly told there's nothing wrong with you and they're looking for answers.

But an answer to your question at least now is if it's the first time that we've seen a patient we can do what we call ad hoc testing proceeding directly to the microvascular testing.

Host: Certainly more convenient for the patient and the physician as well. Now, what about long term outcomes? Are they similar to heart disease in women? Is there any difference?

Gretchen Wells, MD: The long term outcomes, if you have microvascular disease, as opposed to not having microvascular disease, we know this from Carl Pepine in Florida, who has published extensively on this topic, that your odds ratio is in some series up to tenfold higher of having a major adverse cardiac event. So, it is not a benign prognosis. These patients should be managed aggressively.

Host: Wow, that's so interesting. And I'm sure that many providers did not know that. So let's talk about treatment options. Why don't you start with conservative management. First of all, start with lifestyle, diet, exercise, stress, those roles in managing coronary microvascular disease.

Gretchen Wells, MD: Yes, you got it. The Europeans were ahead of us on this one. They published the guidelines in 2019 and with the levels of recommendation, the first group would be the lifestyle intervention. No smoking. Okay, you got to quit smoking. We also advocate an exercise program, and we're not talking heavy duty exercise, just brisk walking, working up to 30 minutes, 5 out of 7 days a week.

We know from the Nurses Health Study that that reduces the risk of mortality by 50%, and that's better than any medication we can prescribe for you. Stress management. People are looking for different tools. This is an active area of investigation. An appropriate diet. This can be fun. Lots of ways to explore that. There are cultural differences and so on into what makes for an appropriate diet. And controlling your risk factors for coronary disease. Now, while this has not been extensively studied in microvascular disease, we do believe that the risk factors are quite similar. Not always, but quite similar. That would be controlling your diabetes, controlling your blood pressure, and as I've alluded to earlier, stop smoking. Weight management is important as well.

Host: That certainly is. And so those are all very similar. Now what about pharmacologic interventions that are commonly used? Are we looking at the comorbid conditions like high blood pressure, diabetes, those things to tackle? Or is there any specific intervention that you want to speak about?

Gretchen Wells, MD: There is not a specific intervention. There are some ongoing clinical trials for the management of microvascular disease. One of the largest is WARRIOR, which is funded by the Department of Defense, trying to come up with optimal treatments for microvascular disease. I will say that that trial involves the highest tolerated doses of beta blockers, ACE inhibitors, or angiotensin receptor blockers, and statins.

Now, this is based on a hunch. We don't know for certain that these drugs will be effective, but that's when we do these clinical trials in the first place. There have been some very small series of medication studied in microvascular disease. We thought for years that ranolazine would be a good option, but once the RY study, which was a crossover trial, came out, it turned out it probably was not that effective at controlling symptoms.

So more to come on this one. We'll await the results of the large clinical trials. The medications that we are using now, which is based on a consensus statement, are for beta blockers in microvascular disease. We have not really talked about vasospasm, but when we talk about coronary functional testing, we typically put these patients into two buckets.

We first test with adenosine, and then we second test with acetylcholine. Adenosine looks at true microvascular dysfunction. Acetylcholine looks at vasospasm. The management of vasospasm, if that is present, is a bit different from the management of true coronary microvascular disease. Vasospasm involves calcium entry blockers and nitrates.

Host: This is so interesting. I'd like you to speak about the multidisciplinary approach. If we're looking at those lifestyles. And we're looking at medicational intervention and even the clinical trials; who all is involved? Because for the woman, she's going to have many providers, especially if she has to work on weight management, stress reduction, diabetes management, all of these things.

Gretchen Wells, MD: Well, I'm glad you brought that up, Melanie. In my opinion, the most underutilized intervention that has mortality data to support it, is cardiac rehabilitation. Cardiac rehabilitation programs are available all over the country. There is an insurance approval in place for patients with angina. We encourage all of our patients with cardiac microvascular disease to enroll in a structured cardiac rehab program.

Those programs indeed have a multidisciplinary approach. There are not only physicians there, but there are also exercise physiologists, health diabetic educators, psychologists, and so on that can help the patient cope with this disease and take control of it. There is no reason that heart disease, particularly this type, needs to shorten a woman's life.

Host: Thank you so much for great information. This was really informative, Dr. Wells. Thank you so much for joining us. And for more information, you can visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. Please always remember to subscribe, rate, and review this podcast and all the other UAB Medicine podcasts.

I'm Melanie Cole. Thanks so much for joining us today.