C. Noel Bairey Merz, MD joins Georgia Heart Institute as a Cardiovascular Grand Rounds speaker during the CME lectures for 2022. Dr. Bairey Merz is the Director of the Barbara Streisand Women’s Heart Center and Preventive Cardiac Center at Cedars-Sinai Smidt Heart Institute in Los Angeles, California. Dr. Bairey Merz discusses differences in women’s heart disease and recent updates on coronary microvascular dysfunction in women. To receive CME credit for this presentation, please visit the survey link. [https://www.surveymonkey.com/r/TW5CPV5]
Okay, good morning and welcome. Grand rounds is provided by Georgia Heart Institute with support from our industry partners. The planners have disclosed no relevant financial relationships with commercial interests. Dr Barry Myers will disclose her relationships and her presentation to claim cmi credits today. Answer the survey evaluation. If you are viewing online, the link will be posted into the chat. Those attending in person will receive the link or QR code at the end of this session. If you have a question for the presenters, please hold until the Q and A segment. Online viewers may type questions into the chat and I will read them at the end of the session and now a few words from Dr Samity. Well, good morning. It's, it's a pleasure to see everyone. I know we have lots of people online as well. It's, it's really a huge honor for us to host this morning's grand round speaker. Um Dr Noel Barry Mertz holds Irwin and Sheila Allen, chair and women's heart research as Director of the Barbra Streisand Women's Heart Center. Um is the Linda Joy Paul in women's Heart health program director, as well as Eric Jay Glazer Women's Heart Research Initiative director and the director of the prevention Cardiac Center at Cedars Sinai Heart Institute, uh which is all all of, you know, is, is the top two or three heart institutes in the United States. Um She's also a professor of medicine at Cedars Sinai Medical Center. Dr Mercer's research interest includes women and cardiovascular disease, mental stress and heart disease and the role of exercise and stress management. Ladies and gentlemen, in reversing this disease, um as as many of you might have heard her on TED talks or on TV. She's a prolific lecturer and a teacher and has impacted generations of women and men cardiologists and really has opened the door for the field of women's heart research um and women's heart clinical care, which as we know is very, very different than, than men's heart disease. Um In addition to all this, Dr Mertz has received numerous, numerous investigational grants and chairs, the N I H S sponsored women's ischemia syndrome evaluation initiative, the wise initiative, which as many of you know was the initial um NIH funded studies that made the observations that women's heart disease. Certainly at the microvascular and at all levels is very different than men. Dr Mertz received has received numerous awards and honors in her extensive publication record spans over 450 scientific papers, over 315 abstracts and myriad of book chapters and countless peer review journals. She's on the editorial board of many of those journals. She's earned her bachelor's degree from the University of Chicago. Um and then went to medical school at Harvard, completed her residency at UCSF and um services, the Chief medical resident. Before completing her cardiology fellowship in clinical nuclear uh cardiology at theater Sinai. We, we had a delightful time at dinner last night with Dr Burkle and um Dr Glenn Henry as you know, is joining us next week. Um and I can't wait for you all to hear both in person and online what Dr Barry merch has to tell us about women and ischemic heart disease and update today. Thank you, Noah. Thank you, my friend. Well, a lovely introduction and um thank you Dr Samadi and we've been, we've been working on doing this. So, um it's great uh folks in the auditorium, our heart institute grand rounds. The majority of folks are still virtual and um it is nice because it's early in the morning, right? So you can still have that coffee and be sitting in your study and and uh enjoy the morning. Alright, let me make it go forward. There we go. These are my disclosures um to my knowledge, they do not represent conflicts, but of course, we always disclose and let's move on. I thought I would start out just by talking about our team. Uh and this is our clinical team, but it's also our clinical research team because I'm a clinical research investigator So we have three faculty, cardiologists, um one faculty, internal medicine, Vascular medicine and menopause trained. Uh and that's turned out to be a real boon for us in terms of getting women that should be off of the hormones because they just had a heart attack rather than trying to negotiate with the G Y N actually have an endocrine vascular medicine trained person. We have two nurse practitioners, we're adding one. Um they do a lot of our protocol work and I can talk about that as needed. We have three dedicated clinical research fellows that are just for us and they're serving a year or two years with the idea that they will become investigators, two basic science P I S and their teams, three research, excuse me, 11 research staff, community education coordinator, where have a fair amount of commitment in our philanthropic side to community education. In addition to G M E um three P S R s, those are receptionists and management assistance. So it takes a team, it takes a village to sort of get things done. These are the kinds of things that we provide and this is a complicated slide. I'm gonna talk today about what Dr. Samadi referred to as the differences in women's heart disease. Uh so we do preferentially try to see folks women predominantly, but about 10% of our population. Now as men persistent chest pain and then suspected ischemia with no obstructive coronary disease. Now fondly called anoka mild cardio infarction with no obstructive C A D, Minn, Oka Takatsu Bo cardiomyopathy or broken heart or stress heart syndrome. And then a SCAD spontaneous coronary artery dissection. Um so these are pictograms, of course, of these two relatively new terms, but if you're reading the literature, you should be sort of seeing these being used more, more often. They're not yet. ICD- 10 codes. They probably won't be because they're more of a syndrome. And I think, I hope to show you that there are underlying ideologies to be diagnosed and pursued and treated rather than saying that this is just the diagnosis. We knew about this quite a while ago. And as the women's ischemia syndrome evaluation, which is sponsored by National Heart Lung and Blood. And we're approaching our 30th year of continuous funding. But this goes way back to the beginning where we were really asking what is going on. And this was a publication by one of our co investigators in 2007, really demonstrating that women in the black bars compared to men in the gray bars had much more non obstruct or even know obstructive coronary disease in the setting of a CS unstable angina, even end stem ease and stem ease. Uh And these were core lab adjudicated uh studies. So this wasn't sort of, you know, just somebody's random idea about whether or not these arteries were truly open. So it was common in women up to a third. Um This turns out now to be increasingly common in men. And uh this is the V A cart which is a registry of every angiogram done at any Veterans Administration hospital across the United States. Um This particular publication by Tom Maddox and his colleagues, 37,000 male patients, most veterans still are men, military service now is about 20% women. So women will be coming to the V A in larger Numbers. But in terms of contemporary data, what this slide demonstrates is that 47% of men now undergoing clinically indicated invasive coronary angiography have non obstructive or normal coronary arteries. So something that we've been studying in women a little bit of the canary in the mind, Uh now we think is increasingly going to be relevant in the type of the phenotype of ischemic heart disease that we're seeing increasingly in men. Well, of course, uh you know, here's phenotype uh epic are ideal coronaries. We know a lot about that, right? We uh we were given coronary angiography in the 1960s. We've been doing it ever since we very good at lumen ology. So, atherosclerotic coronary disease on the left of this slide, well known, we've got a lot of treatment strategies. Some of them are plumbing but increasingly optimal medical therapy seems to be the way to manage most of this in the middle of the slide, visa spastic disease. Some of us learned that as Prince Metals, Angina, uh this, it turns out in big, big studies that actually did functional testing. It's probably about 3% of the ischemic heart disease that we see. Um And these are the patients that you see. Once you put them on a calcium channel blocker, they come back once a year for refills, they don't need anything else. And if you ever try to say, well, I'm not sure you need that anymore. Or your blood pressure is running a little low. They're like, no, I need that pill. I ran out of it when I was on vacation and my chest pain came back. So what was the dark side of the moon was the right side of this slide? And we, we knew coronary physiologists knew that micro vasculature really portended the majority of resistance. It really is the deal maker and yet we knew very little about it because we had become anatomists. So here's what physiologists have told us for decades. Epic Cardio coronary arteries normally contribute less than 10% of the coronary vascular resistance and resistance again is determines flow. And we know we've known this since the 1960s, hemo dynamic significance is present when greater than 70% of the lumen is obstructed. The coronary microvascular chur is responsible for that 70% of the resistance under normal or physiologic circumstances. So who really determines flow then? So here's a pictograms of the epic Ardell coronaries there called Epic Cardio because they're on the outside of the heart, right? And they are controlled in response to nitroglycerin acetyl calling and shear stress. And they have a fair amount of smooth muscle. So they are conduit arteries that are responsive to these stimuli. You know what we're talking about in the micro vasculature. Then are the intra myocardial arterials. They're diving into the muscle, they are highly responsive and they auto regulate with concentrations of metabolites. So ph other things that are saying the heart muscle itself, the cell is saying I need more flow, I need more oxygen at the end of the day to because flow always wants to travel downstream. What happens at the end of the arterials as well as the sub indycar diem is going to be very dependent on that left ventricular end diastolic filling pressure. And if that is elevated, it is going to be hard to fill the sub into cardi. Um So let's fast forward now because we studied 1000 women and now we've studied them for over, we followed them for over 10 years. What we've been able to demonstrate is the impaired visa dilation of the small vessels. And that is tested by dominantly by a denison very conveniently um is uh you know, one phenotype or one end a type and then the increased vessel constriction is the other one and this is most not easily tested by acetylcholine, although it's getting easier. Um and you can have both of these endo types. So uh this is uh you know, now important and on the map and capable of being tested and with 10 year follow up what we've been able to demonstrate. And again, this is a wise was exclusively women, but we imagine that this will be increasingly relevant to men that in the setting of no obstructive coronary disease, the impaired dilation is an adverse prognostic predictor for May's cardiovascular adverse events death. Am I stroke development of heart failure? Um Yeah. Am I as well as all cause mortality? So, um the reduced dilation turns out to be sort of the one that you really want to look for. If you're looking for prognosis, the increased epic Karniol coronary constriction predicted angina hospitalization. And this one is the one that's most closely linked with symptoms. And again, this is not Prince Metal Angina. This is constriction of the micro vasculature in response to these provocative agents. Um And it is predicting Angina. So if you were going to take this now back to your clinic, what would you, who would you be thinking about? Um And number one, we're not talking about everybody that ends up in the emergency room and gets a CT angio as they are so quick to do these days for any amount of chest pain. What you really are looking for our as a cardiologist, as an internist, as a specialty nurse practitioner, pa you're looking for people that look like they have cardiac chest pain and the new chest pain guidelines chaired by my colleague, Dr Martha Gulati. Give you some nice flow diagrams for trying to decide. Does this seem like it could be cardiac chest pain? Um And so this is who you want to test. Um We still start if we're getting a day, no vote, patient who has not already been worked up. Um We pursue non invasive stress testing. Um We don't want to take people up for invasive or even a non invasive advanced imaging if it doesn't look like they have ischemia. So are they able to exercise? And the baseline E C G is okay. Yeah, we do a routine exercise, stress test. We look at all of these bullets. Do they get the symptoms that's very helpful? Um Do they have ischemic E C G changes? Do they have a compromised met capacity? Can they not get out of two stages of a Bruce protocol? And yes, the Bruce protocol is, is useful in women arrhythmias or a hypertensive response to exercise. So we will look for a wide variety of signals that would say this person is not completely normal. We should move on now, that's not conclusive. Of course, you can always add an imaging test. This is what we do in cardiology. The stress echo and the stress spect are not typically useful in this situation if they are positive and you have that handed to you. Maybe a referring physician ordered it. Of course, you can use it. But in general, these two modalities are basically formed to detect epic are ideal segmental disease. They're looking for obstructive CAD in those Epic Ardell coronary arteries. So you'll have one normal wall motion against an abnormal wall motion. You'll have pixel densities on the spec that are down compared to a normal wall. You're not going to see that with microvascular dysfunction, which is quite more homogeneous. And in general, if you're going to see anything, it'll be in the sub in Dakar Diem. So that's where pet CT as well as the dennison stress M R I come in. So these are advanced imaging and you would want to find out what capacity you have in your local labs. Um And what expertise do they have because that's what you would order if you could. Um We do a lot of cardiac M R I. It's a strength for us at Cedar Sinai. Doctor Dan Berman and Dr D B Ali um lead both amazing clinical as well as research facilities. Um and that Black Rim um that is the microvascular sub into cardio abnormality. This is a patient that was having an and stem e and um open arteries or what a surprise, a female or what a surprise. Um But this is the kind of imaging that you can see with cardiac M R I. So when do we go to invasive testing because again, it's invasive. Uh We are looking for patients that have evidence of ischemia. So it's not all the chest pain in the world, no obstructive coronary disease. And then we typically for um a clinically indicated test that they need to have some kind of symptom that is bothersome to them. I'm not saying that we won't go into the silent ischemia phase and, and we probably will, but right now, this seems sort of reasonable to do if you're going to order an invasive test. And then we often will be responsive to patient and physician needs that the chest pain was really refractory to standard medical management. They try to calcium channel blocker, they tried a beta blocker, they even tried reanalyzing, the patient still has chest pain. Everybody's confused, what should we do. Um And then we also will get folks patients and physicians that have a strong preference for a definitive diagnosis. The woman might be young of childbearing age. She's uncertain as is the referring physician about whether or not she should take all this medication. Um, some patients are either rural or remote or even in Los Angeles and their local doc thinks they're nuts and they have been sent to the psychiatrist and the patient feels competent that there's something wrong with her heart. Um So these are the kinds of patients that we would elect for the, for the invasive testing. And we've pub published along with Mayo Clinic and our two registries um 0.6 to 0.7 serious adverse events. Um And so these are infrequent. Um These are typically elective, you're not doing it in the middle of the heart attack. And uh these are quite safe in ex experienced interventional hands. Um We call it functional coronary angiography or coronary functional testing. Now, um we confirm that there's no obstructive coronary disease. We always record L V E D P so that pigtail goes down again. A lot of people have stopped doing that because of echo. Um but it's, it's important to measure and it turns out it's often elevated, which is often surprising to folks. The valves are fine, pumping function seems fine. Um We are still using Doppler flow wires although we talked about it last night, the company is not making them anymore. So we're going to be shifting to the um the EMR catheters pretty soon uh confirm an adequate flow and this is a flow signal. So this is a Doppler signal. It's something that you see in this tracing, but it's not anything that you necessarily see on the angiogram. Um The flow reserve testing to the adenosine is a it's a ratio. Uh And it's just asking how much to the small vessels dilate. I am going to show you some pictures so you can be believers. Um The acetylcholine, the basil constrictive component it's suppose posted dilate um often does promote vessel constriction. And as you can see in this middle, this is the epic cardio coronary, but you can sometimes see it in the micro vasculature. And the way that, you know, it's it's abnormal in the microvascular future is again, you calculate a coronary blood flow ratio. This are these newer catheters and for those of you that are interventional, um these are pretty easy, they're pretty slick and pretty easy. Uh and uh microvascular dysfunction, you see it, that last bullet is an IMR that's greater than 25. So now that we kind of described this, I've shown you the follow up, it's not a healthy thing to have. It's real, uh we should be looking for it. But what if you find it? What should you do? So, our next line of inquiry was finding mechanisms because if you can understand the root causes or contributing mechanisms to a phenomenon, you can start to think about how you might treat it. Um And so we had found, you know, again, if you just take all comers, people that went up to the Cath lab and had no obstructive coronary disease, about half of these patients have coronary flow reserve or coronary blood flow abnormalities. Um And the prevalence is even higher. If you know, on one of those tests, you had a positive proponent, you had some S T segment depression. So if you were just kind of guessing you'd be right, about half of the time. And if you had some real objective evidence, you'd be right, a lot of the time. Um one of the first mechanisms and this was novel at the time, it's not so novel anymore. We did intra coronary, intravascular ultrasound and led by Dr. Carl Pepin. And this demonstrated in our wise subjects that over 80% of the them had coronary artery sclerosis. So despite those lumina grams and they looked pretty darn smooth to most people, they actually had a fair amount of plaque. So this was a little eye opener, but it is telling you about a possible atherosclerotic mechanism. Another mechanism early on is we had access to magnetic resonance spectroscopy. This is a non imaging component of M R. Uh and it is a true gold standard for that tissue, those cells, whether or not they are a scheme IQ because it's looking at phosphor creatine and a teepee ships in response to the stress and what you can see in the red circle. And the red arrow is in our wise women with no obstructive coronary disease. They had myocardial ischemia that was as frequent and of a similar magnitude to patients with lady stenosis all the way on the right and quite different from our reference control group. So this was really the evidence, very solid evidence published in the New England journal that these were not false positive stress test if you remember back in the day. Um And hopefully this is not being done so often anymore breast artifact, right? So it was always a woman. And so the abnormal perfusion was either breast artifact or a false positive. The EC GS were false positive. So we hope that we've kind of put that to rest. And then we really saw mechanistic Lee that this corner flow reserve, as I mentioned before, was really pretending an adverse prognosis. And as opposed to the 2.5 threshold, that's kind of more commonly reserved, which appears to be a male threshold. Um because the research prior was only done in men, that we had a cut point, that was less than 2.32. For our wise women, we also demonstrated that persistent chest pain in the setting of open arteries also had an adverse prognostic. So if that woman a year later, she's still coming to your clinic and she still has chest pain, that was a two fold increased risk if you look at the bottom two lines. Um those were the, we had a smaller uh subgroup within wise that did have obstructive coronary disease and persistent chest pain didn't, didn't make a difference in them. And we think because they were being treated right. Doctors treat what they can see and what they understand. If you can make a diagnosis, you can make some therapeutics. Um And so again, it suggested that we needed to make some inroads in, in considering how to treat these patients. So if we were to say, okay, well, mechanisms to this in OKA include coronary atherosclerosis, true myocardial ischemia, which had an adverse prognosis. And then I'll show you our observational and some randomized intermediate outcome trials um were starting to support therapeutic strategies. However, at that time, existing guidelines focused on symptom management and current clinical practice is reassurance. This is not a problem. So we concluded that therapeutic trials were needed. Let me show you some of the observational data, we're going to go back to the V A cart. And so again, these are men. Um you see a very low use of optimal medical therapy in an elevated one year M I rate following an in OKA angiogram. And if you look at mild, non obstructive, moderate, non obstructive, um the hazard ratio is elevated and yet if you look at the class of discharge medications, very low use and in fact, sometimes they would be pulled off of their medications. They were like, well, I guess, you know, you don't need that statin, you don't need the the low dose of aspirin. Um So this is a very real phenomenon of, you know, black of acknowledgement of coronary atherosclerosis. We have another observation within a randomized controlled trial. This is that Scott Heart trial. And if you remember this in the U K patients that were coming to their GPS, um with stable chest pain, needing to be evaluated, they were randomized into the right of the slide standard of care only. So that was often a stress test and maybe consideration of some preventive medication if your score was high enough versus standard of care. And then a Coronary CT Angio and what you saw within the 4.8 year follow up was they had a lower death rate in the C T NGO group. Um And again, I'm making an observation because this was not the primary outcome of the trial. But what you saw was those that had standard of care plus A C T A, we're much more likely to have a treatment change, meaning an initiation. It was mostly preventive meds, aspirin and statins. Um And they even had more anti an journal therapy. 10%. Actually, the docks recognized that maybe these two things were related at Thoreau sclerosis and angina. And when they did a longer term follow up in a subsequent observation within this trial, um again, death M I was significantly reduced. We have another uh you know, out of the box trial from the U K, this was the orbit of trial. If you remember it, it was quite a stunning and even controversial. Um asking the question. Should we be doing PC I, should we be throwing instance for Angina and the English want to always ask these important questions. They have these nice guidelines N I C E, they're not that nice in terms of regulating what, how they use their social healthcare dollars, right. So they really wanted to know do stents improve uh angina. And so they randomized again, a bunch of patients at five U K sites, uh they all had to be eligible for a PC I. Um and they had, they were randomized to a real P C I as you can see or a placebo P C I. So they actually had an angiogram with a sham PC I, You can only in the U K could you do this? Um And what you see is the sack. Angina scores were no different and the Seattle Engine of the Sax scores pretty well validated. Um And working women and men equally well and what was particularly interested about the lack of, of difference and, and to say it a little more forcefully, those that get the sham PC I had as much improvement in their Angina as those that got the real PC I. All right. So it's not like nobody got better. They all got better. And this was despite improved blood flow in the epic Ardell Coronary arteries indicated here by the improved stress echo scores. So this really tells you something else is controlling Angina. The epic are ideal coronaries are like we know from our physiologist not contributing to, to angina burden. And finally, we have the ischemia trials. So let's look, observation alie within those trial outcomes. And again, this was again, you would only do such a big trial in the US only we would spend this much money on a single trial, but a randomized controlled trial for severe ischemia and looking at optimal medical therapy alone versus optimal medical therapy plus a revascularization approach and kind of everybody knows these results. I'm going to give you Judy Hoffman's comment to the results. The results are on the, on the. Right. Right. So there was, there was no benefit for death Emmy which their original primary outcome and then come combined mace. Uh And what you know, Judy commented on is in the subgroup that had Angina because ischemia trial included silent ischemia. So not everybody had to have angina to get in, you just had to have ischemia. Uh And she said for people without symptoms or those who have never had symptoms or well controlled symptoms, there's really no benefit. So even if you're again doing revascularization for Angina, uh there's not really much of a benefit. Um And so how do we explain Angina? And I work with Peter block and he's always such a good, he's a good way of sort of putting things. And so and he's interventional. So he's like in the club, right? So in summary, a stain attic coronary segment could produce myocardial ischemia by stress testing and produce symptoms of angina treatment by PC I restores blood flow, improves ischemia, improve symptoms sometimes, but he has no effect on mortality outcomes. And in addition, some patients have ischemia by stress testing in angina but have no cyanotic coronary segments. How do you resolve this paradox? Think of coronary disease as a linear disease and it acts vocally and diffuse lee. And in addition, C A D secondarily affects beso motor activity of that distal coronary circulation by chronically releasing multiple vezo active and anthropogenic molecules. P C I does really more than increased blood flow to an already abnormal distal circulation. So, and the prolonged effects of distal coronary bed may be just beginning. The result is chronic myocardial ischemia due to distal vessel path of physiology and what Peter didn't say. But what we're now studying is heart failure with preserved ejection fraction. Because if this goes on long enough, this is what our prognosis data is showing is that these women go into heft. So a new, relatively new but continuing line of inquiry, we now have ultra high sensitivity tiene I levels on. These are original wise subjects and these are women walking around. I mean, these aren't women in the intensive care unit having a C S or N stem is uh and if you just check routine blood samples for high sensitivity T N I, you will see that both the micro vascular constriction as well as the limited coronary and cardio dilation. Folks that have that they have the coronary microvascular dysfunction have positive ultra high sensitivity tiene I. And so this is now we have to R O ones looking at these knowledge gaps, the red arrows that have question marks on it. Uh Those are things that we do not yet know. Um Does this metabolic dis regulation um uh cause a stiffening of the heart shifting. The myocardial traditionally uses free fatty assets as its energy source. Um And uh animal models and some human um orphan diseases demonstrate that shifting back to a fetal myocardial energy metabolism uh is associated with triglyceride, build up in the cell, fatty heart and so is fatty heart, possibly a root cause for heart failure with preserved ejection fraction due to this indolent ischemia. Um We're also testing, are we having micro infarct which will show up on cardiac M R I with late gadolinium enhancement? Uh and does this then contribute to the abnormal strain? Right, your cross linking collagen and you're gonna end up with a dysfunctional myocardial even though the ejection fraction might be normal, above 57% for women or super normal could be 73%. And yet they're presenting in heart failure. So be on the lookout for this. And again, with the idea that if we can identify mechanistic pathways, we might be able to develop novel treatments. So to send you back to clinic with maybe something useful. Uh Here's a case, 59 year old African American female presents with non obstructive C A D prediabetes, hyper lipid E mia. Um she has persistent chest pain. Uh She has exercise induced chest pressure left sided. She also is short of breath, mild dia freezes and it's been increasing in severity. Five years previous, she had a C C T A. Um, it was non obstructive in a couple of arteries 25 to 49%. Her ragged Dennis inspect more contemporary shows no defects and she's had multiple E D visits and hospitalizations for chest pain and acute coronary syndrome. So she's, you know, a frequent flyer. She has not been ignored. The treating physicians have her on Rinaldi seen atorvastatin and some prn nitroglycerin. Well, what would you do with her? So we did pharmacologic probe trials in these kinds of patients. Uh and what's a pharmacologic probe trial? It's a randomized placebo controlled trial in a relatively small group and you're probing intermediate outcomes that, you know, predict Mais predict prognosis too to sort of try to make the case, provide a rationale and some preliminary data for a larger outcome trial. So we demonstrated that Quinn April shown in the top bar um improved coronary flow reserve and reduced angina at 16 weeks. Who knew that ace inhibitors were anti intentional uh fem HRT we before the whole women's health initiative came out, we had the great idea that maybe estrogen was part of this and it really wasn't. Um The women did report less angina although we think probably confused that with their hot flashes. Um if plan Iran did not work, neither did a PDE five inhibitor in a pilot Rinaldi scene appeared to be improving our R M R I flow reserve. But in a larger more definitive study, it was not useful in the more heterogeneous population we also demonstrated within that are wise with Renaldo seen uh that improving coronary flow reserve, improved angina. So we demonstrated uh indirectly but it was an aim of the study uh that the micro vasculature is really the one that you should be going after if you're trying to improve Angina as opposed to Epic Ardell Coronaries. And then here's another intermediate outcome trial done by Colin Berry and his colleagues in Scotland Core Majka. Again, they took folks that were undergoing elective angiography all the way to the left of the slide, stable angina referred in by, by their GPS. Um those that had obstructive coronary disease were off in a registry. Uh And you can see it's half and this was women and men. So go to any cath lab, you know, registry. Now you're gonna see open arteries about half of the time. But if you look at the non obstructive C A D S, those were randomized to an geographic guided treatment versus functionally guided treatment. So they actually had the coronary function testing. And because the cardiologists that we're doing the testing, uh we're not the treating cardiologist, this could be blinded. Um And what they demonstrated all the way to the right is the Seattle engineer questionnaire scores were significantly improved in the functionally guided group. Meaning when you pay attention to testing and you show that they have microvascular dysfunction, you can improve their angina and did it spontaneously improve? No, because they gave the treating physicians this algorithm and it's super complicated. But of course, that's what we do in academics. So here's what you really do um consider optimal medical therapy. Remember that I've this data, the vast majority of substantial atherosclerosis. So, low dose aspirin statin and ace as well as therapeutic lifestyle change. These are our, these are our guidelines for secondary prevention, right? And this is what we do. This is what we should do all the time. And then for the angina burden, if they have that reduced dilation, that's the dentist in response ALFA beta blockers. And we and the Scots use a lot of carvedilol and we use that heart failure protocol because it's super easy. And particularly if a patient is a woman, they're going to do better at lower doses usually of beta blockers before toxicity. Um If they have increased vessel constriction, calcium channel blockers are your friends. Um We use a lot of all of them actually, but verapamil was preferred by the Scots and then adjunctive therapy, we use E E C P for refractory. This is that those funny Japanese space books and Medicare pays for it and it's not invasive and very effective. Um We also send them for high intensity interval training at cardiac rehab. And then for those that have abnormal um no succession which you know, when you inject the contrast or even sometimes the Saline uh doctor doctor that is my chest pain, uh you can use tricyclics for that and or send them to pain doctors. Um Here's our African American case woman, functional coronary angiography. Um we increasingly see um nonfunctional bridges, um they will kind of come out um if you look carefully or if you start to see they are a night is for a site of provocation. As you can see um in this second panel to a dentist and the patient has an abnormal coronary flow reserve 1.8, that's quite low. Uh as well as a dennison induced basic constriction. You can sort of see that in those smaller arteries. Um she then has the acetylcholine and, and this is actually where she has a functional problem at that bridge. Uh And again, it makes sense. We're born with bridges. Many of us have bridges, most of them are non functional, but they can serve as a site of atherosclerosis because of the turbulence because of the internal injury. Um And we don't fix the bridges. We just identify this is, oh why did you get this and why did this woman not or this guy not? Um And then you can see with the nitro glycerin, there's resolution of the basic constriction all the way to the far right. The patient does have an abnormal left ventricular end diastolic filling pressure. So this is another treatment target and a reason why you always put that pigtail down. So, after functional coronary angiography, we now can make diagnosis. Um So number one, she has non obstructive coronary atherosclerosis, there's a, there's a code for that. She has an elevated L V E D P, there's a code for that. Um She had no evidence of heightened cardiac deception. So we don't have to give her those meds. Um And she has coronary, microvascular dysfunction and coronary artery spasm. So we've got a lot of treatment targets. Um So we started Aspirin and an Al April. Remember we're gonna do optimal medical therapy. She was already on the atorvastatin but she has at the rock sclerosis. So we're gonna kick that up to 80. Um We're gonna put her on a cultism calcium channel blocker. Uh and the holocene was not working for her. So we don't maintain that. Uh And we sent her to cardiac rehab and or E E C P and then my slide is coming off at the very bottom. You can see her Seattle Angina questionnaire score at baseline was 51. The way that you look at Saks scores 100 is perfect. You have no Angina zero is horrible. You're in bed with Angina all day. So she's right in the middle and that means she's having multiple episodes of Angina pretty much every day, multiple episodes per week. Uh and so she kicks up to 68 at one year. Follow up a ten-year improvement in a sack score is clinically significant patients will. Thank you. Thank you doctor. You've helped me and um at one year follow up, she's not been to the emergency room where previously she was going about three times a year. So with all that preliminary observational and pharmacologic probe trials, we designed and got the Department of Defense to fund our warrior trial. Women's ischemia treatment reduces events in non obstructive C A D. You can see the investigators are listed there. This is 4422 subjects who are women. It is a woman only trial uh and they have to have persistent angina and no obstructive coronary disease. And the trial design is randomizing to intensive medical therapy which is high intensity statin and maximally tolerated ace or ARB and low dose aspirin versus general primary care guideline risk factor management, treatment of hypertension treatment of dis lipid e mia. The outcome is reduction of mace which is all caused death, nonfatal mi stroke, hospitalization for angina or heart failure. Um this is our design. We're still halfway through. We are up to 2200. We of course have, you know, enrollment has not gone as fast as we anticipated due to the pandemic. Um but it is a pretty easy and we would love to add sites who can make substantial enrollment um because we're probably in another two years and the average patient will stay in about 18 months. But you can see it's a point of care randomization. It is using um guidelines directed therapy patients. 50% that are randomized to the intensive medical therapy are provided the medication and we have a home mail delivery. Uh they can be consented randomized and enrolled virtually. We shifted to all of that. Again, it's point of care. It does not interfere with usual care. Meaning folks that are randomized to the guideline arm is usual care. Their, their care does not change. There's nothing being withheld. So there's really no um there's no risk, there's nothing invasive. Um And let me know if you guys would like to be a sight because this is a federally funded important study for guidelines. So I will conclude um coronary microvascular dysfunction is prevalent in these in OKA patients and this is a diagnosis that now can be made. The majority of these patients have coronary atherosclerosis treatment is low dose aspirin and statin for prevention, persistent angina and evidence of ischemia. Pretty good data. Now that you know, they could be treated, there's going to be benefits certainly from quality of life. There might be benefit for reduction of adverse outcomes. The E S C guidelines have endorsed treatment strategies for their last two sets of guidelines. We finally, with our new chest pain guidelines are uh teetering on suggesting that these patients be treated. Um So again, we still need these large outcome trials. There are two other trials, there's a large outcome trial in Sweden that is way behind us. Uh And then there's a smaller trial in Scotland. Um If you're interested, take a picture of this. Um Doctor Samadi knows where I live and um we would love to have additional subjects uh enrolled. And also we can tell you, for example, Emery is enrolling so you could send your patients to Emery if you didn't want to activate as a site. Um And these are our research subjects in the middle. We always thank the patients first. Thanks to those that become participants because they really are paying forward uh for betterment of not only women, but I hope I've compelled you. I think we have a good future with the treating men. Uh And then we've got our research teams on the other two sides and our funding on the bottom. So I will close with that and take questions if we've got time. Yep. Very good. Thank you. Sure. Thank you. If you are watching online and you have a question, please enter it in the Q and A bubble and we will ask that anyone in the audience with a question or comment. Fantastic. Did you have a question? Okay. Let's take a question online and I see Holly Jones has a question. Okay, we see. Thanks for a great presentation. This is Dr Raj run across. Thanks for a great presentation run across many patients with Ortho static signs and symptoms with CCB and or nitrates, especially with lower L V E D P. Any clinical suggestions, any clinical suggests with medical therapy, dozing strategies? Yeah. No, that's excellent. And the standard that, you know, pretty much we were taught in cardiology is it might be prince metals. So start a calcium channel blocker and we almost always do something like M Lodha Pine because we love that drug because it's such a great blood Pressure drug at his 24 hour half life, it's super easy and yet it does cause hypertension in people that are not hypertensive. And as I think I showed you, you know, you can't always, you can't predict who's going to have sort of the failure to dilate compared to the basic constrictive response. Most of the patients that we see as secondary tertiary referrals have already failed calcium channel blockers. Um And so, you know, a better sort of strategy if you're gonna do empirical dozing, which we do a lot of empirical dozing, meaning we don't test everybody invasively and we don't do advanced imaging in everybody, particularly if the patient is In their 60s and they've had this persistent chest pain. Um and they have risk factors. I mean, when's the last time you saw a patient in your practice that wasn't hypertensive Disl epidemic, pre diabetic and overweight and out of shape. I mean, this is, this is who we see. So we do a lot of empirical dousing, but we do it in young ones as well that are not hypertensive. I really like the carvedilol. I I often start with that beta blockers work in patients that will take them. Um And I think carvedilol is a better tolerated medication. And again, starting with that heart failure protocol, really low dose and then up tight trading until you start to get a heart rate effect and or they start to tell you that they feel better and, and if that doesn't work, um you know, the other thing about nitrates night, you know, Dr Salmon and I grew up when we used to use a lot of long acting nitrates. And we learned that nitrate tolerance is a real problem and the majority of patients will be nitrate tolerant within three months. What does that mean? It's not working anymore because they're up regulated metabolism, enzymatic. You can break it down as quick as you can take it. Um There's data from Japan which Japan has a lot of Epic Karniol coronary basis spasm much more than, than we do. And there are good studies to support that. It's probably an ethnic difference, but here's the point they don't use long acting nitrates because it's been associated with an adverse prognosis in their sudden cardiac death survivors. Um And why is that? Well, you get a drug that's working for you and then three months later it doesn't work anymore. Um So, uh we're not a big fan of long acting nitrates. I use them occasionally but not as primary primary therapy. And then if she doesn't do well, she or he doesn't do well on this empirical treatment, you know, move on, start to get some, you know, you have a good interventional ist here who's setting up a great lab um with a new chair of your lab and get some definitive answers and or then move on, you know, go high intensity interval training EEC P. Um Renaldo scene does work in some patients of Aberdeen, does work in some patients. Um I have a few patients on the pulmonary hypertension drugs, the PDE five inhibitors, if you find something that works, you know, use it. Is that helpful? Yeah, that's great. Let me just add to that because so um no, well, let me ask you about this. So you've got this business of when do you trigger the invasive test? Um I think it's extraordinarily thoughtful the way that you presented the, the whole sort of based on the iceberg of patients that you get and then the criteria that go into who has invasive cath. I think one of the things we found helpful for that patient, Dr Ajay asked about with hypertension with nitrates and calcium blockers is that the ender typing in the cath lab, as you mentioned, does help you figure out if that's the problem, right? Because if, if actually the problem is not, is a spastic, you're flying blind and if your problems that distal microvascular, it's your issue. Then as you pointed out, you actually pivot and focus on this inhibitors and aspirin and other things. So I think that's where the, the, you know, for those patients that are hypertensive with persistent symptoms, something to consider. Um And I'm gonna, I'm just gonna ask one more question, just, just pick your brain. Um So what's your experience been with other beta blockers? Right? Because you worry, especially if you're worried about, you know, Bezos, spastic component or an endothelial dysfunction component about visa spasm. Obviously, carvedilol is both an alpha and a beta. What about Nabil? All, for instance, what are your thoughts and experience with that? We definitely used to be able all it until recently was not generic. So it was substantially more expensive. And, you know, if you, you tell people, look, I can give you this one that I kind of like because I sometimes I split the dose with the carvedilol as well. I might give them a higher dose in the morning and a lower dose at night or I might even have them skip the dose at night if they're having any nocturnal angina. Um So it's, it's kind of a nice drug. You have to have a patient that's willing to take something twice a day, right? They need to work with you. Um, and then Nabil El, I think, I mean, my clinical impression is that it is a better antihypertensive. So if you're having trouble with blood pressure going down too low, uh you know, nab evil and, and, and again, ambivalent all is, you know, most of the beta blocker dozing is boy dozing. Um, and it just maybe, you know, you know, you never know how much women complain of side effects more than men, which they do. You don't know how much of that is because women have a higher somatic awareness there. More verbal. I mean, there's a million psychologic reasons for women to tell us about, you know, side effects versus all of the r Pharmacopeia basically is except for hormone therapy is based on male 70 kg, you know, and uh, you know, so anyway, we look for opportunities to try to customize the dose and be a little more precision medicine. Yeah, I love those little probing investigations you pointed out because it's, you know, that endo types of disease are so varied that to some extent, you don't know where to start from, from a farmer therapy standpoint. We did a study comparing a randomized controlled study with invasive measurements, comparing the Bible wall to wall with 12 week double sequence invasive testing, essentially found no difference. But to your point. Um you know, that's all comers, you know, what about the people that are predominantly visa spastic and clinically we've seen it work really well and people that are nitrate intolerant or can't do the calcium blockers. So it's kind of that clinical expertise in this calm Like syndrome. That, that helps. Yeah. And I think Nabila was really, is a good drug for somebody who says I want to once a day drug. I'm, you know, above 70 kg, I'm whatever. I mean, we definitely use it. Um, and I do think that there's um something to be said for the incessant improvement of drugs, right? Um did you not find a difference in blood pressure? It's what we compared to alternative alot and actually we did not and it was a relatively small study. So we didn't see a significant difference. But the Renault lysine story is very interesting, right? Because I mean, granola scene is something that now is used very, very widely and you're our wise study, which was I think 100 and 20 or 100 and 30 patients showed no difference. We did a smaller stuff using two invasive measurements with revulsion against placebo. And we didn't find the difference and either the Seattle Angina classification or the physiologic testing. Interestingly, we found that if you started out with a CFR of less than two, obviously smaller subgroup, right? Because they come in with disease that you did get a bump in your CFR with Renaldo. Yeah, that was our pre specified subgroup analysis. But when we expanded to the sort of more homogeneous, you know, so you could have the dilation, you could have the constriction, you could have both in the aggregate. We didn't see a difference. So yeah, it wasn't a completely negative trial. But you know, if you, if you hope that reyna lysine will solve all of these problems. The answer is no. But if you can end a type and, or you get lucky, um I would say maybe 20% of our patients are on reality. And then we, if they say yes, I feel better and we do the sack scores and clinic, then you know, that's good enough for us. We don't have to show the flow reserve improves. Um Jennifer, thank you so much, a really wonderful talk. Um You know, as a, as a fellow, I was involved in looking at mental stress ischemia um when I was at Emory with Dr Back Carino and Dr Kiyomi. And um so I was actually running the stress tests on those patients where we had patients that had proven C A D. So they were not, you know, normal coronaries necessarily and we would randomize them were not randomized and we would do a mental stress test, which was a public speech basically, versus a physical stress test on a treadmill and do imaging component. And what we found was really interesting that patients had ischemia on imaging with mental stress and not physical stress would be the same patient. Some of them actually had ischemia on both, but the territories involved were completely different. So they would have like led ischemia on their, on their physical stress, but it would be R C A on the, on the mental stress. Um And back to your point about Takatsu Boo um as being, being part of that spectrum. I'm kind of curious about what your thoughts are on that brain, heart connection in terms of the mechanism of, of this pathology and whether we should be shifting and focusing maybe a bit more on medications that could treat or kind of manage that kind of neuromodulation. Um In addition to the standard cardiac medications that you have mentioned in your, in that new proposal, um I know there's some studies we're looking at sa rise and whatnot, but just curious what your thoughts about our, about this. Yeah. No, you're, you're making good bedside observations that always sort of then stimulate, you know, it's a, that's interesting, that's a knowledge gap. Like I don't really know what to do with that. Maybe we should do some more research. Um, so I appreciate your, your observations we actually did to my knowledge, working with Dr Alan Rozanski and Dan Berman when I was a fellow and published in the New England Journal, the first time that mental stress testing was demonstrated to demonstrate ischemia. And amazingly, we did it with those old Magas and we had blinded, you know, we were blinded to the patient and sequence and amazingly could diagnose ischemia uh in response to the mental stress. Um We did a Stroop word, a math test in the public speaking and the public speaking was about something that you were embarrassed or, you know, um something you've done bad and you had to do it in front of three white coated observers with the. Um and I was often one of the observers with a notepad and it was, it was videotaped anyway, that was in the New England journal. And then we subsequently did intervention studies. We did it with an S S ri no protection. We did it with Valium. They all fell asleep, they couldn't, they couldn't do the testing. Um And then we did it with the beta blocker and in a small case series, the beta blockers blocked some of this, which was interesting because at that time in the silent ischemia era, the silent ischemia investigators, Pippen was one of them. And the Brigham uh there was high heart rate ischemia and low heart rate ischemia, meaning S T segment, depressions on ambulatory monitoring that would happen at different. And so you always think of high heart rate ischemia as being exercised at some kind of activity. But some of these mental stress patients could get quite tackle Kartik with their Esky Mia. And um so beta blockers were effective in and that small small study. And then um Takatsu bow, it's pretty clear from the literature, not our work yet that they do have residual microvascular dysfunction. Amir Lerman and other people have shown that and that we, what you don't know is was that a result of the Takatsu Bo you know, was that damage or was that pre existing? And they actually just had silent, silent condition and then it became, you know, the Takatsu bow might be the tip of the iceberg and there's all this microvascular dysfunction underneath. Um And then I'll just point, you're, you're asking about heart brain. We're doing M I B G scanning. So that's the sympathetic nervous system in the heart. Uh And we're doing um anatomical and functional M R I brain testing in Takatsu Bo survivors. We've only enrolled, I don't know, 20 again, impacted by the pandemic, but it's ongoing and look in the literature, hopefully, in a year or two, we'll have some publication about that. And the idea is that there are like gabba blockers, there are any T norepinephrine uptake inhibitor blockers. I mean, there might be an opportunity and it would be necessarily it would be secondary prevention as much as we now, you know, see Takatsu bows, we talk about Takatsu bows. It's still a very small piece of the acute coronary syndrome pi um And so this idea that we could primarily prevent, I think at least right now seems we can't, we can't predict. So it would be hard to primarily prevent, But because it has a recurrence rate as high as 20%. And because it is now unfolding that they are abnormal after the original event, even though they recover their ejection fraction, they are persistently abnormal. In addition to having documented microvascular dysfunction um, they have residual abnormal strain and often they have persistent chest pain and shortness of breath. So, if half of them are abnormal, then that's a good treatment target. And if we can figure out how to treat them, we would, we would do that, hope to do that. Yeah. Well, you can see. Um so it seems like we have one other question, I'm sensitive to everyone's time, but I do want to just point out that what Dr Barry Murch has shared with us is really the complexity that we're uncovering, right? I mean, it's, it's, it's so amazing to me that the practice of medicine, the contemporary practice medicine always lags behind by a decade or more. Yeah. And it's so right. So we think about patients coming to our cath labs are eco labs are stress labs going in and out quickly. But you can see that the base of the iceberg both metaphorically and really in this case, from a micro vascular standpoint is where a lot of the action is in verse that you're helping us start to uncover that. Um And um it's just so inspiring that work that started several decades ago has now completely mushroomed and has revolutionized the way we think about ischemic heart disease. Um So, uh Suzanne, I know we're running late on time and I know Holly had a question, but maybe we can take one more virtual question and then maybe we can wrap up and, and maybe you can be around for a few more minutes and take some questions. Yes. And if any questions that we're not able to get to, you're welcome to email me and I'll make sure that Dr Mary Morris gets the question and you can have your question answered. Um So you, you touched on this one a little bit already. Um But it says thank you for the excellent talk. A lot of women in my practice seem to be intolerant to beta blockers fatigue very commonly. Which ones do you prefer and are more tolerated in your experience? Yeah. So a little revisionist but um carvedilol and if you, if again, it's hard to remember what somebody says verbally, but look up that core Micah study Colin Berry B E R R Y because they have a really nice treatment algorithm. And um uh so low doses of carvedilol is kind of our preferred go to beta blocker. And then another clinical pearl could be a glass bead. Um I, you know, you can become a magnet for women that are fatigued. And uh here's Noel's approach to fatigue. You, you know, this is not due to your heart until you're in class for heart failure. I know that you're not in class for heart failure. I cannot fix your fatigue. Do you want to talk about your chest pain? And it's a little brusque but uh you don't want to be taking on the weight of the world. Uh and you want to be able to offer, you know, useful information for people that are, you know, not doctor shopping and don't have issues often, social determinants of health that, you know, often we don't have the tools to, to fix that. So um try not to see chronic fatigue syndrome. Well, listen, thank you so much for an outstanding presentation. We're gonna go over to the studio and capture some more thoughts. And so, um as you all know, you can probably see all of Dr Barry Merchants presentation online pretty soon, but also you'll see her interview where she might give us even more pearls. So thank you so much if you don't know what to do, send them to the Warrior trial. Did you? Good. Thank you.
