In this Grand rounds presentation, Dr. Puja K. Mehta discusses Ischemia with No Obstructive Coronary Arteries (INOCA) from prevalence and prognosis, to diagnosis and treatment.
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All right, good morning, everybody. Welcome to pen cardiology grand rounds today, we'll give everyone another minute or two to log in. Um We do have our C M E code. I know there was a couple of months of uh that we were still uh finalizing our approval process with the C M E office. But the code today is 84939. So for any of you on the phone, the code again is 84939. So just like uh prior grand rounds, please feel free to leave any questions, comments in the chat section or the Q and A tabs at the bottom and then uh we'll plan for the last 10 minutes, uh 15 minutes to have a Q and A session. All right. Ok. I think Linda posted it as well. So once again, the C M E code is 84939. All right. Well, good morning. Um Everybody. It's my pleasure to announce our speaker Dr Puja Meta from Emory University School of Medicine in Atlanta, Georgia. Doctor Metha is currently an Associate Professor of Medicine in Emory and serves as the Director for Women's Translational cardiovascular research center. Doctor Metha attended Georgia Tech for college and then the Medical College of Georgia for her medical degree. She completed her residency and cardiology fellowship at Emory before going to Cedar Sinai to complete a women's Heart health research fellowship and then was on faculty there for several years. Her research now at Emory focuses on women with persistent chest pain and evidence of myocardial ischemia but have no obstructive coronary disease. She's doing this by evaluating coronary, endothelial and microvascular dysfunction, cardiac autonomic dysfunction and then putting this all together to try to treat these patients with chronic chest pain syndromes. She currently has an R 01 grant to study mental stress reactivity in women with coronary microvascular dysfunction and is really one of the, the folks leading our understanding of this important disease state. Um This is an issue. Certainly we've all seen in our practices. I know we see this in the calf lab patients present uh sometimes with chest pain or angina consistent with coronary disease or they actually even present with elevated biomarkers. But then in the calf lab, we don't pick up any obstructive coronary disease. We don't see any obvious culprit lesion. So I think there's a lot that we can learn here from puja and with that, I will turn it over to you and great. We are all really awaiting your talk. Thank you. Great. Thank you so much, uh Samir for that kind introduction. And thank you all of you for tuning in this morning and for highlighting this topic, it truly is an honor for me to be invited to present. Uh We will be focusing on ischemia and the setting of no obstructive coronary artery disease. So, over the next 45 minutes or so, uh we'll talk about this and then I'll hopefully have 10 to 15 minutes for Q and A. I have no disclosures related to this talk. What we'll do is go through prevalence, path of physiology and uh a prognosis, talk about diagnosis, treatment and some conclusions. So, when we refer to this syndrome, what we're really talking about is people who have symptoms. So chest pain, evidence of ischemia, um and then abnormal stress testing or biomarker evidence of ischemia, but then no obstructive coronary artery disease. So we go back to the drawing board and we think about what could be possible causes of this patient's uh these patients symptoms. So we think about myocardial factors. So things like infiltrated cardiomyopathy or hypertrophic cardiomyopathy, et cetera. Then we keep in mind noncardiac causes, of course, um whether it's um pulmonary issues, acid reflux, a anxiety, psychiatric illness. So the noncardiac is there. But what we're focusing on today is the vascular function abnormalities and really what we're talking about is a abnormal sort of basal reactivity. So, epicardial vaso spasm impaired microvascular reserves, a problem with vasodilation and an abnormal microvascular constriction. So, those are kind of the vascular function abnormalities. Now, this problem of Inoa approximately two thirds of women and one third of men who are suspected of having ischemia when they undergo coronary. A geography. Uh And this is by uh invasive or a geography or coronary C T and geography. Uh They're found to have no obstructive disease and this is typically defined as less than 50% stenosis uh in, in one of the three epicardial arteries. Now, we know that IOA is not benign. And if you follow these patients for 5 to 7 years, uh you find that it's associated with recurrent myocardial infarction, a stroke, a heart failure, and specifically heart failure with preserved ejection fraction, um and then death. So IOA is not benign and that risk is over five years, is about 2.5%. So put this in perspective and event rate with C AD might be, you know, around uh 3 to 5% IOA is um not as um severe of a risk as having obstructive C AD, but it is not benign. Now, if you were to take these patients, about 30 to 50% of this population, if you were to do invasive testing, you would find vascular function at their maladies. Now, it's estimated that that's about 3 to 4 million Americans. Uh That's likely an underestimate because we don't typically code uh I know we don't typically look for a coronary microvascular dysfunction, then code for it. So it's probably uh more, more than 3 to 4 million this condition. Uh basically, you know, patients go from repeated uh repeated testing and repeated sort of health care utilization, they go from doctor to doctor to try to find answers. So there's high health care utilization and uh symptom disability and poor quality of life. Uh This is one of my favorite slides and this is a work by Doctor Leslie Shaw and the Wise Investigators. This is women's ischemia syndrome evaluation study. And what they looked at here, what I'd like for you to focus on first is the light blue, which is typical Angina symptoms. And if you look at obstructive disease versus three vessel disease, the rates of um anna are comparable. And then if you look at functional disability, this is by uh Daisy, the Duke activity status index, you can see that the physical functioning. Uh there's, there's quite a bit of um disability with having no obstructive C AD. And so what are the typical scenarios that I see? Um Usually it's patients who are referred to clinic because uh they had an unexplained M I. In other words, they had uh uh an angiogram in the setting of troponin elevation and symptoms. But then there was no clear answer or patients were having recurrent rest, emotional stress induced or exertional chest pain and notice I say your rest pain, emotional stress induced pain or exertional symptoms, but they um didn't have any uh you know, sort of, they had regular stress testing and that it was either inconclusive or not. It suggested no obstructive disease. Um There are patients who have had a PC I and have sort of what we, you know, they don't have obstructive disease anymore because they are post stents but uh are still having symptoms and then often younger, uh, perimenopausal age range women, uh between the ages of 45 55 who um have symptoms that suggest myocardial leukemia. So this is kind of uh typically my clinic and um I have uh quite a bit of men as well. So as we'll discuss uh while we're talking about women and heart disease section and talking about ioa and microvascular, it's clear that this occurs in men as well. I want to briefly focus on the first one here uh because this, when there's Chapo elevation and no obstructive ce D, it's increasingly being called Minoa M I A O C A man. And again, this is not a cod thing right now. But uh you know, manoa, it's the uh third universal sort of definition of ami with risen fall of troponin EKG changes uh symptoms and then can have motion abnormality but no obstructive disease. And again, this is, you know, less than 50% sonos. So it can either be normal appearing coronary arteries. Although we all understand, I think that, you know, coronary and gray is uh just a Lumi gram and it's going to miss hidden things in the wall. So, uh you know, less than that 30% or so, less than 20%. So Luminal that, that all is, falls under sort of non obstructive uh C ad uh but then having no overt uh explanation. So you've ruled out other causes such as pe or sepsis or uh Takasu, you know, any of these other causes of triple and elevation. So what is um it's estimated that 6 to 10% of A Q M I presentations are manoa and uh women are more likely to have this presentation. And it's three times more common in women compared to men and especially younger ages uh under the age of 55 and prognosis in manoa, uh just like AOA is not benign and it's about 3.5 to 5% mortality at one year with 25% having recurrent angina at one year. Uh What I find at least is that Mya patient seems to be a very uh it's a different um you know, sort of population compared to the Inoa population. Uh And we'll go over this and the links between Inoa and manoa are not um uh well understood right now. And so when we um talk about manoa and possible causes, I think uh everybody has probably seen slides such as this, which is uh you know, you have to think about the coronary artery plaque disruption, uh epicardial vasospasm, coronary thromboembolism rule out SCAD and look carefully at the angiogram with the interventionalist. Um I am not an interventionalist but whenever I get referred patient who has had a history of Troon elevation from, from the outside hospitals, I try, you know, try to get that CD and I really look for that and review it closely with our interventionalist to make sure that the SCAD wasn't missed. And then um coronary microvascular dysfunction. So those are kind of the uh causes of manoa and then the manoa mimickers, um myocarditis, Takasu and non ischemic cardiomyopathy. And now, um you know, typically if there's troponin elevation, no obstructive ce D in the patients hospitalized uh recommendation uh per E S C guidelines is that uh you just get a cardiac MRI to rule out uh myocarditis because uh approximately a 3rd may have um evidence of, of myocarditis. Um Doctor Harmony Reynolds uh led this uh harp study which is currently also ongoing. But uh now it's including men. This harp study results were focusing on women only. This was a prospective Multi Center study that was observational uh in women who had a manoa event, uh they underwent O C T A three vessel O C T and cardiac MRI. And uh basically what uh was found I'm gonna go through this. Um 60 average age was the 60 years. Uh 3.5% had stem presentation. So, majority of manoa is non stem. Uh There was wall motion abnormalities, two thirds had abnormal EKG S uh mild troponin elevations, um mattering of risk factors such as hypertension, diabetes, hyperlipidemia, um some anxiety and depression and 90% had chest pain. And what was found is when you um come looked at O C T and MRI and integrated the two. And the point here is sort of multimodality imaging um to investigate the manoa event um cause was identified in a majority of patients. So this is a uh a very good thing that at least, you know, 85% of the time. Uh there was uh an explanation as to the manoa event and majority of the mechanism was arosa plaque disruption. So, um this is uh an an important finding and one in five non ischemic process such as myocarditis. Um and 15% had no imaging findings to explain their manoa event. And um in this study, the coronary function testing was not done. So then going back to our, you know, ischemic heart disease, we have acute coronary syndrome. So we talked about manoa, but now let's focus on Inoa, which is the majority of patients and what we see in clinic uh which is in the stable setting. A patient who is having recurrent sort of angina like symptoms and it it sounds like because of obstructive coronary disease, but then they don't have um any obstructive disease on calf. So when we think about vascular dysfunction, think about epicardial coronary. So the larger vessels and then microcirculation, epicardial dysfunction, if you really wanted to clarify it and if you really wanted a definitive diagnosis, you really have to do invasive testing. And it's mainly using acetylcholine. We you pretty much don't do a gonave anymore. So it's really just the acidy Cole and um for coronary microvascular dysfunction, this can be assessed noninvasively or invasively. And it's typically using a hyperemic agent such as Adenine or Diol. And how do we define C MD? So that is a term that is used to describe abnormalities and regulation of blood flow that's not explained by epicardial Laos corros. So we see about 5% of the coronary tree and the rest is, you know, beneath the surface. Uh And this C MD can be from endothelium dependent or independent mechanisms and just have to remember that more than 70% of resistance to flow in the myocardium is controlled by the vasculature. This is one of my favorite sort of physiology path of the slides. And I know it's kind of early in the morning, but I promise this is the only uh slide like this. But I think it's important to kind of uh remind all of us that uh epicardial and proximal arterials, they, you know when the arteries are open and if there's no AROS plaque there, it's a little resistance to flow. Um and they maintain uh the flow mainly by uh shear stress mediated sort of endothelial mediated dilation. And then when we get into the pre arterials, uh that's still under 100 micrometer, these uh arterials, the smaller ones, they're extra myocardial, thicker walls. Um There's myogenic basic constriction to blood flow. So there's a sympathetic control uh there. And then you've got the arterials, uh less than 100 micrometers or so that have high resting tone, but then they dilate to local metabolites. So things like uh the lactate co2 uh hydrogen ions. So, uh you know, those are uh that's the stimulus for these arteries to dilate. And so when we think about risk factors, uh almost all the c ad risk factors are also associated with microvascular dysfunction. So, age hypertension, hyperlipidemia, diabetes, smoking, estrogen loss, um autoimmune dysfunction, all of these sort of lead to three basic uh pathways um through inflammation, sympathetic dysfunction, and hormonal dysregulation. I have a, a strong interest in mental stress and the impact on vascular coronary vascular dysfunction. I won't be talking about that uh research in this talk. Um But um it's one of these uh things that I think a combination of these things kind of impact the vascular regulation uh and uh probably uh leads to to, to symptoms and microvascular ischemia. Um I show this slide here to also um kind of highlight some of the measures for microvascular and vascular dysfunction. So we'll go over that in the next few slides. But coronary flow reserve is an integrated measure. So while we think of that as a microcirculation measure, we have to remember that it's really if you have epicardial aosis, uh it kind of integrates the whole, it's the whole thing here. Index of micro circulatory resistance is more specific to the microcirculation. And then when we talk about acetylcholine responses, what becomes important is the dose of acetylcholine that we use. So if we use lower doses, it basically tests the endothelium um to, to see what the uh whether the endothelium is healthy and responding. Because remember that acetylcholine is stimulus to release nitric oxide and that will lead to in normal circumstances, vasodilation. So if you have decrease in diameter, that would suggest endothelial dysfunction and then you can calculate coronary blood flow. So this is also an integrated marker of the entire sort of vascular tree. If we use high doses of acetycholine, then it becomes a spasm testing dose and then it will test for epicardial spasm. When we refer to microvascular spasm. How do we you know diagnose that because you can't see it. Um And so in microvascular spasm, what's happening is you use acetylcholine but you don't see epicardial vasal construction, but you have EKG changes and the patient says to you um hey, I'm having chest pain when you started the acetylcholine injection and, and this is what I feel at home. Um So the, you know, if there's there, if you reproduce the symptoms, they have EKG changes, but no visible epi cardial spasm, then that's likely microvascular spasm. Now, one thing that's important to remember is that C MD um can be found in many other card, you know, cardiac disorders. But we don't refer to, we don't call these patients microvascular patients because typically when we are talking about microvascular, what we're talking about is people who have preserved ejection fractions. They don't have a history of heart failure, they don't have any cardiomyopathies. So, you know, nothing to explain their symptoms. Um And so this is an important thing to kind of keep in mind is that the myocardial factors, um these can all kind of contribute to shortness of breath or chest pain symptoms, but we're sort of excluding this and then still seeing symptoms. And that's when you really start thinking that maybe this is microvascular disease that we're talking about and then structural problems in the microcirculation. So, you know, underlying inflammation and all those risk factors can cause actual structural changes in the microcirculation um that can kind of cause a problem with impaired uh flow reserve. And then there are the functional mechanisms. Now, the Covas registry, this is the largest registry of patients with microvascular dysfunction. It's an international registry and, and you see the the countries represented there. Uh And um what they find is that uh if you look at the um sex, uh 64% female, 36% men. So this happens in men too. And, um, age is less than, uh, about 15% of patients are under the age of 50. And, and this is kind of what I see in clinic as well is that they're usually in the early fifties to early sixties. Um, that's kind of the age range by the time. Um, patient is, you know, 70 or so. Typically there's, uh, some, you know, risk factors and arthrosclerosis and you have probably reasons to treat anyway. Um So I, but about a 20% a little over 20% were in their seventies when they were first diagnosed with microvascular risk factors, diabetes, uh hypertension hyperlipidemia, I'd like for you to focus on panel B here. Um And this is where uh we don't understand why this is, but this is true. Also in CD population is that women tend to have a lower quality of life and more angina compared to men with the microvascular dysfunction. So even though the mace rate is similar between men and women, the impact of uh the condition on symptoms um and quality of life is and is uh probably women are more impacted by it when we um looked at Emory uh database. And this is work that Doctor Habib Samadi who was an internationalist who did um these coronary function um studies, we looked at our uh population. So women and men, it was about equal numbers and both women and men had vascular abnormalities. More than 85% 90% of people had some vascular abnormality with invasive testing. Now, of course, this is biased because we're only sending patients for invasive testing when the suspicion is uh high enough that, hey, they're having recurrent symptoms. So we really want to give them a more definitive diagnosis. But interestingly, we found that women had significantly lower microvascular flow reserve compared to men. So women, the average was 2.2, whereas for men, it was 2.5. Um another important thing to remember is that uh when you have microvascular plus coronary disease, then that risk is even higher. This was nicely shown by Doctor Teti. And you can see here that as the obstructive c ad uh increases and the severity of microvascular increases. Um that that clinical risk is even higher. One thing I'd like to highlight is that there's a lot of ongoing work now in trying to understand the relationship between microvascular and he path, uh some have proposed that this microvascular dysfunction may be a pre hef path kind of a syndrome because if you look at the risk factors, there are shared risk factors, hypertension, diabetes, obesity in women. And um if you look at people who have a history of half path and when they undergo a pet MRI studies have found that there's quite a bit of low flow reserve despite having no obstructive disease and then the other way around. So if you have people who are diagnosed with microvascular dysfunction and then you follow them for 5 to 7 years out. The highest signal in terms of events is um heart failure, hospitalization and particularly uh half path. Now, let's talk about a, a little more about diagnosis. So this is probably the most important take home slide of this presentation if you wanna take a picture. Um But basically, how do we diagnose this? This is the Coba criteria. And uh so we talked about symptoms. So it's either effort angina rest angina or a prevalent and then objective evidence of ischemia, either by EKG changes or abnormal perfusion defect or wall motion abnormality. And then you have no obstructive disease. Now you could stop there. Um Samir asked me earlier, you know, who do we send for coronary function testing? It's not practical to send uh everybody for this and, and everybody doesn't need it either. So if the suspicion is how you can certainly stop after the first two and say I'm going to empirically treat uh for microvascular dysfunction and assess response. But then there are certain uh patients who you really want a definitive diagnosis. So for example, if you have younger patients, because you know, if somebody is 45 50 years old and you wanna, you know how long to do the the therapies. And um it makes a difference, right? Because about uh 10 to 15% about 10% of patients when we send them for invasive testing, we find no vascular abnormalities. So then that patient can be reassured that uh it seems like this is a cardiac, either no susceptive problem or let's investigate noncardiac causes. How do we definitively diagnose microvascular? So, the cutoffs or coronary flow reserve um either less than two uh by if it's by pet or less than 2.5 by invasive testing um or I M R greater than 25. So that's the index of my circuitry resistance. Um greater than 25 sometimes all you have is the slow flow. So if you have timmy frame count and if you suspect slow flow, then that, that, that's a endothelial dysfunction and that, that may suggest microvascular dysfunction. And then uh we talked about the microvascular spasm diagnosis. So, no visible epicardial spasm but EKG changes and symptoms. So all of these will uh get them a diagnosis, a definitive diagnosis of microvascular. Now, um which non-invasive test uh do you use? Well, you use the test that's available at your center that has the expertise in, in that. So stress pet uh will give you the myocardial flow reserve, stress MRI stress MRI alone will not help you rule out um microvascular. You really have to have that semi quantitative myocardial perfusion reserve index which can be challenging. And you really have to have the uh people who are willing to, to do that extra M pr I and provide that to to definitively say that there was no microvascular and then Europeans. Um there are a few centers that use Trans Thoractic Doppler echo. So it's typically L AD and they use Diol uh to look at coronary flow velocity uh reserve changes. Um This is typically not done in the United States. Now, the problem with all three of these is that they all test problems with vasodilation that none of these are testing vasoconstriction or spasm. And um just in terms of cost, we always have to keep that in mind. Um If you, if you have an outpatient cardiac pet may not be approved by the insurance because uh typically, you know, if you say I'm looking for microvascular, uh sometimes uh you know, that's not a, not a reason that it'll be covered. So you end up going through uh going through exercise, treadmill test or, you know, if they can't do it often, they've had stress echoes and things at other places and then they come to us. And so we have a reason because we're saying they have persistent symptoms. But um they've already had one type of stress test and now we would like a pet and I'm successful about 50% of the time uh as an outpatient trying to get these approved. Um Now also remember that you can have completely normal trad traditional stress test, but you can still have a vascular function abnormality that's missed because of this problem of not being able to test the endothelial function and basal reactivity the Europeans had in the European guidelines. This is in 2019. They recommended uh This is a class to A A and two B indication for invasive A geography um with coronary function testing with uh acetylcholine and uh adenine. If a patient continues to have symptoms, the chest pain guidelines that have come out for us. Um Also, and I was really happy to see this. Um So what is the recommendation here? I just highlighted for you to a recommendation to get a pet for flu reserve or an MRI for persistent symptoms in Ioa and then to a recommendation for invasive testing. If um the others are uh not giving you an answer. This is an example of protocol. So usually, you know, Adenine, either intra coronary or I V um and then acetylcholine and graded doses. So as I was saying, the lower doses to test your endothelial pathway and then higher doses uh testing for spasm and typically, we don't do this in the setting of a CS. Um And so that's an issue, right? Because if somebody has uh is coming in with my and they already had a cast, no obstructive disease, you know, do we send them back for invasive testing? And I typically do not uh because you, I don't want to expose them to another, you know, radiation and another invasive test unless there's persistent symptoms. So you saw that about 25% had recurrent, you know, symptoms because the majority of manoa patients, at least in my experience, you know, they had their event and then they're doing fine. You know, they're, they're on their Aspirin beta block or a blood pressure is controlled and, you know, we don't, they're, they're doing ok. So then I'm not gonna send them back in. Uh but it's only for uh people who have persistent symptoms. Uh This is a bit of a busy slide um and going in a little more into details related to so what we do in terms of testing, but one thing to remember is if you didn't do the coronary function testing piece when the interventionalist calls you and says, oh, there was no obstructive disease. Um I go ahead and ask, you know, what was the E D P? Because a third of microvascular patients will have E D P S that are not normal. They, you know, it'd be 18 20. Um So it, that, that will tell you right away that this could be a pre heath type patient. Um So elevated E D P, was there slow flow? Was there myocardial bridging? Um And of course, these bridges can be also tested with for to see if they're functional uh bridges. Um EKG changes and then uh symptoms during coronary function testing if they did that. Here's an example. So you see the intra coronary acetylcholine. Um You can see the the whole artery here, this is high dose uh acetycholine to test for spasm and then nitroglycerin relieves it. And and importantly here, this this is what I wanted to kind of show is the microvascular spasm. So here in the in panel, C you know, acetal co is injected, but you don't really see any clear spasm but you see the EKG changes. And so this is uh this gives you um diagnosis of spasm. Now, having abnormal flow reserve or abnormal constriction, these are associated with events. So this is for prognosis, it becomes important and the cut-off really less than 2.5 um is what is it with invasive testing? That seems to be prognostic. Here's uh data from wise study for women who underwent coronary function testing and you can see the curves separated around uh 2.3 in this um invasive studies. And we've seen curves like this with pet uh where the curve, you know, sort of separate at C F R less than two. And um with having endothelial dysfunction alone with the coronary, there are lots of sort of studies here uh that show that if you have no dilation, if you have paradoxical construction or um no dilation that is associated with uh events. Now, um in terms of uh you know, another measure. So I M R again, I M R and H M R. So those are more micro circulation and then C F R is more of an integrated measure. So when you think about, you know, putting all of these measures together, uh one thing to remember is I M R because it's measuring resistence. And it's basically um you know, pressure temperature, a sensor guide wire that wire is goes all the way distilled to the tip of the led and then its thermodilution uh technique to, to give you m microcirculation resistance and having there, there are some patients who will have a normal coronary flow reserve. But then if you do I M R, it's the resistance numbers are very high. So you can have, you know, discrepancy in the C F R and I M R. But what's clear is that if you have a low C F R and high I M R, then that's um really uh prognostic and it's a higher risk group. So again, four reasons to do coronary function testing is to clarify and provide a diagnosis, uh differentiate vaso spasm versus abnormal vasodilation versus mixed pattern because the percentage of patients will have mixed pathways and and then noncardiac chest pain because it allows you to kind of clarify the uh strategy as to how to approach uh angina management that the diagnostic findings do have prognostic implications. And if it helps alleviate anxiety and outweighs the the kind of the risk outweighs the benefits, then then I order it in the last few minutes here, I'll talk about treatment. So this is the KMI study, which is a landmark trial uh came out in 2020. And what they did is they took 100 and 51 patients who had uh ischemia, no obstructive disease and underwent coronary function testing versus uh uh controlled angiography. And basically the um referring physician was either provided information about microvascular dysfunction versus uh just standard uh you know, cath with no, no information about whether there was vascular dysfunction or not. And when the microvascular angina was diagnosed, so, when microvascular or vasospasm was diagnosed, it resulted in improvement in angina and quality of life at six months and 12 months because they were more likely to get antianginal medications. And so here's one approach from the mica trial. And what you see here is if they had beso spastic anna diagnosed, then they went with calcium channel blockers and nitrates versus microvascular. Uh they got beta blockers uh as opposed to calcium channel blockers first and then also ranolazine. And this is kind of my experience also that uh my spasin patients don't really seem to respond to the ranolazine. But if they have mixed pathway, um or if they have pure microvascular, then uh they do respond to uh ranolazine. And here's um the various endo types that um they found in this particular study. And you see here, they also report about 11% had noncardiac. So, you know, the the vascular function pathways were ok in about 10% or So, um versus about 20% had both pathways that were abnormal. Uh This is another uh important sort of take home slide that I think summarizes all the possible um things that can be used um for uh this patient population, I always start off with addressing the risk factors because if there's a reason to treat um all of these as a preventive cardiologist, you know, those are sort of the bread and butter that we would do and then whether to use aspirin and statins. Um The Warrior trial right now is ongoing. It's go, it's recruiting 4000 something patients. Uh all women um to see whether a strategy of optimal medical therapy with ace inhibitors, uh statin and aspirin, whether it leads to event uh reduction. So we'll, we'll find out, I think um they're in their final year. So we should be hearing uh the that um to, to see, you know, whether optimal medical therapy helps in the Inoa population, then we have the traditional a antianginals. And if you're suspecting baso spasm, then I go with the calcium channel blockers and nitrates. Roya inhibition is not available for us here, it's available in Japan um and then other agents. So the other key things to kind of remember is um uh so if there's a dein mediated um sort of chest pain, then get the ayin can be used. Um In addition to ace inhibitor, if you notice the elevated E D P even though they don't have a history of heart failure yet. And they're not telling you that, you know, it's not seeming like, like if they had an echo and it's, you know, either grade one diol dysfunction or diastolic function seems ok. But if their E D P was elevated, then I do use um spinal lactone or plain just to see at low doses um to help with their symptoms and then novel therapies that are under investigation, endothelin antagonist, endothelin is a potent vasal constructor. And so blocking that um it can help with the um abnormal vasal reactivity. There was a a pilot study using stem cells so directly injecting stem cells and it showed that there were improvements in coronary flow reserve. So that's another potential. Um The larger stem cell trial um was uh on hold. Um They, they terminated it just because of recruitment problems during the pandemic. Um What about abnormal no deception? So I would say that about 10% of patients when we send them for coronary function testing, they feel they feel a lot of chest pain, you know, um just with the catheter being there and um they likely have an abnormal no su issue. And so for those patients tricyclic antidepressants, like uh low dose Iram or amitriptyline um can be used and then E E C P um cardiac cardiac rehab, by the way, you know, Angela is, is a covered diagnosis. So even if they have no obstructive disease. I do send them for cardiac rehab. Um coronary sinus reducer is being tested now um in clinical trials for microvascular. And the idea here is to um put in uh this device, uh this reducer stent into the coronary sinus. And the back uh pressure will kind of eliminate that gradient between the venus and the arterial system and improve sub endocardial uh blood flow. So this is another promising um strategy. Now, a couple of quick things because I get asked this a lot, you know, a lot of these women have lowish blood pressures. So it's very difficult. They don't tolerate the beta blocker or they can't take the higher doses of calcium channel blockers. So for those patients, I usually will recommend just like a 0.1 of nitroglycerine patch just when they're trying to do their activity. A lot of these patients have nocturnal symptoms. So then I just have them wear the low dose patch if they can tolerate it and don't have a headache. Um when you use Renexa, you know, it has this interaction with Delta. So for those people who have a mixed pathway, so if they have they, they need the spasm drug, but they're also needing a microvascular drug. I usually will just keep the reno ranolazine dose around 500 mg twice a day. And I don't necessarily go to 1000 if I'm using high doses of Delta, just because of that interaction. And it also, you know, they're, they're not happy um because of the side effects with the constipation and then of course, monitoring the Q T interval sometimes um if the heart rates are greater than 80 and they're already on um you know, some of the other antianginals, either they're not tolerating it, then a Aberdeen um if they can get it approved through the insurance that can be helpful. Uh and then for slow flow um Diam has been used in studies Diol and Naval. The other thing is um dual calcium channel blocker because there are patients who often will require very high doses. So, you know, uh I get referrals where cardiologist has already tried calcium channel blocker with, let's say they started 100 and 20th cards uh and the patients still having symptoms. So I just, I just increase it because you can use high doses of DILT or um you know, the calcium channel blocker until you get a therapeutic response. As long as their blood pressure and heart rate tolerate it. Uh And then I will often use combination. So Dim and amLODIPine and I always get calls from the pharmacy that oh they're on two cal and channel blockers and said, OK, we know, but you know, two together sometimes um that can be helpful. Uh The last thing to mention is Tadalafil. So use this um every, you know, 23 days low doses and they don't combine it with nitrates because of the hypotension. The other newer agent to, to mention is very sick, which uh is a soluble cyclic stimulator. And perhaps um would you know, improve N O levels and can be helpful in this population, but I haven't used it clinically yet. I'm just waiting for the trials. So to conclude here, um ischemia with no obstructive coronary artery disease is highly prevalent, not benign in a subgroup of at least 50% will have vascular dysfunction uh problem if you were to send them for invasive testing, which is associated with the worst prognosis, coronary function testing will help you clarify the diagnosis and management and then risk factor modification plus antianginal anti aquatic medications until we have larger uh clinical trials. So with that, uh I'm going to end here and um I did it with 15 minutes left for, for Q and A. Um these are some of my collaborators, you know, I didn't go into my kind of mental stress, reactivity and inflammation and oxidative stress. And you know, that's a whole other talk in terms of mechanisms. But um of course, I couldn't do all of this work without imaging people, the interventionalist, the basic scientists, uh you know, everybody that kind of works in this area and is thinking about this very complex group of patients to try to really understand what's uh what's happening here. So with that, I'm going to end and I'll put this up again so that you get your C M E credit. Thank you was a fantastic talk. Thank you very much for joining us. Uh You covered a lot of great material and uh you've been doing a lot of great work in this area. So um yeah, I'm gonna turn it over to Harvey for, for some Q and A with you. Thanks, Amir. Thanks. That was a wonderful talk. I, I, unfortunately, you've confused all the way. I used to think about things for the last 30 years. So I have to ask you some questions because now I'm you made it. So, so, so so many things I that I missed that I used to have. So first question for me and please others weigh in with questions. I don't mean to occupy the questions here, but so we always call these false positive stress tests. Yeah. So my question is how many false positive stress tests are there? Really? And how many are there stress tests that we just don't understand? They're really not false positives. Yeah, I know that's a great question. Um You know, I usually will say that um I I think a lot of these patients. So, you know, the prior literature, which was this cardiac syndrome. And we used to say that cardiac syndrome X is benign and a subgroup of those patients. So that was a very heterogeneous condition. And a subgroup of those patients clearly have microvascular problem if you did like M R spectroscopy on them, you'll see that they have microvascular ischemia and, you know, invasive testing. So, and that subgroup, the one that have low coronary flow reserve clearly have, you know, worst outcomes. So I think that when you look at the broad group of everybody that's having chest pain, you know, that's a huge group. Um And, and again, because we don't code for vascular dysfunction, we don't, you know, diagnose microvascular. That's why I think that there's, there are quite a bit of people that were missing. Um You know, in terms of these vascular function abnormalities, what's even more complicated is that why is it that women are having more angina with this? And so, you know, there's, there's debate where people will say, well, is it really microvascular ischemia that's causing the pain or is it just a pain problem that women have more sensitivity to pain? And so they're feeling it more? Um And so that is another very interesting topic. Uh And I'm very interested in sort of the brain, heart connection and you know, the pathways of myocardial signals, the nerve endings and that signal that goes up to the brain. Is there a problem with processing those signals? Um So it's, it's just complex. Well, it's fascinating and you're sorting it, all these answers is, is just wonderful. Just a a again, a simple question for you for though, we don't have, most places don't have the kind of testing that you have available to you. So, the, the typical cardiologist sees a patient, they have chest pain, they do a stress test. It's abnormal. They get a cat and there's no obstructive coronary disease. Yeah. What's your, how do you, you talked about managing with drugs? How do you start, you start with the calcium channel blocker? You start with the beta blocker. How do you decide between the two? When do you start with Nola? And I'm just curious if you're not gonna do testing, how, what would your recommendation to be to those people, seeing these patients and trying to manage them as best they can? Yeah. So, um I do think that um if you're so, uh first of all, if there are EKG changes, so let's say they had a stress test and there were EKG changes and they have symptoms. So you've got a reason to suspect endothelial dysfunction. I go ahead and use. So I listen for the symptoms. So if they say that they are nocturnal symptoms or emotional stress induced symptoms, but if they, you know, they'll tell me that when I go walk my dog, I feel fine. So they're not having exertional symptoms, which makes me think that they don't have a fixed microvascular flow reserve problem because they're able to, you know, hike or go walk their dog and they're feeling fine. But then when they're sitting watching TV, they start having chest tightness. Um or emotional stress or um, nocturnal symptoms. So those patients I reach for calcium channel blockers first because it's, it suggests this abnormal basal reactivity problem. If they have a symptom where, you know, when I walk around in my neighborhood with hills, I feel a little short of breath, but otherwise I'm fine. Or, um, if they're having exertional symptoms, it makes me think more of a fixed microvascular that it's a problem of vasodilation. Uh Then I will reach for beta blockers first. Now, having said that what I found is that there can be, you know, remember that uh with that mica study, even that a quarter of them will have mixed pathways. So they have the vaso spasm and they also have the microvascular. So in that case, I look at the blood pressure and heart rates and then, you know, pick I tend to go for the beta blockers first at low doses to see if they tolerate it and if they're, they're fine with it. And if they notice that, yes, I had improvement in my symptoms, then I will add a calcium channel blocker like amLODIPine um to kind of, you know, use both strategies. I I have to, we have to just tell them that look, you're not gonna be able to be 100% angina free. But the importance here is to improve your quality of life and to reduce your frequency and intensity of symptoms. Because most of the time it's just scary for these patients because they don't have a diagnosis and if you're antianginals in general, you know, the safety profile is pretty good. Right. I mean, you know, just try a little Amlodopine and see if it helps them and, and a lot of times that's all I have to do. I don't have to send them for invasive testing. I don't have to do pets. You know, I just, you've got a little bit of blood pressure room. So let's pick one antianginal and then, and see what happens. That's great. That's a nice, that's very, very helpful for us dealing with these people without the uh advanced testing. My other question is, I don't wanna, again, I just wanna see if somebody's got a question here, but I have more questions I could go on for hours here. But um the question here is uh does monoka fall under a type two M I category? Um No, but one of the differential under manoa is that it could be a type two M I because manoa, you know, when we think of manoa, we're really referring to kind of coronary mechanisms. So we're not talking about sort of that high myocardial demand supply, you know, like uh Sagal disease or I don't know, sepsis or, you know, um a knee, let's say with tachyarrhythmias, you know, those would be kind of your type twos. But when we say manoa, we're really talking about coronary causes type one sort of a CS with plaque rupture, uh you know, coronary mechanisms. Got it. OK. Well, thank you. Um Along those lines, one question I had was if someone has um manoa, they come in with an evidence of what we think is a Q M I and they're no coronary disease. Are you getting MRI S and all those people to exclude myocarditis is that, was that part of the algorithm as I remember it? Yeah. So um you know, manoa, they, they call it sort of don't just stop there because it's really like a working diagnosis that you say, OK, this person had a manoa event. So what could it be? And you know, so you're gonna, you know, do a bubble study to make sure that there wasn't a P F O that maybe was an embolic issue. Uh And, and look for a thromboembolic uh you know, cause look for because it will change your management, you know, make sure you rule out SCAD, make sure you rule out tacos. And so then with myocarditis, what the Europeans have recommended is a two B recommendation that if you, you know, have this patient already there, then go ahead and get a card, MRI to rule out myocarditis. Uh We don't do it systematically like we should. Um But you know, I think that it's perfectly reasonable to kind of look and it will help you because if there's a scar and also what what's um important is the timing of the M R because let's say somebody had a manoa event, you know, last month and then if you wait to get an MRI, you may miss the myocarditis, it, it may show you scar, you know, if there's delayed enhancement and it can help you say. Ok, well, was this an M I in like a typical L ad territory or, you know, like a, a coronary artery territory? Um but the timing becomes important uh that if you do it fairly soon, uh you know, within a few days of their event, probably 40 you know, 24 to 48 to 72 hours, you're really going to pick up the, the myocarditis. So that actually along with the questions just ask um from one of our participants is what is the imaging pattern seen on an MRI in Manoa? So if it's, if a patient has Minoa, because you're trying to rule out myocarditis, you'll see sort of patchy diffuse, uh you know, myocarditis type pattern that the MRI imaging people will tell you that this looks like it's inflammatory pattern. Um And because it doesn't fall in one particular coronary R V territory where, whereas, you know, if it's an M I, you'll see delayed gadolinium enhancement, but you'll see something that's like everything else looks fine and then there's one particular focal area that looks like, maybe there was like an embolic event uh in, in, in this territory. So I think that the other thing is that now we're also learning about these microvascular thrombi and M B I like, for example, with COVID-19 and you know, when you do MRI s, uh the thought was could this be micro emboli and micro thrombi? Um so it's, it's just all very interesting. But I think that what's also interesting is often we miss tacos and occult cardiomyopathies, you know, we, we have a minoa event but then they get an MRI and you find that, oh, it's looking more like Takasu or there's, you know, significant L V H or some other kind of cardiomyopathy. That was interesting. I, I'll make one comment and there's another question here. I think part of our problem is and I don't know if you face this or not but getting MRI on inpatient done quickly is not so easy and we're trying to shorten length of stay. So, but it sounds like an important study. Um, somebody asked the question, interesting question. Have you seen any sex differences in how patients respond to treatment? You know? Um, that's a really good question. I have not. And partly because a lot of these studies, you know, they were done on, um, women because they were having symptoms, you know, a lot more. But, um, so I'm not aware of any specific sex differences related to responses to medications. Um, but I don't know that it would be any different even if you had the C AD related Anna, you know, Anna is still an, I mean, if you're having symptoms, you're still having symptoms. So, I don't know that it matters whether it's a microvascular, uh, angina versus C ad related Angina. Um, question for me. Uh, many years ago, the issue was raised as starting beta blockers potentially worse than corny baso spasm unopposed alpha. Is that just a myth? Yeah, that's a really good question. Um I, you know, I, I've asked many different people um about this issue and partly because all these people who get referred to my clinic, none of them are on beta blockers because people are suspecting that, oh, maybe it's beso spasm. And so I'm like, well, I need to reach for something. So I um I have used low dose of Motorola XL 25 mg without any problems and they almost always because a lot of these people tend to have palpitations and they almost always say that they're much better that it helped. So I have not seen the worsening uh with um the beta blocker. Um but I think it depends on which one is used. So I think that, you know, the long, the higher doses of propranolol or the uh alpha, the ones that, you know, may perhaps I've not tried. It's just because of that reason, worse under spasm. But I think um that's helpful. The other one is uh Carol low doses. I use it a lot, 3.125 mg twice a day. Annoying that it's a, twice a day. Um, you know, it comes once a day but it's really expensive. Yeah, but that 3.1 to 5, twice a day seems to really help and then the other one is a low dose of naval 2.5, you know. Um, and people seem to do. Ok, fascinating. Um, I got a couple more. It's just one last question. Um uh You mentioned that sometimes even with a negative stress test. So I read you correctly. You, you think that this syndrome. So now that gets really complicated, you got no core obstructive disease and a negative stress test. So it's purely a clinical. I'm just curious how you, how often you see that and how you manage it. Yeah. So um you know, part of the problem because I have this microvascular anna clinic. I probably have a bio, you know, because I'm getting people who are having recurrent symptoms. But um as an outpatient, let's say that somebody had some, you know, chest pain, you got a stress test, let's say it was a good, you know, stress test, for example, uh pet, OK. And the flow reserve was fine. You can at least reassure them that prognostically because their flow reserve is good. They're re you know, overall that their prognosis is good. Now, if they're having recurrent symptoms, then you're gonna have to treat empirically for vaso spasm because that's the thing that's not detected by pads. So you use the, you know, amyloid or nitrates and just assess response. Um I don't, I, I would say that um because our stress tests are all designed to detect obstructive c ad when you have recurrent symptoms. And if there's a preference for a definitive diagnosis, you really have to send them for invasive testing to, to clarify the vascular dysfunction. Fantastic. Well, we are at time. I wanna thank you for a wonderful grand rounds and very instructive on an area which I think we all wrestle with and your practical approaches to some of this without needing the advanced testing, I think has certainly opened my eyes and I think everybody on the call. So thank you so much for spending time with us. We greatly appreciate it and you have a wonderful day and everybody thanks for attending and have a great day. Um See you. Bye now. Bye bye bye.
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