welcome cardology I a number of speakers prob add a little soed Dr kology um RI is a local talent she attended un of Washington with the bach science inur science and also sence engineer she then moved to the east where she attended very prestigious PhD program where she T where he studied biology and effects on channels unfortunately um she then came back to the West Coast resen followed by prology fellowship and we were lucky enough that combination of Dr and her parents who her to join the division in 2019 and I'm not known her since because she do plan and and we work together U she um is a great and lucky that bide say it's more usually more but uh she is a great she's also a great educator uh we have Fells on Thursday afternoons for the last two years and I've seen her uh teach with a very busy Clinic um besides being a great and teacher she also is very Advocate she is a board member of the ucation fut uh was a president last year she's an expert in women's health and cardology and we're really delighted to have speak to us today and looking to learn about this topic that very thank you thank you so much fed for that wonderful and very kind introduction um and uh yeah and thanks also to Eugene for getting me here today um so I just want to say that you know all those degrees and prestigious universities don't help us do technical uh management but thank you to Don for helping me set this up so I have no disclosures today um and I just wanted to give a very brief uh abbreviated outline of this very complicated topic or at least I think it's very complicated and Broad um and we're just going to concisely review it today in three components what is Syndrome X understanding its very basic pathophysiology evaluating coronary uh how we evaluate coronary physiology and how we treat this um uh disease process yeah and um so I wanted to start off as usual with a typical patient story um at least it's typical in my clinic where um a 43-year-old woman uh referred to me for chest pain she has family history of hyper familial hyper lipidemia and chronic sinus Tac cardia but really no other prior health issues no hypertension no hyper lipidemia herself no diabetes um and she tells me um in clinic that she's had this sort of longstanding intermittent chest discomfort um tends to happen with exertion or stress but it's really not been so severe or prolonged or bothersome so she tends to just ignore it um just FYI this patient is a physician herself so I feel like that's a little bit unfortunately typical of us that we tend to ignore it uh our own symptoms um but anyway so she came to me uh because last week she was walking speed walking up a hill and noticed this chest tightness that took a while to go away and since last week she's noticed it a little bit more often it's she noticed while playing with her kids while uh walking in the hospital or with any kind of stressful um event and now it's also she's noticing that it's taking a little bit longer to recover from this chest pain um she's a never smoker no um significant alcohol use history and then the other interesting thing that she told me while in clinic is that you know I as I was walking here I was speed walking a little bit and I actually got some chest tightness and I have some chest tightness right now I was like well that's great let's get a EKG so on the top um I show you um her Baseline EKG from like six years ago it's pretty normal there's some waviness in the Baseline but no significant St changes that was suggest es schia but while she's in clinic with me and complaining of chest pain we see some St depressions in her inferior leads and in her uh and her lateral leads we keep talking 15 minutes later her chest pain resolves and we repeat another EKG and those St depressions are are gone we just did a mini stress test in our in our clinic by virtue of having her sit there um and took as she said it took her a long time to recover because the STD depressions aren't completely gone away but 15 minutes later um this is what we have and so I ordered a workup um got an echocardiogram no um no cardiomyopathies no valvular disease EO was very normal and then because she's young relatively healthy otherwise we uh opted to go for a coronary CT angiogram um and here's a representative image of her LED and there was no coronary artery disease um for her so she essentially is a 43y old woman with effort angena um and essentially a positive stress test in clinic with me and normal Echo and no artery disease these are the sort of classic syndromes that that are called Syndrome X um and it was first coined in 1973 um by Dr Harvey K from Colombia when he wrote an editorial about the paper above U myocardial function during atrial pacing in patients with angena and no normal coronary arteriograms um the reason the term came about is because in the study they divided the patients into two groups the ones who had the normally coronary angiograms and the that was group X and then the group that had obstructive coronary disease that was Group C um and from there Dr Dr Kemp sort of broadened it to characterize sort of all these patients who um mostly women who had chest pain and normally normal coronary angiograms and it was really Syndrome X was really characterized by what it was um or sorry what it wasn't it wasn't obstructive CAD which is sort of what all our Focus had been traditionally and and there was even debate about whether This truly constitutes as es schia or not so for for a long time this was actually just considered to be a psychosomatic issue in women until we got more objective evidence like my patient who had ECG changes during her symptoms or there were other biomarkers or poor profusion or Prof Fusion defects themselves on Imaging tests or on echocardiograms so then they said okay fine it's not uh well we'll call it esema um but you know it's not real heart disease uh we'll call it microvascular Ana but it's still pretty benign so not a lot of Investigation was done it was a bit of a mystery um as to what it constituted what it exactly was so they did call it microvascular Ana because it obviously wasn't macrovascular disease um um and then uh the women's eskia syndrome uh evaluation group came along who took a cohort of uh women from the late 1990s from all over the US who basically had typical symptoms of angena um some of them may have had a positive um stress test or some may not um but all of these women were for some reason indicated for a cornery angiogram and so they looked at 936 women and of those 42% had obstructive coronary disease meaning all these women with typical Anga symptoms majority of them almost 60% did not have any coronary disease um 60 uh quite a bit of them like 59% of the remaining 60% had no CAD at all and approximately half 41% of the uh of the remaining group had some non obstruct CAD so that's the group that they really wanted to look at was the ones with the symptomatic women who had normal coronary arteries uh versus the ones who had non-obstructive CAD um and when they compared these two women uh or groups of women they find that um they had um uh differences in um in mace in adverse outcomes over five years um and they also compared um the women who had no coronary disease or normal uh coronary arteries uh but symptoms against women who were asymptomatic of no these asymptomatic women did not have any angos but still assuming that you know no symptoms versus symptoms and normal coronaries um there was still um this is what the P value is for there was still some adverse outcomes there so the wise study was the first time that we showed this is not entirely a benign disease process there are poor outcomes that happen most of these poor outcomes were related to uh hospitalization for a heart failure or stroke um and then they went took a slightly deeper dive into let's risk ratify these all these women based on their risk factors how many risk factors do they have if they have zero risk factors versus more than four versus two to three in between and the lightest gray bar here is are the women who were asymptomatic the slightly uh darker gray are the women who who had normal coronaries and then the black bars are the ones who had non-obstructive disease so obviously there is a difference um in uh uh cardiovascular event rates that happen um the the more risk factors you have um and then they also looked at them based on age um and this is actually what I thought was one of the most interesting points the patient that I presented um earlier she would fall into this category of age under 40 which is the the typical group that's dismissed like they're there you don't have any problems this is just all sort of in your head but maybe not but it's still benign and here we see that between um asymptomatic and symptomatic women without with completely normal coronaries there's a significant difference in in outcomes over five years this is not a benign disease okay so what is it what is the Syndrome X um so to kind of go into into it I'm going to take a take us back to our sort of basic physiology and pathophysiology days um here's a map of a coronary circulation traditionally we've looked at just the epicardial arteries that's what we look at when we do our coronary angos um or coronary CT angos um and the main function of the epicardial arteries here is is transportation um they have the um both the epicardial and sort of the arterial arterials here have the um have that classic threee vessel wall the intima that's endothelial cells the media which is the vascular smooth muscle cells and the adventia which is sort of the fibroblast and connective tissue part um and and all those are implicated in how the coronary blood flow adapts to changes in physiology but most of the adaptation and regulation really occurs in this pre arterials and arterials um portion of the coronary and tree um and this is what constituted as a microcirculation and um and particularly this sub 100 Micron group of arteries these intramural arterials are the ones that are responsible for oxygen matching and responsive to metabolites uh changes and metabolites and and really mostly responsible for regulation of coronary blood flow to assess we don't have a good way of looking directly at these arterials unless you think about things like slow flow phenomenon on coronary ngos but we then need to uh find a way of looking at um coronary blood flow in those areas um and assessing changes in that and how that regulation is maybe altered in these uh patients with syndrome ax um but I'll I'll get to kind of the assessment portion in a little bit but going back to what is microvascular uh microcirculation function versus dysfunction at any given time our microvascular is a balance between Vaso dilation vas of constriction and that's really dependent on our endothelial Pathways and endothelial independent Pathways which are more poorly characterized the endothelial dependent pathways are a little bit more um uh investigated and better understood um and and so in micro microvascular dysfunction what ends up happening is that a either we have an increased in Vaso constricted Pro properties of our coronary system or there is a failure of vasod dilation in response to appropriate responses either way um the end result of this kind of Bal uh change in balance is ischemia um the some of the the major uh molecules that are implicated for vasod dilation nitric oxide and endocan one in vasil constriction um there is very good evidence that it's disre regulation of these two molecules and sort of the downstream Pathways and Upstream Pathways related to these that are that are implicated in microvascular disease um this was a paper from our very own Dr bakas and Dr Kim who do a very nice review of what constitutes endothelial dysfunction um on the left here we have uh a healthy endothelium that's releasing um nitric oxide from this Enos which is a endothelial nitric oxide uh synthes um uh enzyme and the enzyme responds to laminer flow it responds to acetycholine to insulin to really release nitric oxide which in turn um leads to vasod dilation anti-inflammatory and anti-thrombotic properties uh when there is dysfunctional endothelium um the Enos gets uncoupled so we have now a decrease in nitric oxide production uh we have an increase in production of reactive oxygen species the um uh the um the permeability of the endothelial layer is increased so we have now influx of macrofagos um into the tissue um and overall it's just a a state of increased inflammation and what can lead to it a whole host of things the typical risk factors that we think about for coronary artery disease also impact endothelial function smoking hypertension viral infection diabetes obesity and LDL there's additional Pathways that I'm not really going to discuss but this is usually the Centerstone of what we consider to be dysfunction and microvascular disease and what is um investigated when we do our coronary physiology assessment so how do we do this M the most comprehensive way is still doing an invasive Corine angiogram um and usually we have to before we can assess the microvascular um or coronary blood flow in the microvascular we have to first rule out epicardial disease we do a part of that rule out process when we say these patients don't have any obstructive disease but if we give them acetyl choline and they have um endothelial dysfunction they can also get vasospasm epicardial vasospasm like you see here um where there's nice normal flow here and then that uh lad artery almost disappears um once we've assessed that and we reverse it with nitrates um in coronary nitroglycerin usually we can move on to assessing the endothelial independent Pathways where we usually give some kind of a um a vasodilator like adenosine or another um another Raz of dilator that causes hyperemia and while we're doing that we measure coronary flow uh coronary velocity in the distal uh segment of the artery sometimes just the lad is sufficient but there's some studies that look at RCA versus lad versus circumflex because it's not homogeneous um and so once we measure coronary flow you can either do that with directly with a Doppler or you can do thermod ution in the LED um you can calculate coronary um blood flow at you measure coronary blood flow at Baseline hyperemia you can calculate coronary flow Reserve at Baseline versus hyperemia and then you also determine uh index of microvascular resistance and abnormalities with those constitute um abnormalities in microvascular flow um the other aspect that's being investigated more and more is um microvascular spasm so we evaluate for macrovascular spasm by this visual assessment of of coronary cross-sectional area after acetal choline but there's also the possibility that these patients might be having spasms in that microvascular bed and which we can't visually see um and one way to do that is okay first you rule out the epicardial spasm and then if they still have the typical ECG changes and angen symptoms with the acetylcholine you diagnose them with microvascular spasm or you can some very infrequently in the studies out there but some places you can do direct measurements of coronary blood flow with a Doppler as you're giving acetyl choline and then um but what's the is this does this actually have any uh long-term implications uh how does this correlate with outcomes and that's where we go back to the wise group and they did a study where they looked at um uh cardiovascular events with adenosine um and you see that for women um who had poor uh coronary flow Reserve that's lesson 2.32 they had um more events cardiovascular events over a span of 10 years than women who did who had normal coronary flow Reserve that's the endothelial independent Pathways they also um looked at women who had coronary blood flow changes in response to acetycholine so again not the macrovascular spasm but we're talking about the microvascular spasm and we also see a difference in outcomes but not um not as significant as the one with the dine there was another group um that wanted to um International cohort that wanted to look at not just women but men and women um most most of the patients that are enrolled in this are from Japan but also Australia and a few other places um and they had very strict definitions of who was enrolled they defined microvascular angena symptoms no obstructive CED and they defined how they Define no obstructive Cad and impaired microvascular function how they Define microvascular dysfunction they had again very strict criteria either decreased coronary flow Reserve in response to um adenosine increase in microvascular resistance microvascular spasm or slow flow phenomenon on Corner Ang geography and again they also show that these patients have increas in incidence of major adverse cardiovascular events over time um but most of these uh events are driven by unstable angena and you can see maybe a little bit of a trend with cardiovascular death but mostly by there are additional components of uh coronary physiology that we can assess with um invasive angiograms though those are not part of any of the standard definitions either with the wise group or the katus group um and that's uh for example just measuring ffr over the entire um uh coronary artery and even though there is not a single obstructive lesion if the ffr is less than 08 then that then it means that there's diffused epicardial um disease uh that could be a component of what we traditionally cons microvascular enome and then the one that we don't talk about too often uh another one of those there're there you have it it's not a problem go away is myocardial Bridge um and that's best sort of for I mean you can visually assess it on coronary angio but that's really more formally assessed by doing a intravascular ultrasound um and looking for um this sort of Half Moon Sign um where uh during both syy and diast where you see external compression uh from this myocardial bridge and um the group in Stanford by Dr treml um did this sort of a little bit comp more comprehensive coronary evaluation in 2015 um again these are 139 patients with angna no obstructive CAD they may or may not have had abnormal stress test so none of that objective evidence always for esia that we're looking for um and they Define uh micraster disease uh dysfunction as as resistance greater IMR greater than 25 and what they find is that you know you take these all cers of again classic Syndrome X and of all of those cers maybe 20ish perc of them have no abnormality majority of them have some form of dysfunction on their coronary physiology assess assessment uh majority of them are myocardial bridge but then there's some with endothelial dysfunction um meaning that a response to acetal choline microvascular dysfunction is a disuss in response to adenosine low ffr meaning uh sort of just diffuse uh epicardial disease and the bridging as I mentioned not everybody has the resources to do that kind of coronary physiology assessment in their cathlab so we want to also look at what are some non-invasive ways of of looking at microvascular physiology or coronary physiology in general and one of the um uh more common ones is cardiac pet or maybe not common but certainly one of the best validated um where the the be the beauty thing beautiful thing about uh cardiac pet is that in addition to just looking at perfusion defects you can actually also look directly at myocardial blood flow so on the top there they have a um the the first patient here is somebody who has normal uh these are stress images no profusion defects their myop parial profusion um Reserve is pretty normal um normal is greater than usually two or 2.5 um here's a patient again classic Syndrome X patient who had symptoms their myocardial um uh Flo Reserve um by by cardiac pet is reduced 1.15 but again no profusion defects that you see on the on the images themselves and then um another person who had those classic syndromes and their uh profusion Reserve is normal and no defects here so they compared um uh and here's the myocardial blood flow and what they find is that normal subjects respond appropriately to a vasodilator um and same with patients who had at at the onset a um normal NPR um and then low myocardial Reserve you can see this where they give them um a vasod dilator and there's not much change in their myocardial uh blood flow when we look at the profusion Reserve uh normal versus allc comers it's it's slightly decreased but then we want to look specifically at the Syndrome X patients here and what we see is that the biggest difference is really um between the normal patients and the ones um here between uh with with the um with the decrease in uh perfusion reserve the point that I wanted to make here is that you can have abnormal myocardial um blood flow and perfusion Reserve in the absence of perfusion defects so you don't always have to have a abnormal stress test to see a dysfunction in mic vascular space and Syndrome X is very heterogeneous it includes patients who have this uh decrease in blood flow versus not um by cardiac pet they also showed that these individuals who had poor um coronary uh coronary flow Reserve um had worse outcomes regardless of gender so this is not just a women's disease not every place has the resources for cardiac pet um and certainly cardiac pet has CT radiation with it um some places can do cardiac MRI and um look at stress profusion and myio semi-quantitative assessment of myocardial blood flow here um and so here's a here's a normal patient who has uh you can see their subendocardial to all the way to epicardial wall is lighting up very nicely during stress images somebody who has uh multivessel coronary disease you don't see that myocardial wall lighting up and then somebody who has micraster dysfunction defined by uh abnormal index of uh of resistance um you see that there is patchy lighting up and most of the um decrease in brightness is in the sub endocardium um and um and again this correlates with symptoms and uh and abnormal coronary physiology this is a little bit more challenging so if you don't have a cardiac pet machine you don't have a cardiac MRI which is really a lot of times at uh sort of academic institutions with that kind of assessment most places do have a echocardiogram and you can assess uh coronary blood flow by Doppler if you can find that lad artery in the distal lad artery in particular and you can measure do Flor flow um at velocity or the vti there um during diast and compare it at RAS versus um hyperemia and um can diagnose somebody with um microvascular dysfunction there um they in this particular study in uh just recently they did a cut off of uh abnormal flow velocity of less than two is uh flow Reserve is abnormal and they Tred to correlate it with abnormal flow Reserve in cardiac Pat the correlation is pretty darn crummy so um and this is also very technically challenging uh being able to find that tiny little artery making sure that you measure the Doppler precisely and in that exact same spot um between rest and hyperemia so technically challenging not the greatest um correlation with what's considered to be the gold standard for non-invasive testing and then then the last thing I wanted to talk about is kind of where we started which is stress testing um and this was again a just pretty recent study where they looked wanted to see whether stress test uh Echo with treadmill or with dobutamine and stress ECG whether they're predictive of microvascular dysfunction or just coronary flow dysfunction and they looked at 155 patients who had angena who underwent the stress test and coronary angio again no constuctive Cad and the sort of outcome is that generally stress tests are poorly predictive of who's going to have microvascular disease or coronary flow uh abnormalities if you look most of these um odds ratio confidence intervals cross one um the only things of note are the stress ECG our most basic stress test does tend to correlate with endothelial dysfunction and if you start including more factors like uh the total number of Mets achieved or their heart rate achieved or blood pressure response Etc if you kind of do a more comprehensive evaluation of that stress test and maybe tends to be a little bit more predictive but stress tests abnormal stress tests are not always predictive of microvascular dysfunctioning so going back to the original point that I made is that you know do we have we have angena we have no obstructive CAD do we really need that abnormal stress test to say this is not in your head no the chest pain guidelines uh that we that Dr gady um has sort of been on the championing uh women's heart health issues um and was a was an author on the chest pain guidelines in um uh just a few couple years ago they do look into this they finally do take into account and acknowledge all these patients who have stable chest pain and no obstructive CAD based on on um either invasive or CT ping NGS and they do recommend them doing further testing it's not class one indication class two but you can do invasive assessment if you have that capability at your institution it's a class 2A or you can do stress Imaging um based on the data that I just showed you stress pet um tends to be or CMR tends to be preferred over Echo um but when you're doing invasive coronary testing they um recommend of course doing acetylcholine again to look at endothelial dependent Pathways and some other kind of vasodilator to look at hyperia to look at endothelia independent Pathways and they say okay if your coronary flow Reserve is normal and you don't have increased resistance with hyperemia basically you have a negative Pro provocation to acetycholine no spasm then this is a non-cardiac chest pain but if you have spasm um Andor that reproducible chest pain or ECG changes with aetel choline then you have vasospasm um if you have if you don't have that spasm but you have the abnormal uh uh myocardial resistance increase in resistance with hyperemia or a decrease in coronary Flo Reserve with hyperemia um then you have then you carry a formal diagnosis of coronary microvascular disease we can't do this level of comprehensive testing with cardiac pet um or cardiac MRI because we can't do that Prov provocative testing with acetylcholine so we can't rule that out but if you see somebody who has reduced myocardial blood flow Reserve um then uh they uh carry the the diagnosis of coronary M microvascular disease all of these diagnoses are great but what do you do what do you do with these patients and that's somewhat been a Holy Grail in this field and um for the longest time of course you know it's hopefully I've convinced you at this point that it is a heterogenous entities and not one therapy is going to work uniformally um so for example here was a study in 1999 who looked at 10 patients uh with angena positive ECG stress test and no Cad and they did this amazing test of let's look at our standard anti- engine of her um let's look at emodine atenolol and isosorbide mononitrate they randomize the order they gave these patients these drugs for four weeks at a time and saw that really of um of all these allc comers of syndrome F no coronary physiology testing here um a tenolol seem to improve the symptoms the best there was another one in 1989 um that looked at 16 patients Pati with Ana SD depressions um and no Cad and here they decided to assess daily esic episodes by halter and evaluating whether they had St depressions or not um interestingly not every patient had chest pain that correlated with SD depressions but also not every SD depression correlated with anenome that said they decided to look at SD depressions and for panel reduce the um number of times they had s depressions and the magnitude or of duration of SD depressions in these patients delm so let's we've you know not shown anything with emodine we haven't shown really anything with Rapa let's go for DM and here they did look at coronary blood flow and coronary uh flow Reserve um and they gave them a Denine or not a Denine but another um uh vasod dilator 6 patients who were undergoing coronary angio anyway and um what they find is that okay so normal coronary flow Reserve not that microvascular dysfunction delm does nothing for them um but also delm nothing for them if their CFR is low also so for endothelial dependent uh independent Pathways there doesn't seem to be any benefit to giving them calcium channel blockers um they wanted to there was another group um pretty recently in 20122 that wanted to look at Del thaism again and do a sort of more comprehensive assessment of looking at acetal choline versus adenosine um IND endothelial versus endothelial independent Pathways and what they show is that there is no um Improvement in cornery function test results um with DM whether it's um just looking at spasm or microvascular dysfunction they saw no improvement in Ana symptoms um or quality of life with delm and they um counted a treatment success if there was normalization of some any aspect of coronary function testing and deltm didn't really help there either but one thing they did find is that if at the beginning of the study at the beginning of the AAL col Coline provocation um their patients who had epicardial spasm if they give Placebo their repeat acetal Coline acetal Coline provocation made no real difference um but for the patients who were on DM more of them uh changed from epicardial to microvascular spasm or no spasm but mostly change from epicardial to micro vascular disease so delm maybe helps with epicardial disease going beyond the traditional U medications that we use they also looked at metformin but this was a odd study because they looked at not at coronary microcirculation but they looked at subcutaneous microcirculation with hyperemia um and Metformin um seems to improve some microvascular um uh um microvascular profusion here um but it also tends to improve more clinically important um St depressions during exercise tests and tends to improve angen symptoms we look at ACE inhibitors um and ACE inhibitors also um seem to improve coronary coronary microvascular resistance and flow Reserve um particularly though with acet F choline assessed um flow reserves and resistance um more so than Placebo um but in alil also clinically important noted to reduce aninal attacks and these patients were able to exercise a little bit longer during stress tests um they there was a different group that went and looked at coronary flow Reserve um and same thing they improved coronary flow Reserve here 2 2.6 to 2.7 um and uh and the change was significantly different there's a future trial that's do doing going to look a little bit more comprehensively at this this is um uh looking at um clinically stable women with no CAD um and uh either doing intensive medical therapy with statins or pcsk9 Inhibitors plus a for ARB um and versus usual care um and they're going to look at outcomes with this treatment ranolazine um it tends to improve um certainly angen um uh and quality of life symptoms and when they looked at um uh using cardiac pet myocardial profusion Reserve um uh resistance index it tends to improve um improve that roline more than of abdine improves Anga and eskee um but not necessarily coronary uh blood flow here and then um when they did ETS on these patients they find that I mean evadine did improve um their time before they got SD depressions um but uh roline had a had more profound effect and but then there was a third study that's like roline what do we do with it okay there was no difference in angena symptoms when they looked at again 22 patients um this is after treatment for 12 weeks and um and they looked at coronary flow reserve and there really wasn't any difference there but then if they looked at subgroup between okay let's look at people who actually had poor corn really poor coronary flow Reserve less than two versus greater than two then start seeing some some effects here um and Improvement in symptoms also the idea again there being that maybe we need to do a better job of doing that coronary functional assessment and really selecting for the patients who have abnormal really abnormal microvascular um dysfunction sanhil improves uh coronary flow Reserve um uh based on uh but the effect is more profound in people who have CF our lesson 2.5 at Baseline and dag glyphosine so now we're getting into sort of more of our um current dat Therapies in heart disease and heart failure and um and so here uh these are the stress images of my cardial blood flow cardiac pet these are the rest images and this is a flow Reserve calculation which is a ratio of these two so um initially the flow Reserve was 1.82 abnormal Placebo didn't significantly change um this group for some reason this particular patient example that they used had a flow reserve of 2.4 prior to dppa uh dapa glyphosine but then after they did four weeks of that therapy um they they had significant Improvement in in flow Reserve um and we see that here there's some novel therapies that are being developed um as I said there were some other sort of vascular dysfunction path uh path Pathways that we didn't really discuss Beyond nitric oxide um R kyes Pathways involved and there was um there's a drug fudal that's an inhibitor prevents microvas spasm uh endothelin a receptor antagonist also improves coronary blood flow um and then there's a very nice review article a couple of years ago that goes through sort of all the other trials um uh studies that are that are maybe supportive of um certainly pcsk9 Inhibitors um and um endothelin receptor antagonist and a few others but the question that we always come back to in cardiology do these therapies actually help with outcomes in the end everything that I've shown you so far is really about symptoms or estd depressions or coronary FL reserves what about out comes this is the only trial that we have to date um the corica trial 151 patients um who had angena and were undergoing routine angos um and didn't have any coronary disease and at that very moment in the calf lab they randomized them and um they all underwent coronary flow assessment with atil choline ad adenosine um but then they put um like a cover over the screen so that the doctor who referred them couldn't see the results um and based on um on the investigation group was really the results of the coronary physiology testing was revealed to the patients and to the doctors and then there were treatment recommendations that were made versus a control group that still underwent that physiological assessment that data that information was not released to the patients or to the to the treating providers um and so so and the treatment plan that they recommended so first is no obstructive disease that was obstructive disease was exclusion criteria and if you first do uh physiology assessment with the adenosine and you see okay they have um uh um uh their physiology assessment by adenosine is normal so CFR greater than two um and IMR the resistance is less than 25 normal uh microvascular function but then they gave acetal choline and you see basos spasm um so vasospastic angena um they really primarily recommended calcium channel blockers nitrates or Lifestyle Changes which really we should be doing for everybody and smoking sensation again should be doing for everybody um then there was a group that had coronary microvascular dysfunction their coronary flow Reserve was less than two their resistance was greater than 25 in response to hyperemia um and they did not have any endothelial dysfunction um uh in response to acet pooline for these patients they recommended beta blockers um there's some evidence that the third generation beta blockers which is nebivolol and carvol they tend to work a little bit better nabol tends to release nitric oxide um and as you know carvol Alpha blocker there's some vas of dilation with that so those U beta blockers tend to be better but any beta blocker Plus lifestyle changes and consideration of Ace and Statin and then the third group was where there was normal invasive physiology and no basa reactivity testing they said stop all anti-al uh disease or therapies discharge from Cardiology um and consider non-cardiac causes of chest pain so for them um this is uh most of the again very similar to what I've shown before about 148% 8 to 14% of patients had normal physiology but all the others had some kind of abnormal coronary physiology um and they found that patients where the information was released to the treating provider and to the patient um they tended to have better angena symptoms um and then they also this was I thought very interesting was um uh they also uh interrogated or questioned the treating cardiologists who had referred these patients for cornering angos um and uh pre- randomization um they really didn't feel very confident of their diagnosis and maybe thought that it was related to coronary disease but after randomization certainly the the Physicians who were given the information from the physiology testing um said yes my patient has coronary dysfunction there were more certain of that and they're more certain of the patients who didn't have coronary disease um it really changed the attitude of the treating physician knowing that data and knowing certainly what the treatment recommendations were um we don't have information on um on long-term outcomes from that even though that's kind of how I set it up as um ultimately coronary micraster disease is just one component of Syndrome X um there are structural issues um like in epicardial disease uh we talk about structural mechanisms like the myocardial Bridge or the traditional plaque model that we talk about uh functional uh disease of the epicardium uh including spasms um that's not often talked about but the only way to really assess that is with provocative testing um and then when we get into microvascular mechanisms of hemia we again didn't really talk today about structural mechanisms um which can be related to hypertrophy amalo doses capillary rare faction obstruction um or Remodeling and then functional mechanisms is really what most of the focus has been to date on um either impaired dilation or enhanced phas of constriction uh whether it's related to endothelial dysfunction versus um non-endothelial smooth muscle cells hyperreactivity and so this is kind of what I want you to take away with is that Syndrome X is very heterogenous there's epicardial disease um there's microvascular disease um we have a little bit of information about how to Target to these specific disease processes um but certainly more data is needed and and these can be also implicated in um uh or other pathologic components that can be implicated in Syndrome X are myocardial Bridge uh hypercoagulability infiltrative diseases vasculitis pain inappropriate pain perception which is what the sort of in your head component was in the past so in conclusion patients with Syndrome X or angena esea enoa enoa um really constitute a heterogenous group of individuals their coronary dysfunction um you have to rule out obstructive CAD first so you can assess coronary dysfunction um but can be differentiated uh based on endothelial reactivity versus um endothelial independent and epicardial versus microvasc microvascular it is not benign and is associated with adverse outcomes management options is is complicated evaluating that because most of these Studies have patients that are like 10 15 patients have different techniques in assessing coronary physiology and have variable definitions of what constitutes microvascular disease and um corica study is sort of the the one study that we had that demonstrated benefit of subtyping and um doing a targeted treatment plan um hopefully with improved outcomes in the long term but certainly Improvement in symptoms ultimately we don't quite know where to go at this time and moment but more data is forthcoming um but in the same paper where Dr Harvey Camp coined the term Syndrome X he did say that you know these heterogenous patients where we sort of know where we don't know what's going on these observations are like the clues in the first half of Agatha kiry novel big fan of mystery novels they may not be readily understandable but we can certainly be sure that they are important in determining the long-term sort of plan for for these patients and I mainly wanted to give a huge thank you to Dr Kathleen Kierney she's our Interventional cardiologist um here at University of Washington who does all of our uh invasive coronary physiology assessment she does a provocative testing um and hyperemia responses and is always a great person to reach out for to discuss hey I have a patient I don't quite know what's going on they have some abnormal test results some don't And discussing the next best step and and interpreting those results so huge shout out to Dr Kieran thank you com I'll start the questioning um so you presented data that patients have first I guess what is the pathopysiology of what are they what do we know that because most of the studies are focused on on symptoms but can you comment on that soone treatments symptoms yeah so the um one of the uh I'm not going to scroll but one of the outcome study looked at um sort of the subgroup analysis found that most of the Improvement or adverse outcomes was really related to unstable angena and then one of the other um I can't remember I think it was the wise group one that showed that it was related to stroke and heart failure and I thought that was actually pretty interesting because um what I don't go into in my talk is that we believe there is a strong component of microvascular dysfunction in patients with stress cardiomyopathies and I have a patient in clinic um I didn't include her images but she had a stress cardiopathy event uh when she was giving a eulogy they did a coronary angiogram no obstructive disease and on the coronary angio they did a LV gram and they found the the takubo um a few months later her Echo had completely normalized but she was still having symptoms she did a stress test there was appropriate augmentation of her LV function but she was still having symptoms so she came to me for a second opinion we did a cardiac pet on her and her myocardial blood flow Reserve was abnormal um typic uh particularly at the Apex in the area where she previously had that so I think I do wonder if some of the outcomes that we're talking about is is related to maybe stress cardiomyopathy and um and vasospastic angena um things like that but but we don't have great data I mean that's kind of the best that we have I had one it's um we use and it's you know it's funny because nitrates are not all patients respond to nitrate and they don't respond all the time to nitrates um and you're right I didn't really talk about it because there it is that um where let's see if I can find the it was a very first [Laughter] one this is it this is the data that we have 10 patients yeah 10 patients made no difference in symptoms um but I think you know um in sort of my I kind of blew past the slide but it does come into play when we talk about epicardial endothelial independent Pathways and whether we how much of a Improvement in cross-sectional area of the epicardial artery we get uh with nitroglycerin intor nitroglycerin so it is a component of assessment that we can do um but there is not great data that it's um of how much of this is related to um syndrome a thank [Music] you oh my gosh that's that's like the big elephant in the room and I don't have a good answer for you I think um some if I can get by on an answer with non-invasive testing than than I do um what I'm finding you know for the example for that patient with the stress cardiomyopathy um patient she just found it I just saw her last Friday she just found it so reassuring to know that it wasn't just in her head and we're trying imor and we're trying um uh emap Pine and actually I'm probably going to switch her to nebivolol um it's my go-to beta blocker now for these patients and and hopefully her symptoms will improve but she at least I think the most that I'm getting from this kind of physi physiological testing whether invasive or non-invasive is reassurance of the patients um and who knows maybe that's just enough to improve their symptoms in the end but I think there are some patients out there who I try empiric therapy I try the non-invasive testing to see if there is any Improvement in symptoms not necessarily testing because as we saw you don't have to have an abnormal ET or stress test to have microvascular dysfunction so I really just go by symptoms and if empiric treatment doesn't work or I'm getting very confusing results as some people respond to am loine for a little bit but then they don't and then they do okay with the Bol or don't I don't quite know which bucket of of um of Syndrome X they fall into then I will refer them to to k k for further testing um but usually I find that it takes a little bit longer with trial and error I have another patient who had um normal coronaries and has had angena symptoms for the past year um and I've been working with him since Springtime on first we tried M door that didn't work we tried mapine he said that didn't work and stopped it for a while we got went up on the dose work didn't work don't know I just started him on n bivol and he's doing much better but I think if I had on the onset just sent him straight to keep for testing I suspect we would have found that he had um probably an increased IMR or decrease in CFR and then I could have done targeted therapy a little bit sooner so the short answer is I mean I don't send every patient for invasive testing um but where I'm running into a little bit of a roadblock and figuring out what's going on whe their treatment is maybe they don't have coronary um abnormal coronary physiology those are the people that that I send to her L asked thomon is asking is forarm vascular resistance still being done so it's um it's a little bit of kind of what I um I I again didn't include that it's not being done now it used to be a marker of um or except it's maybe it's done in like research studies um but it's a marker of hyperemia you um you inflate and then you kind of look at how quickly blood flow returns and um I think if possible cardiac pet um is a little bit better and and more indicative of coronary physiology rather than um than peripheral microvascular disease great just want to take this opportunity and a in person thank you very much thank you