Emily: I'm Emily Kumler and this is Empowered Health. This week on Empowered Health, we're going to look at the leading cause of death in women, which is heart disease1. It turns out that heart disease is really sort of a multifaceted problem under that umbrella of a number of different kinds of conditions, some of which affect women much more than men. This week we're going to be talking specifically about blockages in the small vessels of the heart, which disproportionately affect women2. Men are more likely to have blockages in the big parts of their heart3, which means the testing that most people get in an emergency room are looking at what the men get, not what the women get. So this is definitely one of those episodes that we hope is gonna charge you up to be your own advocate. We're gonna kick it off by going to California.

Janet Wei: My name is Janet Wei4. I'm a cardiologist and I'm the Assistant Director of ourwomen's heart center, the Barbara Streisand Women's Heart Center at theCedars-Sinai Smidt Heart Institute5. I'm also the Assistant Medical Director of theCedars-Sinai Biomedical Imaging Resource Institute6 and have interest in the sexdifferences of cardiovascular disease, specifically looking at pregnancy relatedheart issues in women as well as a woman with chest pain.

Emily: I feel like, let's just start with some basics. Can you explain to us what thedifferences are? I mean, I feel like people think of like coronary heart disease,congestive heart failure or heart attacks, ischemia7 all of these different things.Can you sort of break down what, specifically for women, are the sort ofdifferences or it seems like there's some catch alls.

Janet Wei: Yes. Yes. Thank you. That's an excellent question. When we refer to heartdisease or cardiovascular disease, that is our catchall term for heart attacks, forheart failure, for hypertension, also known as high blood pressure, stroke aswell as arrhythmias. So having abnormal electrical issues in the heart, and thereare certain, differences in women in which various components of thesecardiovascular diseases as well as risk factors for cardiovascular diseasemanifest themselves. We know that for both men and women, heart disease,cardiovascular disease is the leading cause of death. Over the past 20 years, dueto improvements in our ways of treating men and women in treating acute

1 https://www.cdc.gov/women/lcod/2015/index.htm2 https://www.heart.org/en/health-topics/heart-attack/angina-chest-pain/coronary-microvascular-disease-mvd3 https://www.mayoclinic.org/diseases-conditions/angina/symptoms-causes/syc-203693734 https://www.ncbi.nlm.nih.gov/pubmed/164581705 https://www.ted.com/talks/noel_bairey_merz_the_single_biggest_health_threat_women_face/transcript?language=en#t-2399256 https://www.britannica.com/science/arterial-tree7 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.117.027666

heart attacks, death rates have actually been declining8, fortunately. However,the death rates for young women with acute heart attacks.

Emily: So what is young?

Janet Wei: Yes, less than 60 years old.

Emily: Okay. I love that definition of young.

Janet Wei: Yeah. Yes. There's been an increase in death rates for young women, related toacute heart attacks9 and we need to really understand why that is. Because thediscrepancies of the mortality in the past for men versus women used to befocused on discrepancies in what physicians are doing. For example, in the past,women were less likely, if they had an acute heart attack, to be treated10. Theywould be less likely to be taken to a cath lab to have their blockages opened upif they were having an acute heart attack due to a blockage in their arteries. Itwas taking longer for them to taken to the cath lab and there were fewerwomen after they had a heart attack who are getting appropriate guideline based medical therapy compared to men.11

Emily: And you guys call that the Yentl Syndrome12, is that right?

Janet Wei: Yeah. So the Yentl Syndrome is related to that. Exactly. So the idea is thatwomen sometimes had symptoms that were due to a heart attack that weredifferent from men. Chest pain is still the number one symptom that both men and women experience when they have an attack. But women are more likelythan men to have more atypical presentations of that chest pain13. They mightexperience it more as a chest pressure or a chest burning. And it's not alwaysthat classic Hollywood heart attack where typically a man is kind of clutching thecenter of their chest and complaining of an elephant, you know, sitting on theirchest. Women may feel like, oh this feels like heartburn or actually my jaw ishurting or I might be more short of breath rather than having chest pain. I mighteven be having nausea. So some of these atypical symptoms were whatcontributed to lower diagnosis rate of heart attacks in women and men. So ifwomen's symptoms weren't being recognized as a heart attack because theywere not similar to men than they were getting misdiagnosed and then

8 https://academic.oup.com/eurheartj/article/33/22/2771/5311919 https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/syc-2035056910 https://www.goredforwomen.org/11 https://www.nhlbi.nih.gov/health-topics/education-and-awareness/heart-truth/about12 https://womenlivingbetter.org/symptoms/13 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675220/

therefore not getting the appropriate treatment.

Emily: So the symptoms that women present seem less acute, right? Like nauseaversus like stabbing pain in your chest and so I, you know, I feel like the naturalquestion then is are the heart attacks that women suffer from also less acute,right? Cause there's a range of kind of heart attacks. Is that right?

Janet Wei: Heart attacks are all acute. They all happen acutely. However, I think what youhave put a good point on is that there is often symptoms that lead up to a heartattack. So we use the term is angina14. Usually what we refer to as chestdiscomfort due to the arteries in the heart, not getting enough blood flow. Andso women and men's angina symptoms or angina symptoms are similarlydifferent. Just as the acute heart attack symptoms may be different theseangina, more chronic angina symptoms, may be different. And what we'velearned through the National Institute of Health sponsored Women's IschemiaSyndrome Evaluation15, that was led by Dr. Noel Bairey Merz16 here at Cedars-Sinai.She's the director of our women's heart center is that about half of women whohave angina and who go to have their arteries evaluated in the cath lab actuallydon't have obstructive coronary artery disease17, meaning that they don't hbig arteries, that these are the vessels that are not working well. They are notable to increase blood flow to the heart muscle in response to either exercise oreven emotional stress or they may actually constrict.

Emily: So it's not a blockage in the smaller vessels, it's some other problem with them.

Janet Wei: Yes. It's more of a, it's more of a dysfunction. They're not able to dilate or relaxas well.

Emily: So we're going to head to the east coast and get a better understanding of the sort of anatomy of the heart and where the blockages actually occur in women.

Giulia Sheftel: My name is Dr. Giulia Sheftel18 and I'm a clinical noninvasive cardiologist atNewton-Wellesley Hospital and basically I see patients all day. I also spend a fairamount of my time as Medical Director of the Cardiac Ultrasound Lab atNewton-Wellesley Hospital where I'm very interested in imaging and cardiacultrasound, echocardiograms. The heart is a muscle and it needs a blood supplylike any organ in the body. And so I want you to think of the blood supply to theheart as an upside down tree. We're going to start at the top. It's the trunk and

14 https://www.whi.org/SitePages/WHI%20Hormone%20Trial%20Findings%20Questions%20and%20Answers.aspx15 https://www.mayoclinic.org/diseases-conditions/raynauds-disease/symptoms-causes/syc-2036357116 https://grants.nih.gov/policy/inclusion/women-and-minorities.htm17 https://www.fda.gov/science-research/womens-health-research/fda-research-policy-and-workshops-women-clinical-trials18 https://orwh.od.nih.gov/sex-gender/nih-policy-sex-biological-variable

then there might be three or four large branches that take off from the trunk.And these branches they subdivide into smaller and smaller branches. In effect,they arborize, right. To extend the analogy of the tree, arborize. They getsmaller and smaller and smaller until they vary into the heart muscle itself. Sothat is what we call the coronary anatomy. Coronary comes from the Latincoronarius, meaning crown.19 Some very inventive person thought that thearteries looked like you know, a crown. So that's where the term coronaryarteries sort of comes from. So that is the basic anatomy of the arterial tree.And what we're going to talk about today is the differences between men andwomen. In terms of the anatomy of the arterial tree20, both in terms of the bigtrunks and the little tiny vessels, or what I call the twigs. So one of the thingsthat is very interesting as we think about the differences between men andwomen. Let's talk for a minute about the big branches. The top part of the tree,remember I said, you know, you've sort of got what we call a main trunk incardiology. We call it the left main. And that trunk branches into about oh threeor four main branches, let's say. And so there are relatively big arteries. And soone of the things that research has uncovered is that men and women have avery different way of laying down what we call plaque.21 Plaque is a buildup ofcholesterol in the pipes. And plaque is made up of fat and cholesterol and littlebits of calcium. And interestingly enough, plaque, it's not just like a rusty pipebecause it turns out that there's a lot of inflammation going on in plaque22

because lots of cells of the immune system residue in the plaque and thatbecomes important. But it turns out that men and women have a very differentway of laying down plaque, which is similar to the way that they put on weightas they get older. Let's take a man, you might notice that as that man gets older,he's got skinny arms and skinny legs. But what happens to the belly? It getsbigger, we call it a beer belly. It's perturbate right? And so that is sort of a malepattern of laying down fat.

Emily: The actual anatomy of the heart. It's the same in men as it is in women. Butwhat you're talking about is where the blockages occur, correct?

Sheftel: Right, so the basic concept is the same. So yes, the anatomy of the heart is thesame in men and women, right? It's some muscle, it's got hard valves, it has ablood supply, but what I'm talking about now is very specifically, I'm talkingabout the arterial tree or the plumbing, if you will. We're focusing on this aspectof heart disease. The arteries and the analogy that I'm drawing is that as menget older and they deposit fat, they put it right in the belly. And what'sfascinating is that if you look, at a coronary angiogram, which is an invasive test,it's also called a cardiac catheterization. This is an invasive test whereby we put

19 https://www.npr.org/2013/03/25/175267713/womens-health-more-than-bikini-medicine20 https://www.cedars-sinai.org/programs/heart/clinical/womens-heart/services/coronary-reactivity-testing.html21 https://www.mayoclinic.org/tests-procedures/c-reactive-protein-test/about/pac-2038522822 http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

a little catheter tube in a vessel in the groin. It's advanced to the heart and thenwe shoot some dye under x-ray guidance and we shoot some dye into thearteries of the heart, take x-ray pictures, and we can look for blockages. Turnsout that in men we often see great big blockages. The arteries are obviouslyplugged. But in women, we see a slightly different pattern, which is veryanalogous to how women gain weight as they get older. For example, in themenopause, which is they seem to distribute fat everywhere. And I've had manyof my female patients coming in menopausal, perimenopausal and they're verydistressed because they're suddenly developing fat in areas like their belly ortheir arms where they never had it before.23 And it becomes very stubborn andresistant to get rid of. They're very unhappy about that. But it turns out, that ifyou look at the arteries of the heart and women on these coronary angiograms,you don't see these big obstacles, these big plaques. It's the way that it's beingdeposited. It's the way that, for whatever complexity of reasons, mother naturesays in a man, I'm going to deposit the plaque. So it's just, you know, bulginginto the pipe. But for women, the way that they lay down plaque is differentbecause they lay it down kind of just not with one big focal bulge but sort of allover the place. Not just in the middle of the pipe, but along the walls of the pipeand sort of outwardly. So it's not so much that they're pushing it out, that's justmore of a kind of an analogy. But that's the way the plaque is being deposited.So

Emily: And that's true pre and post menopause?

Giulia Sheftel: No, it's typically we see it most, you know, in 50-year-old women and on thatthat's is that women have non-obstructive coronary artery disease more thanmen. So instead of having these huge obstructions, women tend to have morenon-obstructive coronary artery disease. That is to say that is the way that theylay down plaque with this process of atherosclerosis, which is that process oflaying down plaque. That's how women do it. And so there is a very, very catchyword for that. Would you like to know what the word is? It's MINOCA24.

Emily: And that's the small vessel blockages.

Giulia Sheftel: So MINOCA stands for Myocardial Ischemia Infarction and No ObstructiveCoronary Artery Disease.

Emily: So would that be picked up in a cath

Giulia Sheftel: So if you had a cardiac catheterization, which by the way is the gold standardtest that we use to make the diagnosis of coronary artery disease. What you willfind when you do these tests is that in women, more often than men, you will

23 https://www.heart.org/en/health-topics/heart-attack/diagnosing-a-heart-attack/exercise-stress-test24 https://www.cedars-sinai.org/programs/heart/clinical/womens-heart.html

see non obstructive disease and that's what we call MINOCA. Or INOCAMINOCA, it stands for, I don't expect you to remember that, but the way that Ithink about it, these are mini plaques, mini for MINOCA, itty-bitty plaques. Sothe heart is not getting enough blood flow, but it's not because of these hugeplaques that are projecting into the pipe, but they have a lot of non obstructed,they have small plaques that they deposit everywhere. Just the way a woman asshe approaches menopause and perimenopause, is distributing adipose fateverywhere. So that is one of the differences. But another very importantdifference, as we're talking about the coronary arterial tree, is that one thingthat can happen with MINOCA, which is non obstructive disease, is a subset, alarge subset of patients have problems with the tiny little blood vessels at theend of the tree, what we call the little arterials. And it turns out that in women,more often than men, it's those little tiny blood vessels that are embedded inthe heart muscle. Those are dysfunctional. And that's what we call coronarymicrocirculatory dysfunction . 25

Emily: I found Doctor Sheftel's explanation of where these blockages are happening to be really helpful. But one of the things that again is very frustrating is learning how little research there is on this. And so in her practice when she is treating women who have these blockages, she's kind of winging it because there aren't any guidelines to instruct her sort of ability to diagnose and then treat with something that she knows is going to be effective. So she has to kind of personalize everything. She's going to explain to us next a little bit about how this is challenging.

Giulia Sheftel: You know, doctors rely heavily on guidelines to treat patients. That's how we do it. Guidelines inform clinical practice and they help and tell us what to do with any individual. Course there's always the art of medicine, but you always have to put it into context. The guideline, unfortunately right now, there are no guidelines to treat coronary microvasculardisease. There are some interesting studies that are ongoing. There's a very wellknown wonderful researcher, Noel Bairey Merz, and she's the head of the WISEstudy, which is the Women's Ischemia Syndrome Evaluation study to prominentresearcher. And I believe there's a trial now that's enrolling only women. I thinkit's about 4,000 women looking at I believe it's aspirin and cholesterolmedication to see whether we can improve outcomes in these women withsmall vessel disease because in the old days we used to brush it off. You know,the woman was anxious, no big deal. You've got nothing wrong with the bigblood vessels. So see you later. It's your reflux or it's your pinched nerve. Butnow we're coming to understand that the prognosis of these patients with smallvessel disease is not benign. And there are ways, important ways, to treat it. Butagain, we don't have guidelines. So a lot of it is just trial and error.

Emily: Yeah, I mean I think that's tricky because I think historically the guidelines havebeen all based on male bodies, right? So they haven't served women the way

25 https://bio.csmc.edu/6149/Janet-Wei-cv.aspx?_ga=2.226069402.1047648820.1561938373-1454925593.1561938373&_ga=2.226069402.1047648820.1561938373-1454925593.1561938373

that they probably should have. And people would say like, well, their researchdoubly-blind clinical trial, you know, great. But there weren't any women in thestudy, so that's not actually that helpful. Right. And I think there's obviously a lotof information coming out about women and cholesterol that seems to be, youknow, interesting at the very least, sort of suggesting that total cholesterol isnot a good indicator at all for women in terms of heart disease and that, youknow, especially premenopausal women run higher with their HDL and addingthat in somehow is not quite the right way of figuring some of this stuff out.There's also a clinical trial that was done looking at the response women have tostatins and how they're like four times more likely to develop diabetes if they'vebeen put on a statin26, which is a conversation a lot of doctors aren't having with their female patients when they decide to put them on statins. So I agree withyou in general that like the more research the better, but I feel like historically, Idon't think women have been included in on so many of the clinical trials thatI'm not sure we can make that argument in terms of guidelines becauseguidelines seem to be, you know, as we go towards precision medicine, I alsowould hope that we're going towards some pretty basic sex difference in termsof hormonal regulation. And all these other things.

Giulia Sheftel: Right. I agree. I think that there has been a vast, we know there's been a vastunderrepresentation of women in clinical trials, and so I understand what you'resaying is, you know, here, I'm telling you that I feel more comfortable followingguidelines and yet we know that much of that research has been done on menand that's really the problem. That's the crux of the problem that we're doing aone-size-fits-all here, which is why it's so incredibly important that we reallystep up the research game in women. A big thing that I think people don'trealize is that I'm going to come back to this, is that a woman is, you know,much more likely to, to die from heart disease than breast cancer. Breast cancerthese days is, many patients who are very well treated, but you know, one intwo women is going to get heart disease27, cardiovascular disease, in theirlifetime and one in three are going to die from cardiovascular disease28. Andthese are shocking statistics that, you know that I think people forget. And theimportant thing to recognize is that the disease seems to be gaining strength.This whole issue of atherosclerotic coronary artery disease29 is gaining strength inyounger women, younger women, smoking is on the rise30, for example, atcollege campuses. And we are now seeing a rise in heart disease in youngwomen. And that's a problem. That's a shocker. And so I think we need a way topopularize, and to spread the word. I think there have been tremendouscampaigns that have raised awareness of heart disease in women. The red dress

26 https://www.health.harvard.edu/heart-health/heart-attack-and-stroke-men-vs-women27 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901249/28 https://www.womenshealth.gov/lupus/lupus-and-women29 https://www.verywellhealth.com/women-are-more-affected-by-arthritis-than-men-18933930 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006091/

campaign31, the American Heart, the NHLBI32. But I think we're still kind of, forsome reason, I think it still doesn't resonate with women. I remember aninteresting story that my chief of cardiol

Emily: And so along those same lines, I think one of the things that I, you know, I thinkyou know, you just sort of inherit as a bias, is this idea that women live longerthan men. So when you hear statistics about like, women are dying of heartdisease, that, you know, it's the leading cause of death and the statistics thatyou just put out there, 50% can die suddenly. One of the things that I thinkallows people to discount it is this idea of like, oh, well they're old, right? Likewe all have to die of something someday. I'd love for you to talk a little bit aboutthe interplay between estrogen and heart health and why that after, you know,sort of going through menopause becomes a really critical point of heart care, Iguess, or heart, you know, concern for women.

Giulia Sheftel: You know, when people enter the perimenopause they can feel quite poorlywith symptoms33, hot flashes, sweats, sleep disturbance. And so, and we used tothink estrogen was good, we used to think it improved the cholesterol profile.We even used to give it for heart health in the older days. But then we foundout that estrogen is indeed not good for the heart. And that not only was itassociated with an increased risk of breast cancer34, but it also increased the riskfor stroke35 and heart attack.36

Emily: Are you talking about the Women's Health Initiative37, like women taking estrogenwho are 65 or older? Right. I think that's probably important to say.

Giulia Sheftel: Right in that subgroup of patients. But I don't think at this point in time we donot prescribed estrogen for heart health. I think that if a woman's having, youknow, really bad vasomotor symptoms, we can recommend estrogen for theshortest period of time at the lowest doses and I think we can get away withthat.

Emily: So what is it about estrogen before a woman goes through menopause that isprotective?

Giulia Sheftel: That's a really good question. I'm not sure I know the answer to that question.What I do know, is that we're really talking about blood vessels. And again, I'm

31 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815011/32 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.117.03199933https://www.hopkinsmedicine.org/heart_vascular_institute/conditions_treatments/conditions/ stress_cardiomyopathy/symptoms_diagnosis.html34 https://my.clevelandclinic.org/health/diseases/17522-sudden-cardiac-death-sudden-cardiac-arrest35 https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.117.03165036 https://jamanetwork.com/journals/jama/fullarticle/138961337 https://www.ahajournals.org/doi/abs/10.1161/CIRCULATIONAHA.118.037137

not an estrogen specialist, but I think one of the things that, you know, womensuffer from is a disease of blood vessels and women tend to be constrictors.They tend to constrict their blood vessels38. I get a lot of women, for example,with migraine headaches or Raynaud's phenomenon39, they constrict and youknow, it's possible that when the, with the loss of estrogen, that there are someabnormalities there. This is an area of research, but, you know, estrogen may beprotective in the premenopause, but I think the important take home point isit's not protected in the postmenopause and the reasons why estrogen areprotective, you know I think that's a complex area of study.

Emily: Is there any visualization that looks different in a premenopausal versuspostmenopausal?

Giulia Sheftel: Oh, that's a good question. I don't think it's so much that I think it's just thedisease process. You can have a young woman who has diabetes, a smoker. Shemay have blood vessels that look like a 80-year-old woman. You can have a 60-year-old woman who's done a great job of taking care of her health, eatingright, exercising, not smoking, and you know she can have relatively goodlooking vessels. So I think it depends more on the individual, not necessarily the,you know, the age.

Emily: How much is it that we're diagnosing it more. I mean I think it's also reallyinteresting that this idea of these, you know, sort of smaller vessels or SCAD40, likethese other kinds of ways of identifying damage to the heart are relatively new.Right? And so if those are getting diagnosed more in women, are we, does thataccount for the increase in instances, even though we were probably alwayshaving those problems, we just didn't know what to call it?

Giulia Sheftel: I think we were always having the problems, we just never did enough researchor it never came to clinical attention. Again, I think this particular area is stillsomewhat in its infancy in terms of awareness. I think it's still in its infancy interms of research and again, it's research that informs guidelines, but peoplehave to read the guidelines in order to treat patients. Because remember,medicine is a little bit the art and it's also the science and you have to do both ofthose things.

Emily: Well, it's frustrating to hear that we don't have guidelines in place. We don't have enough research. I did want to go back to Dr. Wei and ask her why she thought this was different in women than it was in men. And so what is the reason for like, why is the structure of the heart or the functioning of the heart or dysfunction, I guess in this case, so different between

38 https://www.nejm.org/doi/full/10.1056/NEJM19910725325040839 https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.116.30911540 https://www.heart.org/en/health-topics/heart-attack/about-heart-attacks/silent-ischemia-and-ischemic-heart-disease

women and men?

Janet Wei: That's the million dollar question.

Emily: I mean my go to is always like where is the estrogen, right? Like what'shappening,

Janet Wei: Right? We are very interested in this and we have found that it's not completelyexplained by hormones. Men can have this problem too and it's also notcompletely explained by traditional cardiovascular risk factors. So for example,high blood pressure, diabetes, high cholesterol are important risk factors thatcan contribute to both microvascular dysfunction as well as obstructive heartdisease where there's big blockages, but particularly for the microvasculardysfunction, it doesn't explain it all. It explains only about 20% of the cases41. Sothat's when we think about other causes, such as inflammation. You know,women are more likely than men to have inflammatory conditions likerheumatoid arthritis is more common in women42. Lupus is more common inwomen43 and we are now finding that there are certain conditions specificallyrelated to women. For example, premature menopause. So if a womanundergoes menopause earlier than 40 years old, they're at a higher risk forcardiovascular disease later in life44. Women also who had certain adversepregnancy outcomes, which are things like having high blood pressure duringtheir pregnancy, or a condition called preeclampsia, or even having a preterm labor. So, if they had their baby early earlier than 37 weeks of gestation, thenthat's been associated with at least a two fold increase in future cardiovasculardisease in life.45

Emily: So that's so interesting. I mean, I feel like I had an obstetrician that I haveinterviewed a bunch of times had said to me that one of the things that he lovesabout pregnancy is that it's also sort of this inflection point in overall health thatif you have an underlying condition it often comes out during pregnancybecause of this stress.

Janet Wei: Exactly. It's our first, it's a woman's first official stress test.

Emily: Right.

Janet Wei: Our heart rate, our blood flow has to increase by at least 50% to accommodate

41 https://www.heart.org/en/health-topics/consumer-healthcare/what-is-cardiovascular-disease/inflammation-and-heart-disease42 https://www.cdc.gov/pcd/issues/2015/14_0547.htm43 https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones44 https://my.clevelandclinic.org/health/articles/16979-estrogen--hormones45 https://www.cedars-sinai.edu/Research/Departments-and-Institutes/Biomedical-Imaging-Research-Institute/

extra flow to our baby.46

Emily: And so one of the things that I think is important to just sort of make sure thatwe all have clearly is that it's not because of this complication during pregnancythat later leads to trouble with your heart. It's that during the pregnancy, thissymptom presented itself because it was an underlying problem that you had,probably, right? And that is sort of a foreshadowing of something later.

Janet Wei: That's the hypothesis. You know, that was always kind of the, you know, thechicken versus egg question. And we're now starting to think that it's more thatit's unveiling and underlying predisposition, to cardiovascular disease, but it'sstill not 100%, you know, there's still a lot of research that needs to be done toreally figure out is it the chicken or the egg?

Emily: And so in terms of the research, like what we know about heart disease, whatpercentage of that research has actually been done on women?

Janet Wei: It's been very, very poor. So traditional clinical trials have a very poor inclusionof women, less than 30% in most clinical trials47. And some, you know, in the pastdidn't even include women because women were often excluded because theywere, you know, either at risk of becoming pregnant or you know, had beenpregnant. And so there's been recent pushes, especially by the NIH48, by the FDA49,to include women in trials, both for testing drugs, for testing devices, and forparticularly clinical trial research. You actually have to now state why you're notincluding women or be specific in the inclusion of women. And this goes foranimal research as well, that we not only need to study male mice, we naturallyneed to understand if our mice are men, you know, our mice are female ormale. And that's a requirement now for all our research studies funded by theNational Institute of Health.50

Emily: But I feel like as somebody who's like really in the trenches on this, I would loveto hear sort of when you realized that there were sex differences, you know, and you can speak specifically to the work that you do. But you know, I just sortof like have this imaginary scene in my head of being in med school and learningall this stuff and being really excited about, you know, the mechanisms of actionand the studies that have been done and building upon this research. And thenwhen you at some point realize like, so much of this is really about men's bodies

46 https://www.ahajournals.org/doi/full/10.1161/ATVBAHA.117.30953547 https://www.cedars-sinai.edu/About-Us/HH-Landing-Pages/When-it-comes-to-heart-disease-women-and-men-are-not-equal.aspx48 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845797/49 https://www.heart.org/en/health-topics/heart-attack/warning-signs-of-a-heart-attack/heart-attack-symptoms-in-women50 https://www.menopause.org/for-women/sexual-health-menopause-online/changes-at-midlife/changes-in-weight-and-fat-distribution

rather than women's bodies. Did you ever have a moment like that?

Janet Wei: I did. And actually in medical school, we weren't taught sex differences in healthother than just what we traditionally understand as, you know, bikini medicine51

where you would just focus on breast health, uterine health, reproductivehealth. That was really the only kind of sex

Emily: Oh my God, I love that you called that Bikini health. That's like so funny.

Janet Wei: Right? That's, you know, that was traditionally what was thought as women'shealth is more gynecologic health. But it's much more than that. And we'reseeing these differences in rheumatology or seeing these differences incardiology. And the main difference for me was that because I didn't have thatbackground when I was an intern taking care of a woman with chest pain andrealize, oh my goodness, there's so much more than just looking at theangiogram. You know, the angiogram used to be kind of the end all be all. If youhad a blockage, there you go. That explains your chest pain. But thenunderstanding that women can actually have ischemia. Ischemia, what you hadmentioned earlier is a term for poor blood flow to the heart muscle. So we canactually diagnose ischemia in the absence of obstructive coronary arterydisease, that there are functional abnormalities of these heart vessels that aremore common in women than men. Men can have them too as I mentioned, butthat we need to go beyond just looking at anatomy. We have to look atphysiology. That was really the breakthrough that I had. And a particularexample was the woman that I took care of was actually a patient in ourwomen's heart center and she had seen multiple doctors for her chest pain wasalways told, you know, because her angiogram was normal, was quote unquotenormal, that her pain was unlikely related to her heart. And so here at CedarsSinai, we specialize in a type of test called coronary reactivity testing52 thatspecifically evaluates the function of the small vessels and the large vessels. Andwe're able to diagnose her with microvascular dysfunction. And to my surprise,you know, she burst out crying, not because she was sad that she received thisdiagnosis, but that finally someone kind of recognized that there was somethinggoing on in her heart. It was more of a crying of relief was what she explainedthat it wasn't just in her head, you know, she was kind of labeled that this chestdiscomfort is just in her head or it's just related to stress. But now, you know,there was a way that we could identify it and then now treat it.

Emily: I feel like we hear that story all the time on this podcast. It's like, you want tobelieve that it's not in your head, right? Like that you're really experiencing thisthing and you get a diagnosis and you're like, there's a sense of relief because ifyou can identify a problem, then it becomes something that you can manage.

51 https://www.goredforwomen.org/en/about-heart-disease-in-women/facts52 https://www.ncbi.nlm.nih.gov/pubmed/9386075

Right? Whereas if you're constantly told like it's not this thing that your instinctsare saying it is, that becomes troubling in a sort of psychological way.

Janet Wei: Absolutely.

Emily: So it sounds like you were already at the women's heart center when thathappened?

Janet Wei: Yes. Well I was a trainee as Cedars-Sinai, but had worked with Dr. Bairey Merzwith this particular reactivity testing. So because of her, really, was exposed tothese sex differences in heart disease and became even more interested inunderstanding how we can better diagnose this, both invasively as I mentionedthrough the reactivity testing, but also noninvasively, you know, we need bettertests that are specific to women. And so I've been working over the past 10years almost in this field.

Emily: One of the like basics that I'm still not clear on is that like sometimes peoplehave heart attacks and they die, right? And sometimes people have heartattacks like at home and they don't even realize it until they have like anotherone or there's some other event. And then in the diagnosis of the second ormultiple, they see that there is this scar tissue. Can you talk a little bit about isthere a progress or a progression, I guess to this or do women suffer from thesesince the heart attacks are slightly different, do they also build in some sort ofescalating fashion or?

Janet Wei: Yes, that's an excellent question. So we do know that unfortunately about halfof acute heart attacks can present as sudden cardiac death53. And so it's kind oftheir first time presenting with a symptom. And, and that's why it's so importantto, for everyone, even if they have no symptoms, to really understand their riskfactors, you know, do they have high blood pressure? What is their cholesterollevel? Do they have diabetes? It's very important for them to exercise regularlyand eat healthy, avoid smoking. And so what the studies have shown is thatactually some women who, actually both men and women, who exerciseregularly can build up a greater network of their small little vessels that canform collaterals. So what that means is that even if a big block, big artery getsblocked, the little vessels due to conditioning from exercise strengthening canthen help create little networks to allow blood flow to still go to the heartmuscle, even when a big blockage is occurring.

Emily: So sort of like a river that's like dammed off. And then like little streams form.

Janet Wei: Little streams. Exactly. And that that type of network improves with exercise.

53 https://www.mayoclinic.org/diseases-conditions/spontaneous-coronary-artery-dissection/symptoms-causes/syc-20353711

We also know that for example, if a woman has a heart attack, not due to a bigblockage though, so as I referred to, you know, due to either microvasculardysfunction or spasm, from our WISE data, that there is still a 8% risk of scartissue54, meaning that they actually have heart attacks when there's noobstructive coronary disease and there's a risk about a 1% new heart attacks or new scar that can be formed in the next one year. When we looked at thosewomen who had scar, about a third of them were actually never told that theyhad a heart attack. So that led us to believe that these women were havingunderdiagnosis of their heart attacks because they may either just be sufferingin silence or it just wasn't recognized that their symptoms were due to theirheart.

Emily: Is there any kind of way to check in on your heart? I guess without undergoing amore invasive kind of procedure, like I'm thinking of like c reactive protein55,which is like what I say about everything to check your inflammation. But I sortof wonder like, are there other ways of women being aware of like whetherthey have had a heart attack or are at greater risk?

Janet Wei: Let's try to split that up into two questions. One, for someone who doesn't haveany symptoms, we encourage these women to really understand theircardiovascular risk. So this risk calculator that I mentioned, there was an updatein the risk calculator guidelines by the American Heart Association and by theAmerican College of Cardiology for helping a woman and a man to determinewhether they were at risk for having a heart attack or stroke. And this waspublished in 2018 and you can actually go online, you can Google somethingcalled the a ASCVD risk calculator56, which is also known as the atheroscleroticcardiovascular disease risk calculator. You put in your age, you put in whetheryou're a man or a woman, you put in your ethnicity, you put in the actual bloodpressure numbers, your cholesterol numbers, whether you smoked or currentlysmoke, whether you have diabetes. So these risk calculators will then give youan estimate of your risk for having a heart attack or stroke over the next 10years. And the guidelines now have created extra points that if you have searchand risk enhancers, depending on, for example, family history, the pregnancyoutcomes that I had mentioned, you know, that are specific to women who arehaving premature menopause. Being South Asian ancestry, you know, there arecertain additional risk enhancers. Another one is the rheumatologic conditions,these kinds of inflammatory conditions that will then add to your risks. So I thinkit's important for all patients, men and women to know what their risk is bygoing to their doctor to have this calculated. And then for a woman in particularwho's having symptoms. So whether this is feeling short of breath that's new

54 https://www.acc.org/latest-in-cardiology/articles/2018/04/30/16/43/study-explores-representation-of-women-in-clinical-trials55 https://www.ncbi.nlm.nih.gov/pubmed/2223160756 https://www.nwh.org/find-a-doctor/find-a-doctor-profile?id=1579 r

when you exercise or having any sort of kind of, discomfort really above thewaist if it's chest, even if it seems kind of atypical, you know, in the past peoplewould always focus on whether these symptoms would occur with exercise andif they would get better with rest. But we now know that women can have thesesymptoms even with emotional stress57. May happen kind of at random timesduring the day, not always consistent with exercise. And if this is reallypersistent, they should have an exercise treadmill test58 as a first step forgenerally low risk women. And there are the next steps depending on what theirtreadmill shows. But if these symptoms are persistent and they notice that it isbeyond just being, you know, deconditioned for example, that they shouldpursue further understanding. And not to always take no for an answer.

Emily: I'm Emily Kumler and that was Empowered Health. Thanks for joining us. Don't forget to check out our website at empoweredhealthshow.com. For all the show notes, links to everything that was mentioned in the episode as well as a chance to sign up for our newsletter and get some extra fun tidbits. See you next week

57 https://www.etymonline.com/word/coronary58 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928162/