Thank you, everybody, for coming and sticking through the conference through lunch. So my name's Chris Mullen. I'm Pullman and Critical Care faculty at Brown. There's my disclosures up there. And so really, the objectives of the talk today are to review the epidemiology of PE through the lens of sex, race, and gender. Then we'll examine sex, race, and ethnicity-based disparities in both the outcomes and treatment for acute PE. So before we start my talk, and I think for this whole session, it might be helpful to just remind ourselves what the definitions of sex, gender, race, and ethnicity are. So sex is a biologic variable, male or female. Gender is a social concept or a construct of someone's personal attitudes towards their sex or their gender identity. Race is not a biologic variable. It's a sociocultural construct that is used to group people together in ways that are arbitrary. Ethnicity is sometimes confused for race, but it's really someone's culture or heritage. So with that, let's dive a little bit into the epidemiology of PE through this lens. And so as an overview, it seems relatively simple that the incidence of VTE varies by sex with stage of life. And as depicted up here, the graph on the top right, which shows that people who are female will have a higher incidence of VTE at younger age. And that's because of pregnancy and estrogen-containing oral contraceptives. And then as age increases, the incidence of VTE is greater in males. This graph on the bottom right was a pretty notable paper from the New England Journal in 2004 that shows men compared to women have higher incidences of recurrent VTE after the withdrawal of oral anticoagulation. Again, that's maybe because many of the women had clots that were related to hormonal changes with pregnancy or contraceptives. When you think about the epidemiology of PE, how it relates to race, this is a quote that I pulled from an editorial that Sam Goldhaber wrote about 10 years ago, with the conventional teaching being that Asian-Americans have the lowest risk. People who are black or African-American have the highest risk, with Caucasians or European descents, and then people of Hispanic descent in between. But as we'll see is that the associations are not that well understood, and they can be complicated. And so one of the reasons it's so complicated is that because the incidence of VTE is really poorly characterized outside of Northern America, Europe, and some parts of Asia, particularly as it relates to people of African descent that's really only studied well in North America. And so what I've put here are some graphs looking at incidence rates of VTE by different racial groups. And the take home from this is that black Americans, or people that are black, have somewhere about a 30% to 60% higher adjusted incidence of VTE than European-Americans. And that's about two or three-fold times more than people that are Asian-American, Native Americans, or of Hispanic ethnicity. And so the question becomes, well, why are there racial differences? And it's a really complicated thing to unpack. So this is a really nice review that was written earlier this year. I would encourage you to take a look at this. When I came across this review, I thought that this schematic was particularly helpful. And thinking about what are all of the different possible protective factors for VTE, and what are all the adverse factors. And you can see they're demarcated or grouped into demographic, behavioral, socioeconomic, pharmacologic. It's all these different things. And so it's through thinking about how all these things may differ between people of different races is, I think, very helpful to understand the difference. So this was a schematic from a review that I thought was particularly helpful as well, looking at the risk of thrombosis by ethnicity or by heritage. And what you can see is that some of those factors, genetic, socioeconomic, are different between the different groups. And so I think most notably, or I think what many people may know, is that the prevalence of mutations like factor V Leiden and prothrombin gene mutations are very different between different racial groups. And that people that are white or people of European descent have much higher rates or prevalence of that compared to people who are black Americans or of African descent. However, there are many other risk factors, such as obesity, factor VIII levels, sickle cell trait, as well as other socioeconomic factors and structured racism that may increase the risk of thrombosis in people who are black or of African descent. Similarly, in Asian and Hispanic descents, whether it's a little bit unclear, but whether there's a genetic predisposition that decreases the incidence of thrombus, but this is routinely seen in most epidemiologic studies. So kind of further examining this more, there were a couple papers that I really thought were very helpful and did a lot of nice epidemiological methods to answer some of these questions. And so this first data is from a paper that was published by Zakaianol and Circulation in 2014. And what they did was to look at the differences in race, particularly people that were black or white, and VTE. And they used sort of three prospective cohorts, the ARIC, the atherosclerosis risk in communities, the cardiovascular health study, and the regards, which is like regional or geographic differences in stroke, if I'm remembering that correctly. And so what they sort of found was that sort of the adjusted hazard ratio for VTE was sort of different in different cohorts. So people who are black had a higher adjusted risk of VTE in the cardiovascular health study, but not in the other two. Sort of interestingly, if they looked at just PE and not VTE together, that association was no longer seen. But in the cardiovascular health study, there was an interaction between race and region in the sense that people who were black who lived in the southeast had a much higher rate of VTE than people who were black who lived in other regions. But I think kind of the study that I think really sort of hit home with me was sort of a subsequent analysis that these authors did in the ARIC cohort. So what they did is they found that 65, that the VTE rate was 65% higher. It's sort of a crude estimate in black, in people who are black compared to people who are white. They adjusted that for age and for sex, and the hazard ratio for VTE was a little over two. But then they looked at all of the different confounders and mediators between the relationship of, between race and VTE, and sort of adjusted those or put those in their statistical models, and the sort of hazard ratio decreased by 75%. So what that tells us is that the higher incidence of VTE in people who are black compared to people who are white has nothing to do with race itself. It has to do with the fact that people who are black have much higher sort of incidences in the comorbidities that are associated with higher VTE. But if you start looking at race and sex together, it gets even more complicated and probably not that well understood. So this was a study that looked at the risk of recurrent VTE after sort of an unprovoked VTE, DVT or PE, and they found that males had a higher incidence of recurrent VTE compared to females. However, that the rates were sort of similar between black males and females, black women and men as far as the recurrence, and that there was a higher rate of recurrent VTE in black and Latino women versus Caucasian or white women. And so what this sort of says is that there's sort of a really complicated relationship between race and sex as far as, again, recurrent VTE. All right, so switching gears a little bit into sort of the sex differences and the racial differences and outcomes related to a QPE, and sort of you can imagine kind of given the fact that sort of there are many sort of different associations that are sort of make the relationship between incidence of VTE with sex and race complicated, it's sort of a similar thing for outcomes. And so I would sort of say that kind of when I take a look at the data, so there's really probably sort of a say it's relatively mixed when you look at sort of the association between sex and outcomes in a QPE. There was a study that looked at about a nine year window from the National Inpatient Sample Database that showed that sort of adjusted that women had worse outcomes and more complications for acute PE. So that's depicted here in this forest plot where being female was associated with a higher risk of death, discharge to a nursing facility, and shock. Another more recent sort of single center study showed that women that presented with PE were older, had less comorbidities and less RV dysfunction compared to men or to males, and at higher mortality on unadjusted analyses, although adjusted for those risk factors, the mortality difference was not the same, or sorry, was the same, excuse me. And in the CDC Wonder database, age adjusted mortality was higher in males than in females, and that it seemed like it was increasing in the male population, but not in the female population. Sort of similarly, when you look at, so there are differences in outcomes by race. And so the literature on this is primarily looking, again, mostly in the United States, looking at the differences between black and white race. And people who are black have an higher risk of, or sort of increased hospitalizations for acute PE, increased mortality with some sort of estimates of 30 to 50% higher, increased complications and longer hospital length of stay. These are sort of graphs on the right there from the paper by Barco and colleagues that was published in Lancet Respiratory Med in 2021 that shows that being black, people had higher age-adjusted standardized mortality rates than white people. And then this is a study that I think is really worth sort of highlighting, it was published very recently, because it's really one of the only studies that's actually looked at ethnicity and not race. And so if you look back at some of the older data, sort of Hispanic ethnicity is sort of lumped in with race, and we realized that ethnicity, particularly being Hispanic or Latino, is sort of separate or different from race. So this was also done at the place where I did my residency, so I have a lot of affinity for that. It was a single center study that looked at all patients that came with acute PE, because it was in its Columbia University Medical Center in New York, a very high percentage of patients, 37, identified as Hispanic or Latino. But they also asked the patients for their self-reported race, and the majority of them actually reported either they didn't report it, or they sort of reported other or multiple races. And so in this, Hispanic or Latino ethnicity there was sort of a minor difference in some comorbidities, but no real difference in PE risk factors. Hispanic and Latino patients had less severe PEs, but there was no difference in mortality specific to, or mortality or PE-specific interventions when adjusted for the severity of the PE. Sort of last, looking at sort of anticoagulation and then sort of interventional procedures, this and other studies have shown, I'm gonna go fast for time, that being that black patients are less likely to receive DOACs compared to white patients and other races, this is not the only study that's reported that. But what I'll sort of end with is thinking a little bit about sort of the interventional procedures for VTE, particularly with mechanical thrombectomy for acute PE sort of on the rise and probably here to stay for a while, we should sort of think about this. So I think it's pretty well established that for many diseases, people who are black are less likely to be offered procedures or surgeries, things like carotid endarterectomy, early lung cancer surgery, valve surgery. So sort of looking at the racial differences for IVC filter use, in the United States, we probably use too many IVC filters and we probably should in general be using less and people who are black compared to whites were more likely to get IVC filters, less likely to get them removed or they would wait longer to get them removed. And so I sort of will end the talk sort of thinking a little bit about what about catheter-based procedures for acute PE? And so this is not something that's been around for that long and so there's not a ton of data. I think probably the one that the highlight, it was published in CHEST earlier this year that showed for the National Inpatient Sample Database that there was increased mortality for females undergoing mechanical thrombectomy compared to males. This is sort of adjusted for comorbidities. The mortality was higher, procedural bleeding was higher, vascular complications, blood transfusion were higher. Sort of notably in this, there was no sort of assessment of the severity of PE. And another sort of smaller study looked at higher bleeding rates on longer hospital length of stay for non-Hispanic blacks compared to other races. And so this is sort of a table of the percentages of the different sort of races or ethnicities that are included in that CHEST study as well as in the FLASH registry, which is the NREs registry for their mechanical thrombectomy device. Not sort of surprising numbers given what we know about the population of the United States and sort of the incidence of PE across different racial groups, but sort of something to sort of think about that as we sort of advance sort of our knowledge of who benefits from mechanical thrombectomy, we really should make sure that we think about sort of access to that and disparities and outcomes amongst sort of different racial groups and sex. So hopefully I've left this sort of whirlwind talk with, I left you with more questions and answers in the sense that associations of sex, race, and ethnicity on VTE outcomes are really complicated. They need to be better understood. And I think as we really sort of use mechanical thrombectomy and catheter procedures for the treatment of acute VTE, we really sort of need to make sure that we pay attention to some of the disparities that may end up arising. So with that, I'll say thank you and pass it to my colleagues. Thank you. Pulmonary Critical Care Fellowship at Temple Hospital in Philadelphia, and I'm gonna be talking about exogenous hormones and their association with venous thromboembolism, particularly pulmonary embolism. This is me, I have no disclosures except that I run our Twitter account, templebccm. Please follow us, we post some fun pictures, or I post some fun pictures. So here are my objectives. Primarily in this talk, we're gonna be talking about estrogen and testosterone for my portion. So here's estrogen. It's a lipophilic hormone that has an effect on the transcription of a lot of different proteins down the line, and one of the things I think we're all familiar with, at least anecdotally, its use is to alleviate symptoms associated with menopause in patients who are going through that. And it's available in two different formulations, transdermal versus oral. And these two formulations are actually metabolized quite differently, so oral estrogen is subject to first pass metabolism in the liver, and it's hydroxylated to less potent forms. So actually, with the transdermal formulation, you get up to 20 times more bioavailability than you do with the oral formulations. And at the same time, transdermal estrogen is reported to have a lower risk of venous thromboembolism. And the reason this is thought to be is that the active metabolites that the oral estrogen is metabolized to have quite profound and quite pro-coagulant effects on the coagulation cascade. So you see associations with increased factor VII, prothrombin one and two, CRP, D-dimer, and thrombin, all of which make you more likely to clot. And you see decreased levels of plasminogen activator one, and TPA, both of which make you less likely to clot. The estrogen also binds directly to fibrinogen, which activates it and promotes thrombosis. And there has been no real association seen with transdermal estrogen treatment with any of these parameters. So we know that VTE incidence is increased in those undergoing estrogen-based hormone replacement therapy. And we know that there is an impact on the coagulation cascade. The association hasn't been directly proven. Many of the studies that evaluate this have shortcomings, including small sample size, inability to directly compare oral versus transdermal formulations. So we think this is why, but we haven't directly proven this yet. So what about oral contraceptive pills? I think this is something that we all have seen a lot of patients on, heard a lot of anecdotes about increased levels of clotting with these medications. And pretty much since the get-go, since these medications have been available, they've been associated with an increased risk of clot. The first case report was within a year of them hitting the market. And we know that the incidence of venous thromboembolism in women who are taking oral contraceptive pills that contain estrogen is about three to five times more than women who are not. Similar to transdermal or oral estrogen for hormone replacement therapy and menopause, it does increase a variety of the clotting factors in the coagulation cascade that lead to increased risk of thrombosis. And here is a diagram of the coagulation cascade that I never thought I would look at again after medical school, but here we all are. And I really like this. It's from a great website, Evidence-Based Medicine Consults, that shows pretty well, I think, the different parts of the coagulation cascade that OCPs have an effect on. So you're gonna see increased levels of factor seven, factor 10, five, and factor two or thrombin. And we're gonna see the greatest magnitude of increase in factor seven. This is a really great diagram. That's actually about 20 years old now, but I think it really well highlights the relative risk in patients who are on oral contraceptive pills and also have an additional risk factor for VTE. So on the left, we're gonna see patients who are not, essentially have no risk factor for VTE. They don't have factor five Leiden, and they're not on OCPs, and they only have 0.8 in 10,000-person-a-year incidents of having venous thromboembolism event. If they're just on OCPs, then that triples. If they just have factor five Leiden, it is increased by six times. But if they have both of them together, the effect is actually more than compounded. So really important whether we are seeing patients who come to us already on these medications or whether we're prescribing them ourselves to really just take a good history and ask if they have any additional risk factors, whether it be smoking, a family history of clotting, or a personal history of clot themselves. Here are a list of 10 commonly prescribed OCPs, and I was also very intimidated looking at this. There's just so many, and these are only 10. There's a lot more. But I think the important things to note are the varying doses of the estrogen component from 20 to 50, and that they all have a progestin component. Some of them have a little bit of antiandrogen as well. And in the meta-analysis that I found looking at the different types, there is about a four-fold increase, and there is a bit of a dose-dependent response. So the people who are at most risk of clotting were in the 50-microgram arm. And about testosterone, this hasn't been as clearly associated with VTE as estrogen has, but there is a subset of patients who are on testosterone therapy, about 12% in this meta-analysis that I read, who developed polycythemia, greater than 52% hematocrit, who did have an increased risk of VTE compared to those who did not. And here is the Kaplan-Meier analysis from that paper with orange in patients who did not develop polycythemia and blue the patients that did. And they had a 3.9 versus 5.2 risk in developing VTE or a major cardiac event, which was statistically significant. And they also had a significant difference in their time to first clot. And this was a meta-analysis involving 50,000 patients. Again, it was a primarily Caucasian population, and they did not differentiate between different types of testosterone replacement therapy. I do just wanna say a couple words about gender-affirming care, just because it's becoming more prevalent as more patients have access to it. And a lot of people who are transgender consider this to be an integral part of their care. And there's not a ton of data about testosterone and VTE in this population. A couple of highlights from a case report that I thought was important to mention. A transgender male who was an adolescent was undergoing a gender-affirming mastectomy. He was on oral OCPs and testosterone injections with a BMI of 40. And he got quote, unquote, appropriate VTE prophylaxis. And it's in quotes because I'm not sure we know what appropriate VTE prophylaxis is in this patient. And he ended up having a bilateral PE post-op. Thankfully, he did not require any major interventions. He completed his six months of AC. And then he opted afterwards to forego the oral OCPs for an implantable birth control method that had a lower risk of clotting. And on further history, after the fact, it was revealed that he actually had an extensive family history of clotting. His clot-able workup all came back negative. But just important to highlight that especially in these patients, we should be doing everything we can to mitigate their risk prior to having them undergo a surgery that is known to be a risk factor for clotting. And then just for time, my last two slides are about patients who have a VTE while undergoing hormonal therapy. And these are some guidelines from the Endocrine Society. Basically, in both tropical estrogen and any kind of testosterone therapy, you're going to want to consider discontinuing the hormonal therapy while you're actively treating the clot. See if there's anything reversible that you can do and effect change on. And if not, then you should consider having the patient on anticoagulation therapy if after an informed consent discussion with them, they would like to continue with hormonal therapy. And that's all I have. Thank you. We're going to make a little bit of a switch, go from pulmonary embolism to pulmonary hypertension. I'm going to look at racial and ethnic and gender disparities in pulmonary hypertension. My name is Raju Reddy. I'm an assistant professor of medicine at the University of Texas. I have no disclosures. So today we'll briefly touch on the definition of health disparities, explore racial representation of minorities in clinical trials in the United States, and explore how we tend to have racial disparities and gender disparities, and finally touch upon how disparities tend to affect pregnant women in particular, and briefly talk about some methods that we could do to address racial and gender disparities in caring for our PH patients. So briefly, the definition, these are defined as health differences between population groups. These differences are linked to racial ancestry, social, economic, or environmental differences. And generally speaking, racial disparities tend to affect minorities more than the minority population. So let's look at the minority population in the United States. According to the 2020 U.S. Census Bureau, the current population of the United States is 331 million. Minorities constitute 38.4% of the population. Hispanic individuals make up 18.4%. African-American individuals make up 12.4%, and Asian individuals make up 6%. Despite this increasing number of minorities, they're not adequately represented in clinical trials and registries. And this could essentially be a problem because we develop a lot of risk stratification tools. And when we apply these risk stratification tools in caring for a broad swath of the population, while it's derived from one particular group of patients, that could potentially be problematic. So when we look at minority representation in clinical trials, I mean, if you look at the reveal registry, when we look at the Hispanic population, they constituted about 8.6% of the population, whereas the expected number that we should have enrolled in that study was about 11.5%. If you look at the pulmonary hypertension scientific registry, which collected data on patients from 2015 to 2018, Hispanic individuals constituted 9.6% of the population. And similarly, in the pulmonary hypertension association registry, they constituted anywhere from 2.2% to 22.8%. The 22.8% tends to happen more in the West Coast, so I think the West Coast were doing a better job, perhaps, of enrolling a population that represents what we see in the United States versus compared to some other places, and 2.2% is from the South. Amongst African-Americans itself, in the pulmonary hypertension scientific registry, they constituted 7.4% of the population, whereas they made up about 12.4% population in the 2020 US Census Bureau. So as I mentioned, this could be potentially problematic. The reason is they're deriving a lot of risk stratification and treatment strategies, not necessarily including what we encounter in caring for our patients. So when we look at Hispanic population and how their outcomes are, we generally have found that they have a higher hospitalization rate. This is a study from Bernardo and colleagues at Stanford University. They obtained data from the Pulmonary Hypertension Association Registry. What they found in this study was Hispanic individuals, at the time of diagnosis, are younger, they have a higher pulmonary vascular resistance, they tend to have lower access to Medicare and private insurance, and they're more likely to be on Medicaid or have no insurance at all. As a result of this, potentially, they tend to have higher number of ER visits, 3.1 versus 2.1, compared to the non-Hispanic population, and they also tend to have higher incidence of per-person year hospitalizations, at 2.6 versus 1.8. And interestingly, we know from prior PH studies that increased number of hospitalizations is associated with increased mortality, but in this study, they did not find any difference in mortality. On the Y-axis is transplant-free survival, on the X-axis is survival in years, and there was no difference between Hispanics versus non-Hispanics. And why was that the case? I think one particular reason that we think that's the case is because the number of Hispanic patients who were enrolled in the Pulmonary Hypertension Association Registry were younger. And in fact, when they looked just solely at age as a potential, when they adjusted for age, they found that adjusting alone for age took away any effect of mortality, suggesting that age has a big impact on mortality. What about other races? So previously, we knew that African-Americans tended to have higher age-adjusted mortality rate. That was an old study published back in 2008. So a more recent group looked at the exact same question. They used the CDC Wonder database. They looked at age-standardized mortality rates in patients with group 1 to 5 pH between 2003 to 2020. The U.S. standard population in 2000 was used to calculate the age-standardized mortality rate. And they stratified this by gender, race, urbanization status, age groups, and subtypes of pH. And what did they find? The first thing to notice in that figure there, on the Y-axis is age-standardized mortality per million people, and on the X-axis is the years. So first thing we can all notice is that we've made a substantial reduction in mortality in caring for our pH patients. But there is still a separation. In triangles is the Caucasian population, and in the circles is the African-American population. And when we look at age-standardized mortality rates, comparing Caucasians versus African-Americans, African-Americans tend to have higher age-standardized mortality rates. And this is as of 2020. So there are some limitations to this study. It's an ICD-based diagnosis, and we all understand the limitations of using ICD-based diagnoses for research studies. And more importantly, I think they do not adjust for confounders such as socioeconomic status. So if you look at studies that have adjusted for these things, we can look at data from the REVEAL registry. This was a prospective registry of 3,500-plus patients. These patients were all diagnosed by right heart cath and followed for a minimum of five years. And we look at the hazard ratio for Asian, black, and Hispanic, there was no difference in mortality amongst these groups. So what this study highlights is that if we care for all of our patients, perhaps at expert centers, maybe we could potentially narrow that gap. But the study also highlights that we, physicians, should partner with each other in the academic centers and community centers while caring for these patients. Now let's look at males and females. So what we know from prior literature is that patients younger than 60 years old, whether male or female, there is no difference in mortality. However, older patients defined as age greater than 60 years or more, there's a significant difference in mortality. In this study, in the REVEAL registry, the two-year mortality for males more than 60 years old was 64%, and for females was 77.5% survival. In this registry, the hazard ratio for mortality for men was almost 2.2 compared to women. Similar findings were noted at one year. In other registries, in the French pulmonary hypertension registry, female sex was also associated with a lower three-year mortality. Now another area that I think we are all going to have to address is caring for our patients who are pregnant. So approximately 1.9% of patients become pregnant within six months of diagnosis of pulmonary hypertension. The complications include both maternal and fetal complications. This includes heart failure, death, preterm delivery, and low birth weight in about a third of patients. Given this high morbidity and mortality burden, the European Society of Cardiology and the Pulmonary Hypertension Association recommend against pregnancy. So given the new legal environment that we're living in, this could potentially become a disparity. So what I'm showing here is a map where access to abortion is still legal, and the Pulmonary Hypertension Association advocates for medical care driven by clinical judgment and patient-clinician relationship, including legal, safe, affordable access to contraception and abortion. So how do we address this racial and gender disparities as we care for these patients? So I think first thing that we should do is have a uniform definition when we collect data on race and ethnicity. As Chris mentioned, often race and ethnicity gets interchanged in several studies. Second, ensuring adequate enrollment of minority populations to ensure that we're representing the type of patients that we care for and we have the same patient population being represented in clinical trials and registries. In addition to that, incorporation of health disparities training into medical education curriculum, which I think we're doing in several universities. And then finally, I think physician involvement in the development of health care policy is crucial. Thank you very much for your time today. Hi, everyone. My name is Dana Kaye. I'm coming to you from Cincinnati, Ohio. It sounds like the Bengals won today, just FYI if you didn't see the game. I'd like to thank you for the opportunity to speak today, and I have no disclosures. So today I'm going to discuss the role of hormones in pulmonary vascular disease. We're going to first review gender differences in the prevalence of pulmonary arterial hypertension and RV function. Then we'll review some of the most common sex hormones and their effect on the pulmonary circulation. And then hopefully by the end of the presentation, we'll have a better understanding of the role of hormones in PVD or pulmonary vascular disease and how they affect our patient population. So as most of you may know, pulmonary arterial hypertension is more prevalent in females. The first registry to show this was the multicenter registry from the National Institute of Health completed in 1985, which looked at patients with idiopathic inheritable PAH and found a higher prevalence of PAH in women compared to men with a ratio of 1.7 to 1. Since then, multiple other registries have been done around the world, including the Reveal Registry in the United States, the European Comparer Registry, the French National Registry, and the Chinese Registry, all of which have shown a higher prevalence of PAH in women compared to men as outlined in the chart. Interestingly, and as Raju mentioned in the prior presentation, both the French and Reveal Registry have noted that women have a lower risk of death in PAH compared to men, even though women have been found to have more profound vascular remodeling and more plexiform lesions. The data from the Reveal Registry showed that five-year survival in newly diagnosed cases of PAH was 53% in men and a survival of 63% in women. So overall, although women have a higher prevalence of PAH, they tend to survive better with it. And you can argue that the better survival of women may account for the difference in the prevalence that we see. Survival in PAH is closely related to RV structure and function in the setting of pulmonary vascular remodeling. The thin-walled RV is vulnerable to increases in afterload and pulmonary vascular resistance. And as shown in that fantastic diagram from the noted paper in 2017, initially as the afterload increases in pulmonary hypertension, the RV first compensates by coupling and enhancing contractility. Eventually, with further increasing afterload, the RV dilates in an effort to preserve stroke volume. Then as the RV further dilates, it results in uncoupling and increased heart rate and increased energy requirement. One study that explored a difference in RV function among genders was the large population-based MESA-RV study, which measured RV indices via MRI in participants without cardiovascular disease. And in that study, they found that females have a higher RV ejection fraction and they have a lower RV mass and RV volumes. Now, looking at RV function more specifically in the pulmonary hypertension population, in surveying the genders in the PH population, Jacobs and colleagues, in their paper published in CHESS in 2014, found that although both genders had improvement in PVR with treatment of their pulmonary hypertension, women's RV function was significantly more preserved than men. They showed that RV ejection fraction improved in women, even though it declined in men. And there was a 39% difference in transplant-free survival. Now, let's talk about the main sex hormones and their effect on their relationship to PH and RV function. We're going to start with estrogen. So there are three main estrogens in the body, E1, E2, E3, and with the most potent being E2, which is also called estradiol. There are three main estrogen receptors as well, but the most important ones are the alpha and beta receptors, which are expressed on endothelial cells, smooth muscle cells, fibroblasts, and cardiomyocytes. And estrogen affects cell pathways most commonly by acting as a transcription factor leading to gene expression. So the study done by Burt and colleagues in 2018 showed a relationship between E2, or estradiol, and pulmonary hypertension. They showed that increased levels of E2 had been found in men and postmenopausal women with PAH as compared to healthy controls. Higher E2 levels are associated with increased risk of PAH, worse functional class, and even lower six-minute walk distances. In regard to the effect of estrogen on the RV, we have animal studies that suggest a protective role of estrogen in the RV function. Additionally, we have some observational studies in humans through the MESA-RV study, which again showed higher RV ejection fraction in patients that had higher E2 levels. The detrimental effect of estrogen on the pulmonary vasculature and the protective effect of it towards the RV leads to what is termed as the estrogen paradox. It describes the discrepancy between increased susceptibility to PAH among women with better outcomes in the gender, as estrogen has been noted to be cardioprotective towards the RV, as well as disease-promoting in the pulmonary vasculature. Now let's talk about testosterone. It binds to the androgen receptors that are present in pulmonary vasculature and cardiomyocytes. Observational studies suggest that testosterone results in vasodilation of the pulmonary vasculature and that testosterone leads to more RV hypertrophy and fibrosis. There have been some human studies, such as the one done by Ventitello and colleagues in 2016, which looked at a population of 23 men with PAH, and they noted no difference in the total or bioavailable testosterone levels compared to match controls. And so testosterone can be protective because it can result in some vascular vasodilation, but detrimental to RV remodeling because it leads to RV hypertrophy and fibrosis. When it comes to progesterone, although there are progesterone receptors on endothelial cells, cardiomyocytes, there has been little research on the role of progesterone in pulmonary vascular and RV remodeling. Animal studies suggest a vasodilatory effect of progesterone on the pulmonary vessels, and there really hasn't been any association noted between the level of progesterone in women with PAH compared to those without PAH. So there's no association between the levels of progesterone and PAH severity or RV function. Now DHEA is a pro-hormone of E2 in testosterone, and it's probably the most exciting hormone when it comes to PAH because it's been noted to have a pretty robust role in PAH and RV function. Going back to the study done by Baird and colleagues, lower levels of DHEA have been associated with PAH, worsening hemodynamics, and lower six-minute walk distances, and worse survival. In regard to the RV function, lower levels of DHEA have been associated with RV dilation and dysfunction. So overall, DHEA seems to have beneficial effects on both the pulmonary vasculature and RV function and is protective overall in someone that has pulmonary hypertension. Most recently, we have the EDIFY study, which is underway, looking at DHEA on PAH and RV strain using MRI, and hopefully it'll give us some enlightening results. So putting it all together, sex hormones are important and have been associated with significant effects on the pulmonary vasculature and RV function, and we need to put more effort into understanding these disease-modifying endogenous agents. So far, we can say that although estrogen has a disadvantageous effect when it comes to pulmonary artery remodeling, it has been shown to be RV protective. Testosterone leads to some vasodilation, but is detrimental when it comes to RV remodeling and fibrosis. Progesterone has been noted to have some vasodilatory effects, but these are just animal models and we really need more studies done in humans. And DHEA is shielding in PH by resulting in vasodilation, reducing PA remodeling, and being RV protective. With this knowledge, we need to remember that hormones are not benign in their effect on the pulmonary vasculature and the right ventricle. We use hormone therapy in a variety of settings, including post-menopausal management, fertility treatments, and gender-affirming therapies, to name a few, and it's important to keep in mind their potential effect on the pulmonary circulation. Of course, we need to continue research to further understand the role of hormones in pulmonary vascular disease and understand their longitudinal effect on the pulmonary circulation. Thank you, and don't forget to evaluate.

sex

race

gender

epidemiology

treatment

pulmonary embolism

pulmonary hypertension

incidence

PH