 Okay, so it's a real privilege to be asked to come and talk to the esteemed audience about an issue that I've actually grown to become interested in based on a couple of observations that we've made. My day-to-day practice is interesting. It's a combination of patients who have coronary blockages or valves or adult congenital heart disease, and you see differences between genders in many different ways. But there's a unique aspect of patients that I treat that have very end-stage disease of either the lungs or the heart. And in those cases, when we're talking about transplanting the organ and you have a donor and a recipient in the immune system, there we really start to see some very interesting differences in patients depending on the gender that they have. So I'm going to kind of highlight an overview of both my own personal experiences, as well as what's been published in the literature to give kind of a flavor of what the landscape is like when it comes to gender-related outcomes in heart and lung failure and mechanical support. So I'm going to start with a brief sketch on lung transplants. This is where I noticed something that was kind of interesting. So lung transplant happens the same way, whether it happens in females or in males. There's really no difference, although there are sometimes issues related to stature and average sizes and wanting to get the right size fit. But in general, the procedures perform the same way. One of the things that I was very interested in in Minnesota was looking at what determined whether some people did better or worse after a transplant. Because lung transplant, especially out of all thoracic organ transplants, has the Achilles' heel of rejection at about 10 years, 5 to 10 years that is about 50% at 5 years. So it's a big deal. So I did a study where we reviewed about 879 transplants at our center at the time. And it was actually looking at what was going to be determining a better or worse outcome. And I was kind of focused on the donor, the distance. I was focused on the recipient's level of illness, on comorbidities like coronary disease or different things that would probably make an impact. And what we found was there was only one factor that made a difference. And it was none of those. It was actually just the gender of the recipient that determined the longevity of the graft and how long people survived after a lung transplant or bilateral lung transplant. And this finding was pretty striking to us. It had been shown to some degree in other large-scale center studies using the UNOS database. But it was very striking in a large single-center experience. Whether we adjusted for all of the different things that the different individuals had or not, it was very clear, and maybe you'll be pleasantly surprised to know at the Women's Symposium that it was the females that did, by far, better than the males. So we had about 80% survival at 5 years for females, which is, like, you know, better than an aortic valve replacement. I mean, that's really, really a good outcome. And males did worse. So we looked at this in a couple of different ways, and whenever we do studies in transplant, we also have to consider not only the gender of the recipient, but we have to consider the gender of the donor. And there are some notable differences when people get a gender-matched transplant versus a gender-mismatched transplant. And we know that especially in heart transplant. And I'll talk about that. So we had to explore that in this particular study as well. And what you see is what has been shown to be true over and over again that when you have a female donor to a male recipient, so a female donor to a male recipient, those seem to do the worst by far. That's the black line here. There's been the lowest survival out at 5 years than either the females in general, which did superior, or males that received male donors. Irrespective of this, females did better than males, but especially if the male received a female donor, then they did particularly worse. We also looked at rejection. So is there potentially some effect that's going on in the immune system, or females rejecting more or rejecting less, or males rejecting more? And what came out at 5 years was that males did worse in terms of freedom from rejection. So they had a much less chance at 5 years. They had about a 20% chance of being free from rejection compared to the females who had about a 40% chance, almost twice as much, twice as likely to be free from rejection. So why could this be, and why is this an issue? And by the way, this now has prompted, we're in the process of submitting NIH grants in collaboration here with Texas Heart, analyzing specimens from every transplant that we do to try to understand whether there are some immune, cytokine-related cell factors that are different in the recipients depending on the gender that could then allow us to offer the same benefits to any gender, irrespective. But there are clearly other differences. There are psychosocial factors that could play a role, access to care. There are hormonal differences for sure. There are also physiologic differences. And then there's thought to be immunologic differences that may be related to differences in the hormonal milieu of the recipient. Just to highlight a couple of potential things. It's been studied in kidney transplants, actually, a fair amount in animal models that looks like the kidney organ expresses a lot more HLA antigens. So they express a lot more antigens that could potentially cause the immune system to attack the organ. So they have to be immunosuppressed a little bit more than the male graphs do. And this is an animal model, and it's fairly well characterized. And when we look at animal models of female heart graphs, it seems that those actually do worse than males, and it's reversed by blocking the estrogen receptor. So one of the interesting theories is that when you have a lot of estrogen around the organ, the donor organ, it can actually stimulate the endothelial cells to recruit the immune system. So it can actually be a pro-inflammatory agent. So if you have more estrogen in the system, that can be pro-inflammatory. And monocytes in particular are cells that get triggered by estrogen and go to the graft. So blocking the estrogen receptor seems to improve this in animal models at least. When we look at primary graft dysfunction is a big problem, and you see here the lungs, you can barely see them. They're all white on both sides. They have oxygen in, and basically the organ just gets stunned after the transplant. It's not so much rejection. It just gets stunned from having no blood flow, being transported, and then transplanted. And in this large study that just came out actually in 2018 from the lung transplant outcomes group, they noticed that one of the biggest predictors for developing primary graft dysfunction was female status. So female status was associated with significantly greater incidents of graft dysfunction after transplant. Now that goes a little bit against what our observations were initially, but it tells you that the story is complicated, and the interactions between gender may be specific to anything from the disease process. If it's pulmonary hypertension might be different than if it's ILD or if it's COPD. And there might be differences in the whole immune milieu, et cetera, but there are clearly differences. One of the studies that we're starting here in February, which is going to allow us to fine tune this, is we're changing the way we're transporting organs. We're starting with lungs, and then we're going to move into hearts as well. Using a device that lets us evaluate and transport the organ and collect samples from the organ throughout transport and treat it and make it better. And it's called the organ care system, so we take this with us in flight. So we're not so much taking the organs on ice anymore. We're actually going to transport them in this device. What we're going to be doing is checking samples from, and we're establishing funding for this, checking samples from different genders to see if we can detect differences in the donor that come, and we think that this is going to give us some clues as to specific disease categories that do better for different genders and what the mechanisms of that might be. Switching gears to heart transplantation. Again, a heart transplant, we do about 2,500 heart transplants a year in the U.S., a similar number of lung transplants. And heart transplants are performed probably in the same way. Again, they're just like lungs, irrespective of gender. The donor organ is protected in the same way. So is there a difference between the outcomes of a heart transplant between females and recipients, and should there be? So a lot of people have looked into this, and there's been about two or three very large-scale registry databases that I want to highlight that have studied this question. And this one in particular by Cush and colleagues that was published in circulation looked at the influence of donor and recipient sex mismatch in heart transplant outcomes, analyzing the ISHLT registry. 6,584 heart transplants, which is incredible. Now this is worldwide. In this, they identified that male recipients of a female donor, not unlike what we had discussed earlier, male recipients of a female donor had a 10% increased chance of dying. So now that's after adjusting for other factors that could be related to this, they still had a 10% increased chance of dying. And when they look at the other way, female recipients of female donors, so females that were matched, female to female, had a 10% decrease in mortality. So I suppose if you had to choose, and if you had the luxury of choosing as a female recipient of a heart transplant, it would be nice if you got a female graft. Those seemed to do the best. Now it is interesting to also note that there are many more transplants done, at least in this era from 1990 to 2008 in males than in females. That's another interesting kind of discrepancy in the field of heart transplantation. And that is probably equalizing out now, but it's certainly notable here. That's a male combo is the most popular. And it does the best. So that's going to slant a lot of the data towards suggesting that maybe males do better with heart transplants. And in fact, that's what seems to be the case when you look at the largest registry. So it's almost opposite to what we saw in lung transplant. Now when we look at this, in this particular study, overall survival out to 20 years, which is great. So that means we have patients surviving very, very long with heart transplants. For males, on average, it was close to about 20, 25%. And females, it was about the same actually. But this just highlights the difference where if you were a male recipient of a female graft, you did worse. And if you were a male recipient of a male donor, you do better. And for females, it's the opposite. Now, could it be that cardiac allograft vasculopathy is at play? That's one of the biggest drivers for rejection or failure of the organ over time is that the coronary artery starts to get thick and narrowed. And this is a known phenomenon, unfortunately, that happens. So they looked at this in this large registry. And when they saw females that had female donors with male recipients, they had a pretty high rate of coronary artery obstruction in the donor. About 40%. So that was pretty high. But it was the same as male to male donor to recipient. So it's hard to say that that is the reason for why the grafts tend to fail afterwards. And it's not entirely clear from this particular study. Another study looked at 67,855 heart transplants by Kazmerik et al. They also identified in this particular study that males did better than females. And when they looked at male donors to male recipients, they had an 84% one-year survival compared to a 79% survival for male donors and female recipients. One thing that's interesting about heart transplanted was shown very nicely in this study is that the five-year survival was not different between genders if they survived beyond one year. So it's that first year that matters a lot when we look at discrepancies between female and male. It almost makes you wonder that, you know, it's that one year you really have to focus on. So anything that could contribute to worse outcomes such as being very sick, very ill at the time of transplant, anything you can possibly modify between genders, you want to do so. So if you're female, you want to get access to transplant centers early. You want to try to be in the best shape possible because if you make it through that first year, the outcomes are going to be the same. How about the waiting list? So this is another hot topic because in the waiting, there's a scarcity of organs. So unfortunately we can't really choose, you know, what we want. If we want a female or a male donor, you don't get that many choices. And hearts even worse than with lungs because with lungs you can get single rights or single lefts. In March it's even more rare. So 16% of patients die on the waiting list. That's a huge number. So 16% of people die. The chances of a female dying compared to a male is three to one. So females tend to have a much more likelihood on average of dying on the wait list, three to one. And this was a very good study looking at this in the Journal of Circulation this year. Sex differences in mortality based on the UNOS status while awaiting heart transplant. With risk adjustment, so trying to put all the comorbidities such as hypertension and diabetes together, female status was still a significant hazard for death, especially for UNO status one. So what is status one? So status one is the sickest of patients. So if you're particularly sick on the wait list and you're female, that is the one that seems to do the worse. And it's unclear. We don't truly know why. We have no idea why. And you can see this here. You know status one A, females do worse than male. You know status one B, it was the same thing. But you know status two, which is a little more stable. And status three, it's the reverse. Females do better than males. So what it kind of drives you to think or postulate is that if you're female and have heart failure, first off you want to try to recognize it early, get treated early. And ideally you want to be on the wait list not when you're really sick, but when you're in better shape. Because then you'll do better on the wait list to be more likely to be transplanted. This was an interesting study, the new heart study that looked at EKG monitors for all new donors. And so they basically wanted to look to see if there were any subtle signals in the EKG that could predict whether a donor was going to reject or not. And it was a nice database and it was prospective and it allowed us to get other information. Several centers involved in this. There was a publication that really zoned in on the effects of gender on the donor graft and had a couple of interesting observations. When you compare females to males in this cohort, the male patients seem to be sicker. So in terms of the comorbidities, not so much their unostatus or their inter-max status, but they seem to have more comorbidities like diabetes, 42% versus 21% for females. Hypertension is 63% versus 49%. Dislipidemia, elevated cholesterol, 62% versus 45%. History is smoking way more likely, 52% versus 35%. 26% is schemic heart disease, so from coronary blockages versus 12%. So on the whole, and 35% more likely to have a ventricular assist device. So on paper you would think that the male's going to do worse with this particular cohort. Despite that, women had a greater episode of rejection than men did. Even though the men had more comorbidities and were sicker, women also had more hospitalizations in this cohort. Now thankfully there was no difference in mortality afterwards, but you have to assume it's a pretty small group. So I think that this probably was going to, if one group was going to do worse, it was going to be the males because they were very ill, they had assist supports, they had diabetes, cholesterol, etc. So the fact that they was equal suggests that there is some disparity there. And if you probably had more numbers, you would see what they saw in the larger databases, where males did a little bit better. A couple of different mechanisms that could be responsible. Cell death is a process that kind of involves the immune system, but also is a little bit irrespective of that. And it happens whenever you take any organ and you have it without blood and oxygen, and you transplant it and you give it brand new oxygen, the cells die, just like they die in a program fashion as people get older in life. But they die very fast from this brand new introduction of blood flow. It's called a schemia reperfusion. So this particular study looked at, it was kind of interesting, it took biopsies of every donor organ both before it was transplanted, when it was transplanted, and then a week after it was transplanted to see if they can detect differences between gender. So cell death happens in a very structured way, a very programmed manner. That's called apoptotic cell death. There's also a second type of cell death that's called necrotic cell death. This is from a publication I had just a few years ago that the mitochondria get kind of ravaged after 10, 20 minutes. You can see them very, very fragmented and burnt out by a lot of production of free radicals that happens when they're devoid of oxygen. So these are in cardiomyocytes. This is more of a necrotic cell death pattern as opposed to the program. In this study that analyzed the donor hearts, they found that females had significantly higher amounts of necrosis or evidence of necrosis based on the markers that they looked at in the donors. So after the donors were transplanted, they detected more necrosis, more of a necrotic pathway in those donors than the males did. And when they looked at the apoptotic, which is a more structured, more programmed cell death that's responsible for aging, for instance, in the apoptotic cell there was really no difference between the males and the females, although there was definitely more apoptosis one week after the transplant for both genders. So it tells us that necrotic cell death pathways may be accelerated in females compared to males. When they looked at other apoptotic cell death markers, there was really no difference between the genders. Switching gears for a moment now to mechanical support. So when we talk about transplant, a lot of times because there are so many deaths on the waiting list, we have people on mechanical support because there's just not enough donor organs to go around. So thankfully we have ventricular assist devices which were in many ways not only invented but tested and pioneered here at this very institution that we're talking in, which is phenomenal by our very own Dr. Frazier and colleagues. So this is a ventricular assist device. I'm sure many of you know what this looks like, but it takes blood away from the ventricle, pumps it into the aorta, and it works great. And we're using it more and more now for a variety of cases where we think that somebody maybe, even people might be too high risk for a certain operation, sometimes it will go straight to a ventricular assist device. Or if a person is waiting for a heart transplant or waiting for a long time and we think they'll do better with a ventricular assist device, we'll do that. Is it possible that there are differences though in outcomes for ventricular assist devices between females? And that was one of the tasks of this talk. But I looked into this and it seems like there are. So I'm going to take you through a couple of them. The most important, the most significant up front is bleeding. So bleeding complications are pretty important with ventricular assist devices because you have to be on a blood thinner. So you have to because it's a mechanical device. And if you stop the blood thinner, you can have a stroke. So you have to be on a blood thinner. And this particular publication at the end of last year by Yavar and colleagues, they found that the freedom from bleeding was significantly better if you were male compared to females. So females had a way greater chance of having bleeding with ventricular assist devices even when they controlled for other risk factors. This is the breakdown of the different causes for bleeding. Gynecologic was not an insignificant portion of the bleeding, but females had a greater amount of gynecological as well as nasal pharyngeal bleeding. And so they speculate that there might be something in the mucosa that is different between the genders that allows for more bleeding in females than in males. How about stroke? Stroke is another major comorbidity that we think about with ventricular assist devices because you have this pumping constantly into the aorta and that pumps to the head. So there is definitely a risk of stroke with any of these devices. And could there be a difference in the risk of stroke between genders? In this particular study published the end of last year, looked at the Intermax Analysis, which is our largest registry for ventricular assist devices and compared various risk factors and outcomes. They looked at 7,000 LVAD patients. There was a 10% stroke rate overall, which is very, really pretty high. Female sex was associated with a 50% increase in the rate of strokes with VADs compared to males, so 50% more likely to have a stroke. They didn't have obviously a clear explanation for that, but they hypothesized that maybe it's the endogenous estrogen production, which is a little bit more pro-thrombotic. And that could potentially be responsible for greater amount of clot formation, greater amount of stroke. Of course you could also hypothesize that maybe it's because they had so much more bleeding that stopping anticoagulation could lead to stroke. So it's unclear, but clearly there's a discrepancy in two very large scale databases in these two important morbidities. This study by Bloomer and colleagues published in last year looked at sex-specific outcome disparities in patients receiving continuous flow LVADs and reviewed a variety of different studies. Again, there was in this one a 90% increase in stroke risk for females compared to males. Females were also twice as likely to need a right ventricular assist device. So right ventricular assist device is what I consider probably the third most important, I hate to rank them, but the third most significant problem that we can have after an LVAD. The LVAD is by definition left ventricular support, so it relies on the right ventricle in order to function. So if the right ventricle fails, now we have a problem because you're going to need also a right ventricular support device. You're going to need both. So the fact that females were twice as likely to fail on the right side is very significant and important to note. They did have in this meta-analysis, which is pulling together all the studies together on average, they noticed the similarities in renal failure. They did not detect a difference in bleeding and infections were the same. There were similar mortality for both groups. In this study now looking at a different pump, this is one that's coming out now that we're analyzing here at the Texas Heart and a couple of other centers. This is a momentum three trial looking at the heart mate three, which is a smaller pump. So could it be that there are differences in pumps that relate to issues between genders much more so than the gender itself? It's possible. In this particular trial, the preliminary data that was released probably at the request of the FDA demonstrated that the outcomes for males and females in terms of predicted probability of death or stroke or re-operation was the same. So that's real good. It tells us that this particular device, the heart mate three thus far with the first couple of hundred patients functions the same irrespective of gender. How about a broader worldwide European VAD registry? So this looked at gender differences in the EuroMax, which is the European registry for patients with mechanical circulatory support. This was kind of neat because they highlighted all the individual differences in the types of patients, comorbidities and characteristics between males and females receiving a VAD in Europe. So they had 815 men compared to 151 women. So right away that tells you there's a little bit of a discrepancy there in terms of, and it's unclear why more men would be getting VADs than females, not unlike the story with heart transplants. When you look at the ages, they were about the same. Males were a little bit older. The amount of smoking was significantly higher in the males. Also the amount of cardiomyopathy was significantly higher in the males due to coronary blockages was significantly higher in the males and dilated cardiomyopathy was significantly higher in the males. The males had a little bit higher risk profile than the females did. This breaks down the differences in complications. So when they looked at ischemic strokes, the females had a 8% incidence of that, a 0.08% per month incidence of ischemic stroke compared to males, which was not significant. There was also no difference in bleeding in the brain. Major infection was the same. Renal dysfunction a little bit more with females than males. Pump thrombosis was about the same. RV failure was significantly, ribentricular failure was significantly greater in the females and in the males. That was consistent with the data that we had from Intermax in the U.S. Erythmias was also a little bit greater in females and major bleeding was greater than females. So the European data is sort of similar to the U.S. data. This just further clarifies that the events, the percent events per one month of ischemic strokes, about 1.55 in men compared to 2.5 in women. So even though it wasn't statistically significant, it's very possible that if they had more patients, they would have seen a difference with more strokes in females than in males. And this just kind of highlights this a little bit more. When they looked at survival probability, the chances of surviving was higher with males than it was with females. So in conclusion, there does seem to be differences for women and men in thoracic organ transplant. It seems like women do actually better with lung transplant than males do for reasons that are not entirely understood. Males seem to do a little better than females on average for heart transplants. Women do slightly worse with vans, and some of that seems to be due to bleeding, RV dysfunction, or strokes. These results likely can be improved with increased awareness, with restructuring or awareness of access to care for both genders, risk factor modifications, getting patients in earlier, making sure patients are being followed early with their primary care providers and cardiologists, and probably making some adjustments in anticoagulation regimens and immunosuppression, depending on the gender. There needs to be greater awareness of right ventricular dysfunction, I think, in females compared to males. It's a very important thing. But every time we go back to do an ILVAD, we think about what are the chances of them having our right ventricular dysfunction. My partner Dr. Morgan has come up with beautiful algorithms for determining that, but I think that we have to think more about the possibility of it happening in females and what we're going to do to adjust for that or to predict that. There needs to be further research into methods of gender-specific tailored regimens, and hopefully here with our study on blood-related factors between genders, we'll be able to find additional mechanisms that can help tailor our therapies further. So with that, I want to thank you again for letting me talk to you guys about this topic, and I'll take any questions.