 Good afternoon. It's my pleasure to be here. It's also an honor to share the virtual heart failure podium with Illuminary in the Field, Dr. Joe Rogers. I've been given a somewhat difficult task in that I've been asked to provide a balanced and nuanced discussion of heart transplantation and LVAD support in women, but I've been asked to do it in under 10 minutes. So given the very severe time constraints, I'm only going to be able to provide a very broad overview, but I hope to touch on some of the most important points. And the way that I plan on doing this is by defining the concept of advanced heart failure and discussing the clinical significance of the diagnosis and transition to a review of women's access to heart transplantation and sex-specific outcomes, followed by discussion of sex-specific survival and adverse event rates following LVAD implantation and winding up with a few comments regarding a potential sex-based bias in referrals for advanced heart failure therapies. Over 75,000 people per year in the United States die of, quote, advanced heart failure and over half of them are women. Advanced heart failure can be broadly defined as persistently severe heart failure despite maximally tolerated guideline-directed medical therapy and adherence to lifestyle modifications. The European Society of Cardiology provides us a more granular description of advanced heart failure, defining it as patients with persistent New York Heart Association functional class 3-4 symptoms with clinical signs of fluid retention and or low cardiac output with objective evidence of severe LV dysfunction and severe reduction in exercise capacity or functional capacity with at least two hospitalizations over a six-month period and the presence of all the above despite optimal tolerated guideline-directed and device therapy for heart failure. It's important to tease out the subpopulation of heart failure patients that have advanced heart failure because overall these patients do not do well on oral medical therapy. There have been at least four landmark clinical trials looking at mortality on medical therapy in the advanced heart failure population demonstrating a one-year mortality somewhere between 60 and 94 percent. So this approaches the mortality with severe aggressive forms of cancer and lands somewhere between metastatic lung cancer and pancreatic cancer. Because these patients have such a poor survival on oral medical therapy, they are the patients that we want to direct toward our advanced therapies, which are heart transplantation and durable mechanical circulatory support, typically with an LVAD. For eligible, and that's the keyword, eligible advanced heart failure patients, heart transplant affords the best outcome. We can expect would transplant a one-year survival of about 91 percent with a median survival somewhere between 11 and 12 years and improve quality of life. So if heart transplant affords the best outcome in eligible patients, how many women have access to heart transplant? Well, we can start to get our hands around this by looking at the number of patients placed on a heart transplant list per year. This is data from the US OPTN registry. This is looking at the number of patients placed on the heart transplant active list per year. You can see from 2005 to 2015 to 2018, there were more and more patients added each year. Although even though from 2015 to 2018, there was a slight increase in the percentage of women added to the wait list, women still remain vastly underrepresented and only represent about a quarter of the patients referred and listed for transplant, suggesting that patient women really do not have the access that they deserve to this therapy. Once women are added to the wait list, how do they compare to men? There are some very clearly defined sex differences in baseline characteristics. At the time of listing, women are more likely to be younger, non-white, have a lower BMI, have dilated cardiomyopathy, have a worse functional status but yet better invasive hemodynamics, have Medicaid as their insurance and be on inotropic therapy. Women are less likely to have an ischemic etiology for their heart failure, have diabetes, be hypertensive, use tobacco, have an ICD in place and importantly be on LVAD support at the time of listing. Once women are listed for transplant, how do they compare to men with regards to survival? Unfortunately, women have an overall worst survival, a higher mortality while they wait for a transplant. This is data from the scientific registry of transplant recipients looking at survival stratified by their weightless status at the time that they were listed for transplant. On the left, we have the UNOS 1A which at the time was the most urgent transplant listing status and you can see that women overall have a worse survival compared to men while waiting 1A for a transplant. In the middle, we have the next tier of severity, the UNOS 1B and again, women have higher mortality, worse survival while waiting for a transplant, waiting status 1B. On the less urgent status, status 2, women actually had a slightly better survival than men, but overall if you add all three statuses together, women have a worse survival, higher mortality while waiting for a heart transplant. The reason for this remains unclear but it's led some experts to suggest that we should consider perhaps having sex-specific criteria for heart transplant weightlifting to account for this difference in mortality while patients wait for a heart transplant. After patients are transplanted, there are again some sex-specific differences. This is data from the International Society for Heart and Lung Transplant Registry looking at survival in men versus women for transplants performed between 1982 and 2015 and you can see that women actually have a better survival than men. Women had a median survival of 11.5 years versus 10.5 years in men. So after a heart transplant, women had better long-term survival. They had a lower risk of cardiac allograft vasculopathy. They had lower risk of malignancy but did have a slightly higher risk of antibody mediator rejection. So we had a brief discussion of women in transplant. I want to move on to women in left ventricular assist device support. Before we dive into sex-specific differences in outcomes, I want to spend a moment talking about the rationale for LVAD support or try to answer the question that I get every Thursday in heart failure clinic, which is why can't I just get a heart transplant? And this is a very important question because if we know that heart transplant affords the best outcome, then why would we ever use mechanical circulatory support? And I don't want to trivialize the issue, but I do like this quote from Lynn Warner Stevenson. A heart transplant is the answer to heart failure the way the lottery is the answer to poverty. And what she's really trying to say is that a heart transplant is a wonderful thing if a patient gets it, but the vast majority of patients with advanced heart failure are not going to receive a heart transplant. Well, why not? Well, the truth is that at the time of referral, most patients are not candidates for heart transplant and that may be because they're too old, they're too big, they've had a prior malignancy, they have pulmonary hypertension, they may be too frail, they have end-organ dysfunction and we're not sure how much the end-organ dysfunction will improve after transplant and that leads us to the concept of LVADS as a bridge to decision or a bridge to candidacy and often will place an LVAD and then reassess the patient after cardiac output has been restored as to their candidacy for heart transplantation. Another very important reason is that donor organs demand vastly exceeds the supply. This leads to a potentially very long weightless time with a potentially high mortality while patients wait for a heart transplant. This leads us to the concept of LVADS as a bridge to transplant, which we implant LVADS to keep a patient both alive and healthy as they await for transplant. And there's a wealth of data to support improved weightless and transplant survival after LVAD implantation. If we're going to try to tease out sex-specific differences after LVAD implantation, it's important to recognize that women are vastly underrepresented in the large randomized LVAD controlled trials. So I have a couple of examples here. On the left, I have the heart-wear bridge to transplant trial in which there were only about 25% of women enrolled. In the middle, we have the heart-wear destination therapy trial, which only enrolled 22% women and on the right, we have the landmark momentum trial with the heart-mate 3LVAD that only enrolled 19% women. The relatively low percentage of women involved in these trials really complicates using these datasets to look for sex-specific differences in outcomes. We can turn to our registry data to try to get some information. This is data from the Intermax Registry, which captures most of the FDA-approved LVAD implants. This is data for survival LVADs implanted between 2006 and 2010. And what you can see is there was no difference in survival between men and women that received the older pulsatile flow LVADs and there's no difference in survival between men and women with the newer continuous flow LVADs. Unfortunately, this data is a little bit difficult to apply to our modern practice. The Intermax dataset does not discriminate between different types of continuous flow LVADs and this dataset includes LVADs that are currently no longer clinically relevant. Both the heart-mate 3 and the HVAD hardware device are the two continuous flow LVADs that have been most recently used. The hardware LVAD endurance trial, which was their destination therapy trial, did not report sex-specific data. However, their bridge to transplant trial, the so-called advanced trial, plus their continuous access protocol did specifically look for sex-based differences. And in this combined dataset, there were 236 men and 96 women, so 41% were women. And in this dataset, there was no difference in survival or stroke at 180 days or one year and men compared to women. There were some differences in advert event rates with women having increased incidence of right heart failure, renal dysfunction, respiratory dysfunction and a longer length of stay. If we're trying to look at sex-based outcome differences with the heart-mate 3 LVAD, the data is even more scarce and we really have to turn towards single-center observational cohorts. So this is data from the Columbia University experience with the heart-mate 3 LVAD. This was presented at the International Society for Heart and Lung Transplant Meeting in 2019. And what they found was compared to men, women with the heart-mate 3 had similar incidence of guideline-directed medical therapy and intermax profiles at the time of implant. There was no difference in post-implant survival at three years. There was no difference in gastrointestinal bleeding and there was no difference in the incidence of stroke. So I'm going to wind up with some take-home messages. Mortality on medical therapy and advanced heart failure is high in both men and women. Heart transplantation and LVAD support both improve survival and advanced heart failure in men and women. Women have worse survival while waiting for heart transplant compared to men. Once transplanted, women have overall better survival compared to men. There's no difference in survival following LVAD implantation for men versus women. There's no difference in major complications in men versus women following LVAD implantation with the contemporary continuous flow devices. And compared to men, proportionally fewer women undergo potentially life-saving heart transplantation and LVAD support suggesting a potential sex-specific referral bias. And it is my sincere hope that by presenting this information to you today and demonstrating that women actually have a better survival after heart transplantation, have equal survival after LVAD implantation and no increase in adverse event rates after LVAD implantation that we can overcome this referral bias and increase referrals of women with advanced heart failure to the life-saving therapies that they both need and deserve. Thank you.