Good afternoon, everybody, and welcome to the final day of CHESS 2023 here in beautiful Honolulu. I'm Dave Shulman, I'm here in my role as past president to, and actually the best role of past president of all the presidents, is really to recognize the outstanding things our membership do. And so today, I am here to formally announce an award, an honor lecture, and I'll get into it in a moment. The Distinguished Scientist Honor Lecture in Cardiopulmonary Physiology was established back in 1973. And has since been given to a well-respected and published original investigator in pulmonary and critical care physiology. As you all know, this year it's my privilege and pleasure to present this award to Dr. Jane Elwing. Dr. Elwing has been faculty at the College of Medicine at the University of Cincinnati since 2007. Currently a professor of medicine, excuse me, and the director of the Pulmonary Hypertension Program in the division of Pulmonary Critical Care and Sleep Medicine. Her clinical and research focus is pulmonary vascular disease and pulmonary hypertension. She has shown a strong interest in medical education, has been very involved with the American College of Chest Physicians since fellowship, when she had an opportunity to participate in the chest leadership and education workshops early in her career. This is a launching pad for future involvement in chest. She's been a leader in the chest pulmonary vascular network since 2018, and is the current chair of the Pulmonary Vascular and Cardiovascular Network. Over the last three years, she's been awarded the Chest Distinguished Educator Award and has served on the Scientific Program Committee since 2019. She remains highly engaged and active with chest and is sincerely appreciative of all the opportunities chest has provided to her to educate, grow, and lead over the last two decades. There's a last part, but I'm gonna go off script for a minute and just to say a few words. I have not had the pleasure of working with Jane, but I have heard from many individuals who have had the pleasure of working with her, underneath her, have appreciated the hard work and dedication, the education, the amazing things she's brought to chest. In large part, it is because of people like Dr. Elwing that chest has achieved the kinds of things it has and has put together the program it has for the benefit of everybody here and those who've attended other meetings. So, ladies and gentlemen, I ask that you join me in welcoming Dr. Jean Elwing to present the Distinguished Scientist in Cardiopulmonary Physiology on our lecture. So we are gonna be talking about the flow of progress in pulmonary hypertension, from pathologic descriptors to understanding complex mechanisms, and we're gonna do that in an hour. So let's see how we do. This morning, I took some out because I was like, oh, it's just too big. So, all right. And as we know, I've been here with chest, working with all of you for quite some years, and this is so much fun for me. I'm so happy with everybody's successful lectures and sessions this year. It just makes me so proud. So thank you for supporting me and coming to my lecture. So what I want to make sure we start with is understanding pulmonary hypertension. It's a common cardiovascular syndrome characterized by elevated pulmonary pressures and many underlying conditions. The observed prevalence has doubled in the last 10 years, and it's estimated to affect about 1% of the total population globally. The most common cause of pulmonary hypertension worldwide is left heart disease followed by lung disease. But regardless of etiology, it portends a poor prognosis, and we need to understand the underlying cause to best address it. Pulmonary arterial hypertension is rare, progressive vasculopathy, leading to right heart failure and ultimately patient demise. Today, we're going to focus on PAH, and we're going to take a journey with the discovery of this condition. All right. This is what we understand now. This is a multifactorial process, narrowing vessels, changing vessels, and ultimately leading to that increased vascular resistance and right heart failure. It took many brave, brilliant, and dedicated people to get us where we are now. So what I want to do today is really examine the history of our current understanding, and then go through a little bit of epidemiology and clinical features, summarize our progress, and review some clinical trials, and see how we're moving the needle, and discuss the future. So let's start with the early history. And what are we talking about when we talk about early? Dr. Galen, who lived 129 to 216. He was a Greek physician, writer, and philosopher. He had a dominant influence on medical theory and practice in Europe from the Middle Ages to the 17th century. He did have a lot of insight. He believed the blood was produced in the liver, so maybe, reached the right side of the heart by the vena cava, but he's connecting the dots here. Pulmonary artery, which he conceived to actually nourish the lungs. But he did note that it came from the right side of the heart. He theorized a small amount of blood seeps through the lungs from the pulmonary vein, and then is exposed to air, where it becomes nourished. But the blood actually didn't go through the lung vasculature, it went through the interventricular septum in his understanding. So although he was not aware there was a pulmonary vascular circuit, he did demonstrate that there was not air in the vessels, but rather blood, which was a big step. Now, there is this gentleman, Dr. Al-Nafis, who is actually not very recognized. He's an Arab physician who was born near Damascus, and then he moved to Egypt. And he made several very important contributions to the early knowledge in the Islamic Golden Age. He was the first person to really challenge Galen. And he said that the blood could pass through the lungs, and did not pass through the interventricular septum. So that was a big step. He didn't get credit for this, but when Dr. Al-Tawani was going through information in the 1920s, he found a manuscript describing this, and brought it to attention. And in that manuscript, it says, when the blood has become thin, it's passed through the arterial vein, which is what they're referring to as the pulmonary artery, to the lung, in order to be dispersed into the substance of the lung, and mixed with air. So describing this vasculature we know now as our pulmonary vascular tree. Then there's Dr. Michael Serratius. He was from Spain. He didn't fare very well with his description of the pulmonary circulation. He wrote about it in a book about Christianity, and he noted air mixed with blood was sent to the lungs, and then to the heart. And that was actually not well accepted. The church accused him of heresy, for denying the Trinity, and opposing Galen, and he was actually burned at the stake. So be careful about that pulmonary vasculature. So it can get you. But the same arrangement was transfusion of the blood from the portal vein to the vena cava occurs in the liver. He said it also happened in the lungs. So he was describing that vasculature. Now, at about the same time, a Flemish anatomist described the pulmonary circulation. But it actually took him a little time to understand what was happening. His first book, he agreed with Galen. And then he came back in a book in about 10 years later, and he took that statement out. And he said, I still do not see how even the smallest quantity of blood can be transfused through the substance of the septum of the right ventricle to the left ventricle. So understanding that that was a muscle that was probably not being permeated by liters of blood every minute. So he said, however much the pits may be apparent, yet not as far as I can comprehend by my senses, passes through the septum of the heart from the right ventricle to the left. So getting a better understanding. Remember, there's no microscopes at this time. Now, he had a person who trained with him, Dr. Colombo, and he took on his role and became the chair of surgery in the same location. And he really took this to the next level. And although this pulmonary circulation had been previously described by Dr. Al-Nafis, he did not know that. And he actually took credit for describing the pulmonary circulation. And so many times when you read, this gentleman gets credit. So he wrote, the function of the pulmonary vein is to lead blood with air from the lungs to the left of the heart. If you observe cadavers, as well as living animals, you will always find the pulmonary vein full of blood. So in these quotes, I tell you today, it's so much different than it was 10 years ago. You can find amazing things if you just keep searching in the internet. Now, when do we really get an understanding of small vessels and capillaries? Well, it's Dr. Malpighimi who had the first microscope. This was an Italian scientist who made outstanding contributions in many areas. He was the first biologist to make use of the newly invented microscope and is best known as the discoverer of the pulmonary capillaries and alveoli. So what did he say? By diligent investigation, I have found the whole mass of the lungs with the vessels going out of it attached to an aggregate of very light and very thin membranes, which tense and sinuous form almost an infinite number of orbicular vesicles and cavities, such as we see in the honeycomb of the alveoli of bees. So it kind of gives you an idea of where we get some of our terminology. But a beautiful description of this mass he's seeing in the lungs. Okay, so now we know there's a pulmonary vasculature and we know that this is important, of course, to advancing the understanding of this disease. But now we've got to talk about pulmonary vasculopathy and how we found out about that. Now, Julius Klopp is from the 1800s. He was a pathologist from Austria. He had a patient in 1865 who died of progressive ankylodema, dyspnea, and cyanosis. Post-mortem, he saw these small pulmonary vessels and right ventricular hypertrophy. And he said that this sometimes happens with inflammation, but there's very limited information about him and he does not get credit for finding pulmonary vasculopathy, unfortunately. So he described an endarteritis pulmonalis deformans, so a disease that was characterized by an increase in the mass of the inner lying skin, which grows out to form pseudomembranous connective tissue. But he was really the first descriptor. Who gets credit for it? Ernst von Romberg. He's a German physician, he must have been louder. He assessed a 24-year-old in 1891 who suffered from severe dyspnea, drowsiness, and cyanosis prior to death. Post-mortem, he saw pulmonary vascular disease with increased thickness of the pulmonary arteries and termed it pulmonary vascular sclerosis, okay? And he noted that he remained bewildered by the etiology of the pulmonary artery thickening and he could not confirm any coexisting lung or cardiac disease which contributed to its development. And that was the one thing about him that was different than the previous gentleman. It seemed that he thought it was idiopathic or primary. All right, now simultaneously, we have Dr. Erza. He is a professor in Buenos Aires, Argentina. He was lecturing on this clinical syndrome of pulmonary vascular disease, similar to von Romberg's case. And he described a young patient in 1901 who died three weeks after admission and the autopsy showed enlargement of the right heart, right wall thickening, right atrium dilation, but everything else looked pretty normal. And histologically, the pulmonary arteries were hyperplastic and the middle layer and the intima were abnormal. So he said this was different than other entities he's seen at the time. And he actually called it a black heart because of the severe cyanosis. And that is the thing that's a little bit different than what he describes versus von Romberg. Von Romberg's patient became cyanotic at end of life. So there's a little argument about that. So one of Erza's students later named pulmonary hypertension after Dr. Erza, but in 1913, he decided it was related to syphilis. And that was the one thing that got him a little bit off track because we weren't able to reproduce that. So Oscar Brenner, he was from Massachusetts General. He saw more than 100 cases of this condition of people with pulmonary hypertension. And he reported, yeah, they have cyanosis, but they're not that black color in terms of cyanosis that Erza described. And they actually had a little warring and a little in their writings that they really disagreed. Primary pulmonary vascular sclerosis was described, and he noted it to be a rare condition, even though he saw 100 of them. He identified these as idiopathic, or at that time, primary pulmonary arterial lesions. So he noted that these patients had significant hyperteria at the right ventricle, and he really believed that there was this vascular sclerosis and it was primary in many patients. And really, I think this is where the terminology PPH, or primary pulmonary hypertension, started. He went on, as I said, this is a little warring ideas, in 1921 and said, basically, that's not syphilis. You are wrong. The one thing he didn't connect is he really didn't connect the RV abnormalities to the pulmonary vascular abnormalities. So that was really later that we understood that. All right, so now we've got to try to figure out how to look at this, how to image it, and how to really understand it. In the meantime, and I actually took this section out because it got a little big, but people were reporting associated conditions. People in Cairo were noting schistosomiasis was associated with pulmonary vascular lesions, and people were reporting chronic pulmonary emboli, and so we were gathering all of this information as we're trying to understand it more. And this, actually, I thought you all would be interested in one of the first diagnostic assessment was the Heiler dance, and they used this until the 50s. So you'd have systole and diastole, and you'd see the dancing of the pulmonary artery getting larger and smaller, and larger and smaller, in which you can see here. So thank goodness we don't do that anymore. That would be a lot of fluoro. And then they said, another person said, a naysayer, well, that's just because there's big cardiac output and stroke volume, and so they had people run up the stairs and see if they could reproduce it. You can't. Your pulmonary artery does not do that unless you have true pulmonary vasculopathy and increased pulmonary hypertension, pulmonary pressures with increased resistance. So how did we get from there to invasive hemodynamics? Well, this was actually an interesting find. French physicians, physiologists in the 1800s were doing heart casts on horses, and they have their text available on the internet. If you speak French, and you can read French, you can read it, but it has all of the waveforms and beautifully described information about this. So take a look if you can, just of interest. All right, and then coming in is Fick. You know, we talk about Fick. How long a paper do you think Fick's paper is about the Fick equation? Well, I have it right here. It's a little bit longer than this, but that's it. But you have to be able to read German. But you can find all of these interesting things. He was a mathematician, physicist, physiologist, and his major research area was muscular contraction, but he, of course, helped us understand cardiac output. And you need to know that to get to the next step. People were wanting to get into the pulmonary artery and get blood so they could use the Fick equation. This gentleman, Mr. Forsman, who is a urologist, just wanted to be able to do a procedure. So he's a fascinating gentleman. So he's like, they can cast horses. Why can't I cast people? Well, he's really a urologist first. But he still wanted to do it. His bosses said no. And he's like, well, what if I do it on myself? Absolutely no. But he found a nurse who would help him in 1929, dear Gerda. And he actually got her to help. You know, we need our nurses to help us prep and get all our supplies. And then he tied her down and cast himself. No lie. You can find everything in the literature. So this is supposed to be a picture of her, but I could not find her on any, I could not find her to verify that. But this is a picture of him with a nurse that unfortunately probably would have sued him today. And this is a picture which is supposed to be the urinary catheter that he used to catheterize himself. And it actually just went to this location. And he went, he got up, got his X-ray, and then he danced it further. So fascinating work. But, and then of course he was fired. But it later won the Nobel Prize, so that's interesting. So here, then we got some cardiologists interested in hemodynamics. And Cornand and Richards, they were at Columbia, and they said, we can do this. And so they started doing heart catheterizations and got blood, they got into the right atrium, and it took about five years until they got out to the pulmonary arteries. And in 1959, with Dr. Forsman, they got a triple Nobel Prize for the development of hemodynamic assessment with heart catheterization. So, so important, a huge finding, but they got there through tying down a nurse. All right, so how did we get to where we are today? Well, it took Swann and Ganz to really figure out how to get a flow-directed catheter. So they had to get a device that would flow with the blood. And the story is that they were watching a sailboat, watching it go down the water, and said, huh, maybe we can do that with some sort of a sail. And now, of course, we've got infusion pours, and we've made this a, you know, a very useful tool that we still use, brand Swann-Ganz. All right, so here's the timeline. We've got Forsman trying out the catheter, and then really starting to use it for clinical assessment at Columbia. They get the Nobel Prize, and then we started to really advance the use of the right heart catheterization to be able to assess patients. Okay, what happened then? Then we made a drug that helped people lose weight, but also triggered them to have significant pulmonary vascular disease. I always say, if something makes you lose weight, it's something, you gotta be careful, because that's never easy. So what was the response, and how did we do with that? Well, in the 1960s, we're in the epidemic of pulmonary arterial hypertension. It followed the consumption of Menorex, which was a catechol derivative. It was sold over the counter. So quickly, the drug was released, and then it was recalled. Not very long period of time. And nearly half of the people who developed pulmonary hypertension had passed away within 10 years after that. So that triggered the first World Health Organization meeting to try to understand this condition, in 1973. So we've got, this is, the pace is not as fast as you would like. But still, from initiation of this drug to the first World Health Organization meeting, 1973. Okay. So it releases norepi, increasing concentrations of serotonin. Serotonin stimulates cell growth. This excessive cell growth causes vascular obstruction, and that's how we assume it's causing pulmonary arterial hypertension. You probably have to have the right genetic milieu, and maybe some other triggers, because not everybody developed it. But this is our overall thought process of how this epidemic occurred. All right. So then we got some rhythm with doing these world symposiums to try to get together as a globe on how to manage this condition. I mean, this is like really rare until we really poke the bear a bit with this medication exposure. But look at the time here. We've got 1973, and then we go all the way to 1998, and then we're going at a tempo of every five years going forward. So just know, every five years, you get to learn some new stuff, because we're gonna change something. So this first meeting in Geneva was in 1973. They talked about primary pulmonary hypertension. And they recommended a registry. So the registry actually didn't happen, but the NIH in the U.S. formed a registry just for U.S. patients. And that's where we started to learn about the severity of illness, the short lifespan. And this went on with 32 centers entering patients until 1987. And then as I mentioned, the next world symposium didn't occur until 25 years later. So I want you to just, for a second, think about the pace people were learning things. I'm talking thousands of years now, okay? And we have to learn things so fast. It's amazing to me that we're able to keep up. So things change so fast for us. So we don't have time for a breather. So pulmonary hypertension diagnosis continues to evolve. The world symposium guidelines are very helpful to us. And now we're gonna dive into those and see where we are with diagnosis. And I wanna make sure you're aware of recent changes. Okay, definitions. We were at a definition with a mean pressure of 25 or greater for many years until 2018, 19, when the sixth world symposium changed it to a mean pressure of more than 20. And then we had to define things a little bit better over time because now we are changing, we're lowering that pressure cutoff, we're including more patients. And we actually lowered the pulmonary vascular resistance also because we've learned that pulmonary vascular resistance, even over two portends poor prognosis. And we're trying really to break down subgroups to be able to better put our patients in these manmade groups, so we can manage them more easily. So we have precapillary disease, disease from pulmonary vessels, isolated left heart numbers with increased left-sided filling pressures and normal pulmonary vascular resistance, and then combined disease. And now we even, to make it more complicated, we have taken out exercise and we put it back in. But we didn't say we're gonna treat it. We just said that if you exercise and your pulmonary pressures go up much more than you would expect with your cardiac output, that's a problem. There might be disease of the pulmonary vascular bed and we need to pay attention. All right, I wanna leave you here in these changes with why they changed. Okay, so why did the pressure change from 25 to 20? Is it just arbitrary? Actually not. They looked at the VA data, more than 20,000 veterans, following them for about three years and found that after a mean pressure of 19, mortality increases linearly. So what do you, you're just like, oh, I don't know. That's all forms of pulmonary hypertension, but we're just saying the presence of pulmonary hypertension portends poor prognosis and it starts to take off at the level of 19, 20. And then we say, well, why did we really change that PVR? And that is a little point of contention among many patients or many providers and we'll see what happens as we work through this over the next probably five years. But this was born out of looking at 40,000 veteran data points with right heart catheterization and outcomes for more than three years, and they found that at about a PBR of 2.2, mortality increases significantly. And then people were like, well, those were all older gentlemen in the VA system. They don't really apply to our traditional PAH patient. So Vanderbilt looked at this and found through a validation cohort sex-balanced group that they found the same thing. At that PBR around 2, we have increased mortality. And it's most pronounced, if you look in this section here, in those patients with the pre-capillary pattern, elevated mean PAH pressure, normal wedge, and that increased PBR more than 2. So what about exercise? Okay, exercise has been in and out, and we studied it, and we did clinical trials. As I said, all we can say, if your mean pressure goes up dramatically, much more than your cardiac output, it's abnormal. And what we've used as a cutoff is a slope of more than 3 millimeters of mercury per liter per minute. And that is really normal to be less than that if you're less than 60 years of age, and even most healthy patients above age 60 will be in that normal range. What do we know about heart failure patients? If they go higher than that slope of 3 or greater, they have worse outcomes. Again, we are just at the infancy of understanding how we'll use this going forward. All right, so then we have clinical classifications. How have we changed them over time? How have we modified? Well, we know, as I mentioned, pulmonary hypertension is even more common than it was 10 years ago, 1% of the population. The vast majority are left heart disease, with the PAH and CTEF groups being the small ones, the rare ones. And we know that the vast majority of people will have post-capillary pulmonary hypertension because they're mostly left heart related. But those patients that are pre-capillary could be pulmonary arterial hypertension, hypoxia, chronic PE, and miscellaneous. And of course, we're concentrating on the PAH patients. But let's see how we've changed and tried to adapt the clinical classifications to fit new knowledge. So what ERS ESC did is they said, we have idiopathic patients, and with any idiopathic patients, we have either vasoresponders or acute vasodilator non-responders. So they broke them out to try to strengthen that difference in those acute vasodilator responder patients having a very different outcome when we treat them with calcium channel blockers. But we do know that we can do vasodilator challenges on the idiopathic patients, heritable patients, and drug and toxin patients, even though it's not a subgroup of those. The one thing they also did, which it's a little dance with this, we had PVOD, which is a rare form of PAH, which is very difficult to manage, and PCH, which is a type of pulmonary vascular disease that also affects the capillary bed. And they took it out of a sub-subgroup of group one and put it in as a regular subgroup. So just showing that we're just tweaking those categories a little bit. And the one thing they changed from the World Symposium is they took out sleep apnea and said you really had to be a hypoventilator to get pulmonary hypertension. And that's actually pretty important because it makes us look to those patients that hypoventilate for elevated pulmonary pressures and your routine sleep apnea patients probably not having severe pulmonary hypertension. So here's what the new clinical classification looks like with these changes I mentioned. And then here in the group five, they just kind of cleaned it up. They separated it out and just make it a little bit broader categories to be able to put your patients in because this is unfortunately a wastebasket of disease. We have no idea how to manage properly and we have to over time pull them out, study them so we can see how we can change their outcomes. All right. Pulmonary hypertension providers across the globe have learned about clinical course conditions through clinical trials and registries. Let's just go through the course of disease and see what our current understanding is. We have vasoconstriction, we have arterial changes, we have plexiform lesions, we have thrombosis and recanalization. All of these things are happening. But what's actually happening to our patients? All right. You get some trigger. Maybe in the 70s you were exposed to fentanyl. Maybe you developed lupus and your blood vessels start to change. Because of that, the resistance in the circuit changes. Because of that, the pulmonary pressures start to change. And this disease marches on. You have initial mild symptoms but then it worsens and your right heart is trying to adapt. It's not going to just let this fail. It's getting thicker and stiffer and then it starts to maladapt. The cardiac output starts to go down and your lesions in your lungs get worse to a point of no return. We cannot meet people here and hope to move them all the way down here without significant effort and loss of patience. So of course we've done a great job trying to increase awareness of this condition. But our goal always is to meet people as early as we can in this pathway that they are taking with their pulmonary vascular disease. All right. Hemodynamic assessment for pulmonary hypertension was developed and right heart catheterization numbers were standardized. What does that mean in terms of clinical trials and treatment? All right. So we're figuring out how to diagnose people from right heart cath. We're standardizing how we're using them. We've got the Swann-Gans catheter. What the heck do we do with the data now? Okay, so they tried a lot of drugs. And of course you know none of these really worked but they learned about physiology. So they learned that hypoxemia was bad for the pulmonary vasculature and caused increased pulmonary pressures and they tried different vasodilators. They tried acetylcholine. They tried vasodilators in different circumstances and they even found that sometimes they worked but not uniformly. And then more recently, 1980s to 1990s, they found that calcium channel blockers worked in a subgroup of patients. And that was at the time you would do a calcium channel blocker trial and then use calcium channel blockers if they had effect. But now you know that we're more safely testing patients with acute vasodilators without the negative effects of calcium channel blockers. That could be a whole talk. All right. So at the same time, we're trying to figure out other things. In 1980, 81 was the first heart-lung transplant. 1995, we finished the trial for epiprostanol. And just envision this. 1995, you don't have a lot of resources. You have a telephone and we're giving people continuous IV infusion and say, it's two to five minute half-life. Good luck. Right? Like you can't, you don't have a cell phone. You don't have an internet. You have probably a really clunky pump and a really clunky line. And you didn't even know if you were supposed to flush it then. They were flushing and that was riddled with difficulty. So they figured out in a 12-week trial that you reduced mortality by 20% in patients who were exposed to epiprostanol. Now that lit the fire in terms of treatments and people searching for ways to help patients with pulmonary hypertension. And then 2001 to 2015, a flood of medications were studied and approved. In the three major pathways, prostacyclin, nitric oxide, and endothelin. And here they are. So look at that progress. This is the flow of progress with pulmonary vascular disease. And of course, we will hopefully have a few new ones in the next few years. All right. Currently multiple medications are available and we've learned a great deal over the last three decades about timing and combination. What do the guidelines tell us and how are they so important in patient care? Well, what's our most recent guideline? ERS ESC 2022. And we like to jump to the next guidelines, the next guidelines. So we'll always be talking to you about what's the most recent guidelines. So what does this help us with? This helps us understand, in large groups of patients, which patients are likely to have longer survival and how likely will a patient experience mortality. And we're extrapolating that from registry data, right? So you take a patient, you risk assess, and you put them in a category and you assess their risk of mortality based on a score. And that score was derived by large registry data. But very helpful, because we are not so good at guesstimating how our patient's doing. If you meet a 24-year-old and they can walk into your office, they're not on supplemental oxygen, you might really underestimate how sick they are. Whereas their heart may be really dilated and they may have a very high BNP and their pressures may be through the roof and their cardiac output may be low, but they can mask it. So it's very helpful to get objective data. And with that objective data, we can take what we've learned about our studies and then plug our patients in. So we see our patients, we risk assess them, and we determine, are you high risk? Game over. You're going to get the most aggressive therapy. And you know what the most aggressive therapy is? Go back to that study with epiprostanol, which I told you you would have your phone on. You had your phone to call when your two-minute half-life drug ran out. That's still our best medication in terms of infusion therapies. We have a few options, but we look to infusion therapies for our sickest patients. But if you are less sick, lower intermediate, we can give you combination therapy. And we've learned over the last decade and a half what combinations have the best outcomes. Now, what do we do from there? We don't stop. We used to say stabilization's okay or maybe just don't get any worse. Now what do we want? We want you to be low risk. We want you to walk 440 meters. We want your BNP to be normal and you to be functional class I or II. If you don't get there, what do we do? We give you more medication. And more medication may be adding things or switching things. And if you're intermediate high or high risk, we give you infusion therapy. So this is the only disease that is out there that still can say we are willing to give somebody lifelong medication that's an infusion. There's nothing else like it. We have patients that have been on therapy 20 years and they're still having their line, their drugs, and until we find something better, we're going to continue to do that. All right. Now we have a lot of medications. What's in our future? All right. So our previous focus was vasodilation, vasoregulation, a balance. We used to have a teeter-totter that told us, you know, we have too much vasoconstriction. We need to increase our vasoactive mediators. But we know now that's only part of the story. And I showed you that picture with all the disordered vessels. Of course, vasodilation is not going to fix all that. These drugs do have antiproliferative properties, but that's not their prime focus. These are our backbone of therapy. We could not be here without them, but we need more. Okay. There's been a paradigm shift. It was previously dominated by increased vasoconstrictor tone and thrombosis, and now we're looking at structural changes, cell growth, inflammation, recruitment, infiltration of circulating cells, and we want to attack those. We want to stop those pro-proliferative pathways and see if we can change how those vessels actually look and function. We'll see if we can do that. So here's a normal vessel. Thin-walled, and here's our disease vessel. We have all of this to contend with. And why is that happening? Multiple mechanisms are occurring that are causing this to happen. And that is due in part to vasodysregulation and abnormalities of growth factors and some other things, like hypoxia at the cellular level. So we've got all of these things happening. All right. As I mentioned, we have many things that we will have to look at to be able to potentially reverse or cure this disease, but I want to mention a few of them. Okay. Growth factors. Expression of growth factors is increasing pulmonary arterial hypertension. It's promoting cell proliferation, survival, migration, and vascular remodeling. This is a target, and I'm going to show you how. BMPR2. You're like, ah, that's the genetic form. And it is. 70% of our heritable patients have an abnormal BMPR2 gene with more than 140 distinct mutations, but I'd like to tell you also that our other patients, even without genetic abnormalities, have low BMPR2 expression. If you look in the top panel, semi-quantification of lung tissue shows BMPR2 is lower in people who have associated pulmonary hypertension and primary pulmonary hypertension at that time, which we call idiopathic now, and even lower in the BMPR2 mutation patients. And this is looking at mRNA, and this is showing lower expression of BMPR2 in all different forms of pulmonary arterial hypertension. Idiopathic, heritable, drug and toxin, connective tissue disease, porta-pulmonary hypertension, and congenital heart disease. So it's playing a role, even though the patients do not have a genetic mutation. Inflammation. Inflammation is also playing a role. We think of it in our patients with lupus and sometimes mixed connective tissue disease, but playing a role in our other patients also. It's been very hard to find a solution to this, but I am certain that we'll be continuing to look for drugs that reduce the chemokines and cytokines we see and that impact on growth factors in collagen deposition we see because of inflammation. And then one thing I think is important to also remember is these cells are in a state of stress. There's local hypoxia. There's shifts in their glucose metabolism, oxidative phosphorylation to glycolysis, and this is the same theory we have for the development of cancer. We have dysregulated cell growth. So this is probably back here also playing a role, and maybe correcting some of the other mechanisms would have a positive effect on this. All right. All of that, all of that discussion, all of those amazing people finding things and testing things and putting catheters in their own heart, does it actually matter? Well, let's talk about survival. So you remember after the menorex outbreak, we had the NIH registry, and this is where the NIH registry patients lie in terms of survival. Two years, about 60 percent. Three years, about 50 percent. There was no therapies then. I actually think about those mostly young women with their uncontrolled pulmonary hypertension going to the NIH for this registry. Can you imagine? They had no medicines. They were swollen. They probably had ascites. Probably cyanotic. And they did that for us so we could compare how we were doing going forward. So thank you. So let's look at what we learned from the French registry. 354 patients. This is 2010. I tried to highlight these so you could quickly look at what year it was. And their observed survivorship was improved over the NIH registry, and we were starting to have some of our novel, our modern therapies then. All right. Reveal. A little bit later, 2006 to 2007 for prevalent patients and out to 2009 for incident patients. And three years, almost 70 percent survival. So, again, pushing the envelope, pushing the needle a little bit further towards improved survival. Now we're going to go all the way to 2022 and look at the French registry. More than 2,000 patients could be included, and this helped us understand those patients who were sicker, how long they survived versus the patients who were less sick. And here's our patients with lower status, the one I showed you earlier, how to put them in a category and say they're green and they're doing well versus those in the red category that had the high risk of mortality and separating out. So, yes, we made progress, but those sick patients are still, they are not doing well if we don't intervene. So what if we do intervene and we change the level of risk? So you have an intermediate risk patient, you treat them and then you bring them up to low risk. If we can get them at first follow-up to either be at low risk in terms of move up to low risk or stay at low risk, we have very good life expectancy. This is not 10 months, this is 10 years. Now think of the initial registry, and then you think of these folks that are surviving out 70 percent 10 years. So very different situation. And then you're like, well, but that's only the well patients. They're surviving. I want you to look at these folks. Still, the French registry, they do a beautiful job collecting data for us to review. Triple combination, these are our six patients coming in with high risk features. These are patients who literally have hardly anything that's going in their direction. We treat them aggressively at first follow-up, and we've changed somebody who has 0 or 1 low risk feature, and we pop them over here, and they can have four low risk features. So what does that mean? That we just put this patient up here. It's not easy. It's three drugs. It's still that half-life that may be 2 to 5 minutes or an infusion therapy that's four hours, but still a lot of work for a patient, but we have truly changed that person's life. Okay, so what about long-term? Big groups? We can, if we offer transplant, we can say to our patients, if we're aggressive, if we stay on track, in groups of patients, we can exceed that 80 percent survival if we include transplant as an option at 10 years based on the French registry data. If we don't include transplant, we still have a 70 percent survival even in our sickest patients at 10 years. So much different than when you used to meet a PAH patient, and they would say, get your affairs in order, sell your house, get your finances, write your will, because you're not going to be here very long. And that actually was very consistently happening for our patients. Outcomes have improved, but we haven't cured the disease. But there's exciting things coming. So what do we have here? We have multiple pathways, and you're like, oh my God, busy slide, but I'm going to pop it out for you. Remember how I told you earlier, growth factors? Well, we have drugs that work through and addressing growth factor issues, and we also have drugs that can affect the BMPR2 pathway. So all those things I mentioned that we're understanding, we're actually real-time assessing, and hopefully we'll be able to use those pathways to better knock down this disease. Okay, so what progress has been made recently in the drug arena? Well, one medication called cetatorcept is trying to balance out that low BMPR2 effect we see in our idiopathic and associated PIH patients, and that is a medication we've studied. The study is called the STELLAR trial. We were involved in that, and using a medication every three weeks that tries to bind activin and reset the balance of BMPR2. So what did we show? We showed in the phase two studies we could impact pulmonary vascular resistance, and in the phase three study, we helped people be more functional, walk further, and we met eight of the nine secondary endpoints. So across the board, looking like this drug helps people function and also improves many other factors. Every three weeks, injection, very different than the two to five minute or four hour half-life continuous infusion therapy. Is it going to replace our other drugs? We don't have any intention of that. We're going to have to figure out how to use this medication in our current structure of treatment, but we do have a therapy that's been shown to be effective in phase three trials, and we're hoping that this might be available to us in the very near future. All right, another drug that just finished phase two, seralutinib, working through growth factors. So as I mentioned, we're learning more, trying to now target these true vasculopathy-causing agents. So the TORI study, phase two, randomized double-blind placebo-controlled trial, just finished phase two, and it showed us that we could impact pulmonary vascular resistance. In the short term, there was 86 patients. At 24 weeks, PVR was significantly reduced by seralutinib, and a reduction of 14%. If you tease out and look at the functional class three patients, the PVR reduction was at the 20.8% range. There was reductions in NT-proBNP, which also occurred. Now, this is phase two. It helps us know that we're hopeful this might be a possibility for our patients in the future, but we have phase three, and that's underway. Phase three, we'll look at more detail on how this medication could potentially be a therapy for our patients. All right, what else do we have? We have, as I mentioned, the seralutinib trial, phase three. We have an inhaled imatinib trial, where we know that some tyrosine kinase inhibitors may be effective at improving pulmonary vascular disease, but they were riddled with difficulties with side effects. But if we inhale the medication, we may be able to deliver that drug more safely, and so that's what that study is trying to sort out. And then, as I mentioned, with the cetatorcep drug, we don't really know how best to fit it in our current armamentarium, so we're studying it in Zenith in sick, more advanced pulmonary hypertension patients, and Hyperion in earlier patients, and we're also looking at some other agents in these novel pathways. So more to come. It's going to get even more complicated. So what do we mean when we say the flow of progress? Well, we started out, as I mentioned, with the discovery of pulmonary vasculopathy. Well, we're going to blame it on Dr. Romberg. The previous gentleman is not going to get credit. And then we start to really understand what is happening. We develop hemodynamics. We have the first WHO meeting. We start to develop drugs, and then it really takes off. We have oral therapy, additional infusion therapies. We continue to have those world symposiums to better understand disease, better group disease, and we keep marching along to where we are now. We're at the point where we're really looking at novel therapies. We're trying to find ways to reverse disease, and if we're fortunate, there is a future that potentially could have cured disease, and then we'll be all out of business. So with that, great progress has been made in the understanding and treatment of pulmonary retention. Current management strategies have improved outcomes. Novel therapies are being developed, and we're really looking to the future for even further improvements in outcomes. All right. Thank you.

Distinguished Scientist Honor Lecture

Cardiopulmonary Physiology

Dr. Jane Elwing

pulmonary hypertension

medical education

American College of Chest Physicians

chest pulmonary vascular network

treatment options

risk assessment

PH