Scientific understanding of what's more accurately called pulmonary arterial hypertension (PAH) has improved, explains pediatric critical care specialist Jeffrey Fineman, MD, but the condition continues to take young lives. To help pediatricians pick up on suspicious symptoms and histories early, he describes common storylines heard in the exam room and explains the value of identifying genetic causes and associated syndromes. Noting that personalized specialty care clearly supports survival, he offers guidance on selecting workup options and making speedy referrals.
OK, well, as the title would suggest, I hope it suggests anyway, that uh this is a field that's really grown tremendously, and we've made tremendous strides, but we have a long, long way to go, so. Um, my disclosures are I really don't have anything relevant to this talk, although our PH service does participate in, uh, industry sponsored clinical trials at times. What I thought I would do is just go over the definition of pulmonary hypertension and talk about the vascular phenotype, a little bit of the classification, the epidemiology, with focus on uh uh genetic etiology, congenital heart disease, and some of the drug toxins. And then a little bit about persistent pulmonary hypertension in newborn, and then end with our therapy, the new therapies and um latest outcomes. So, it's kind of a, it's not a perfect title, pulmonary hypertension, because it's, it's, it's nomenclature that's Defined by hemodynamic parameters, not like underlying disease states. So many of us like to use the term pulmonary vascular disease as opposed to pulmonary hypertension or pulmonary hypertensive vascular disease. But the way it's defined now, and this is recent, for, for decades, it was a mean pulmonary artery pressure of greater than 25 millimeters at rest or 30 during exercise. But just recently at the last World Congress, Uh, 22 years ago, it was changed to 20 millimeters of mercury rust, and that's based on adult data suggesting that some adults with mild disease like with mean PA pressures between 20 and 25 actually have adverse outcomes, uh, worse, uh, higher mortality, increased risk of cardiovascular events, etc. What that means for the pediatric population right now is unclear. What we're gonna do as a pediatric group in terms of whether we treat these patients or not, is still kind of evolving. Then the calculated resistance of 3 woods units remains uh within the definition. And it's both a structural disease where the vessels become remodeled, kind of like a cancer overgrowth of smooth muscle cells, and a functional disease where the blood vessels have this increased propensity to be able to constrict to such things as hypoxia or acidosis, and an inability to relax to normal uh things. So this is just a cartoon of what a um blood vessel looks like. Here we see a healthy artery and the blood in the aluminum here and then this. Uh, right away or here is the endothelial cells that line the blood vessel, and in many of the pathologic pulmonary hypertensive disease states, what's felt to be the first inciting event, whether it's from congenital heart disease and abnormal mechanical forces or certain drugs, toxins, is that the endothelial cells become uh dysfunctional. And that leads to by mechanisms that are Increasingly understood and increasingly less understood, uh, vascular remodeling this muscle layer and the smooth muscle cell becomes thick, you can get some inflammation and, and intimo, uh, hyperplasia. And ultimately in subsets such you get dysplexiform lesions, which is basically a polyclonal, um, proliferation of endothelial cells. Again, very similar, similar things to cancer. And ultimately, um, even clots that basically where you lose um the small arterials, and you get the so-called pruning of the pulmonary vasculature. This is a classic paper by Heath and Edwards in 1958, where they used autopsy specimens to look at the different grades. Of the pathology, and um there's actually 6 grades of pathology, they're called Heath and Edwards grades. Really clinically, I must say, uh this is not really utilized at all, but I thought from a historical perspective it was worth mentioning. And then the cardiologist will tell you that although uh there's appropriate focus on the pulmonary vasculature, ultimately the signs, symptoms, and outcomes are related to right heart failure. So this becomes uh um Um, a, a disease of the right heart. So you can see in the schematic that something happens, and we'll go through many of the different etiologies where pulmonary artery pressure begins to rise, uh, your calculated resistance is rising, and you maintain your cardiac output, and you're kind of compensated. But at some point, you become decompensated where the right heart starts to fail, and, and then you start becoming symptomatic, um. And then ultimately you pay pressure may fall a little bit because your flow is actually so low. This is a couple of studies, but there are multiple multitude of studies that suggest that Your risk of dying is not because your mean pulmonary artery pressure is X or your pulmonary vascular resistance calculates to Y, it's how the right heart is responding to that increased resistance. So it's indices like your right atrial pressure, your cardiac index, um, indices, or echo indices, etc. that really dictate a patient's symptoms and prognosis. So in many ways the cardiologists are correct, this ultimately becomes a a disease of right heart failure. And the pediatric symptoms, obviously, which are important to recognize their their symptoms of right of heart failure. But as you can see here, they're just symptoms that that You know, are, are, are symptoms that you see every day with, with other, with other issues, but by far and away the most common is dyspnea, fatigue, and exercise tolerance. Obviously in infants is failure to thrive. Irritability, etc. A syncope will occur in about 20% of patients, pediatric patients compared to about 10% of adults. Rarely do you see the leg swelling, but you can see some hepatomegaly from the right heart, uh, failure, um. Million advanced forms you see dyspnea at risk, but what brings them to medical attention is that they already have heart failure, so you can imagine they already have advanced pulmonary vascular disease, uh, by the time they, they may have some symptoms, which is a real problem. And I can't over um emphasize this enough. They often have a history of of reactive airway disease. So, unfortunately, we'll see an idiopath that is a female predominant disease. They present in their early teens. They have a very, very similar story. Parents thought that they were lazy kids, they never kept up with their friends or siblings. They had a puffer, they weren't able to go to PE because of of um their reactive airway disease, although the puffer really doesn't help all that much, and they've never had an emergency visit for reactive airway disease. It's extremely common to get that type of story. And this is a study from our colleagues in the Netherlands, um looking at um 362 patients. The mean age of 7, so it's a slightly younger cohort, you can see that. 65% had dyspnea with exertion, 40% fatigue, 20%, as I mentioned, syncope, and then it decreases from there on. So dyspnea with exertion by far and away the major one in fatigue. And in this cohort, the time from onset of symptoms to a diagnosis of pulmonary hypertension was about a year and a half, and I feel like anecdotally our experience is even longer than that, um, where it can be for several years, um, where they've had symptoms. This is the classification of, of pulmonary hypertension, and I showed this slide, not because you're gonna be tested on it, but to show you that this is A spectrum of different diseases, right? And with that becomes a spectrum of different underlying pathobiologies. Um, unfortunately, um, our treatments are all the same for all of them. So although we've made tremendous progress in this disease, and I hope you, you feel that way at the end of this webinar, we are decades behind, for example, cancer. So right now, If you have mild disease, you get one treatment. Uh, which can be given as an oral agent. If you have moderate disease, you get a second pill, and if you have bad disease, and you get a third, um, treatment, which is a procyclotherapy, which is continuous. Either IV or subcutaneously, but the treatment approach is based on disease severity as opposed to underlying biology. So it's as if you have cancer and you're saying that the 75 year old male with prostate cancer and the 40-year-old woman with breast cancer both have the same disease and they're getting treated with the same drugs, which is obviously um silly, but that's kind of where we are with this, so that's why I put this up here, but Just to give you some insight group one is pulmonary arterial hypertension. That is where the problem is on the arterial side of things, and that's where the idiopathic group is, where we don't have an underlying uh secondary cause, hereditary, where there's a family history and other genetic known um causes, which we'll talk about, drugs and congest congenital heart disease as well. Uh, left heart disease is group 2, much more common in adults, um, than in pediatrics. Group 3, lung hypoxia disorders, so altitude, for example, but the emerging pediatric population is the expremature baby with chronic lung disease. Uh, chronic thromboembolic pulmonary hypertension is group 4, again, not very particularly common in children, and then group 5 is a hodgepodge of, uh, different. A multifactorial mechanisms where we don't really know where to put them. So, Uh, 13 academic centers about 12 years ago now of North America, we got together and decided we would work together and start doing studies together. So the first thing we did was, uh, we created a registry which now has over 2000 patients, but at the time of this publication, we had 1500 patients and just looked at, uh, the epidemiology of pediatric pulmonary hypertension. So adult medicine is obviously is, is certainly, uh, simpler than Than pediatric medicine. So, their epidemiology is group 1 is the most common, followed by group 2, followed by group 3. Ours is not that that uh simple. So, group 3 actually, particularly with the bronchopulmonary dysplasia population emerging, has actually become the most common uh type of pediatric pulmonary hypertension, followed by group 1. And then you can see that group 24, and 5 are really much, much smaller, um. And I just wanted to say that the the the etiologies and the epidemiology can vary by by country, and this is obviously a worldwide problem, um, and you can see the different uh epidemiologies based on different regions, and let me just uh show tell you that. The most common form, and obviously this is much more common in adults, but the most common form of pulmonary vascular disease or etiology of pulmonary vascular disease worldwide is schistosomiasis. OK. Congenital heart disease is a, is, is, is a major factor in uh In Africa. As well as Asia. The underlying mechanisms are multifactorial. We just, you know, that that we we really need to, to um add to this slide almost every other week, but endothelial injury, we talked about inflammation, alterations of metabolism, coagulation. Genetic predispositions, which I'll talk about. This is just uh an algorithm for um Pulmonary hypertension, and the, the message here really is um You know, that you have to just be suspicious of it, right? I mean, without thinking about it, you can certainly Um, these symptoms are so kind of vague that you can, you can call it something else very, very easily. So, the point of this really is that you have to think about it and, and be suspicious of it. And then this gives you an idea of all the different tests when we have a pediatric patient that's already been diagnosed, but for, for your, um, Purposes, obviously echo is where you make the diagnosis, then we'll do a right heart cath and do a whole bunch of studies looking for secondary etiologies like collagen vascular disease, obstructive sleep apnea, for example, etc. etc. HIV scleroderma, etc. um, congenital heart disease, but obviously we need to get to this echo, cause that's the important thing and that's where you make the diagnosis, and so the pivotal tests here are history, your exam, where you're here. It's not that easy to appreciate. I'm not minimizing it, but a second heart sound would, would be the concern. Uh, ECG which may show RV strain or RVH if it's been going on for a while, and in chest X-ray, you may see an increased, um, Pulmonary artery on chest x-ray. So that's really where the focus should be and ultimately then you get an echo, and that gets you to us and then this extensive workup um that we do. Let's talk a little bit about the, the family, the hereditary group because the genetic etiologies have really emerged over the last decade, and it's really important. I think it's helped us in many ways, and now just of this year, we have a new drug that's purely based on what we know from genetic etiologies, which I'll talk about. So, Uh, this is another slide that needs to be updated almost every other week, but. If you have a patient that has a family history of pulmonary hypertension, greater than 70% of them will have um A mutation in BMPR2, and that's part of the uh TGF beta, uh superfamily of drugs. And this we, we now have a new drug that's just been approved in adults that focuses on this cascade, which is very exciting. Um, so this is, uh, the most common by far and away. Um, it's interesting because of the female, um, predisposition that if you have the mutation and you're female, you have about a 40% chance of getting the disease. And if you have the mutation carrying it and you're a male, it's about 10%. Overall, about 20% of patients that carry this mutation will end up developing pulmonary vascular disease. Another big one is uh TBX-4, which I'll, I'll talk about. It's an interesting story, and it's emerged as the second most common pediatric form. FOXF1 for alveolar capillary dysplasia or melanin pulmonary veins, which is a fatal um Um, developmental lung disease, so getting a genetic panel can help with that, etc. and the list goes on and on. But TBX 4 is a very interesting story, so, um, It's been known, so it was first shown to be on chromosome 17 in 1996, and in 2002, it was shown that um mutations of TBX4 are associated with what's called small patella syndrome. So these are adults that have had hip, knee problems, and a classic splitting between their 1st and 2nd toes, OK. Um, in 2013, it was first described as as causing pulmonary arterial hypertension. In neonates in children, but not so much in adults. Basically, if you have the mutation you present as an adult, it's gonna be with the orthopedic issues, but you can develop pulmonary hypertension as a neonatal or a child, and then as a neonate you can also develop severe developmental lung disease that was also found more recently. And so here, here are the classic um findings for small patella. You can see here the wide space, and in fact, this is now emerged, as I said, the second most common genetic um etiology. So if we have a new patient and being worked up as an idiopath, we'll have them as well as their parents. First we ask for any family history of besides pulmonary hypertension obviously, but um any family history of Joint problems, and then we have, we look at the patient and the parents, we have them remove their shoes and socks and take a look at their feet. So, this is just a nice study by Zoo that went at whole genome sequencing in about 150 pediatric and 250 adult PAH and you can see that if you're gonna get pulmonary hypertension from TBX 4, it's gonna be early on. You rarely present as an adult with pulmonary hypertension. It's an interesting phenotyping where the BMPR2 can present kind of throughout the spectrum of ages. So, It's been very helpful to us. It aids in identifying an ideology or a diagnosis. We just feel uncomfortable labeling someone as an idiopath because that just means we don't know what's going on with them. Um, it, if we have an ideogenetic etiology, then we screen the family, and then we guidelines are emerging and what's appropriate for family screening, we can, we'll talk, show you a case where we're, it's guiding us. Aid in guiding treatment strategy. So for example, we know. That BMPR2 mutation, uh, pulmonary hypertensive patients have a worse outcome. They have a more aggressive disease than non-BMPR2. So if we get a BMPR2 mutation back, that'll guide us in terms of being more aggressive with our therapy. Aid in identifying mechanisms of the disease. This is that whole story would be in PR2, the TGF beta family. So clearly aberrations in that cascade are, are causing pulmonary vascular disease, and we now have a new drug targeting that, and hopefully that will be more, more to come. And again, aiding potentially identifying novel individualized therapeutic targets, that's the ultimate goal. Cancer has gotten very close to that. Uh, we need to do a lot of work to get there. So this is a This is an interesting story that I think speaks to the previous slide. So this is written up by my colleague Elena Emmon and uh in our group at UCSF. So, We care for a child who's now actually um over 21, so she's now with our adult colleagues. Um, but this family, when she presented at 13, her father had passed away from pulmonary vascular disease. She had had, he passed away following lung transplantation. Um, the grandfather was on what we call triple therapy, all three drugs including continuous protacyclin IV infusion. And there was one other sister. Um, who we screened, and she had the mutation. She was an older sister, OK. The mother who was, you know, obviously very, was very, very, uh, knew a lot about pulmonary hypertension, was very involved, even though this child's echo was completely normal, before she went to college, she really insisted that we do a cardiac cath. Um, we ended up, after a lot of meetings, etc. we ended up doing the cardiac cath. Uh, the echocardiographers were very happy that her, her cardiac cath matched her echo, that she had a completely normal echo. I mean, pulmonary pressure was 15, resistance was normal. Her output was normal, and she was completely asymptomatic. Current guidelines are to screen for a year, every year, we screened her in 6 months later, she was completely fine, normal physical, normal echo. She went to Europe for the summer before college and started college. 9 months later, she starts having uh dyspnea with exertion and had a syncopal episode, and she had advanced pulmonary vascular disease. So this was um This was kind of a a report of how how rapidly progressive uh this disease can be, um, which we didn't really understand before, and it will probably modulate this one year screening probably needs to be shorter duration. And then Getting to the, you know, the issue of knowing the genetic diagnosis in terms of um guiding our treatment decisions, we have a, we've been running uh the International Neonatal and Childhood Pulmonary hypertension conference in San Francisco, um. This is gonna be our 18th year now, and Wendy Chung, who's now the department chair at Boston, when she was at Columbia and she still does it, she's a leader in, in, in genetic, uh, pulmonary hypertension. She was at the conference when we got back the testing of one of our patients. She was, um, a young patient, she was 20 months old, and we got back this uh ATP 13A3, and it said, um, unclear, uh, meaning, you know, in terms of the report. So I showed it to her on the phone while she was sitting in in the audience, and she said, Jeff, we have 4 of these patients who are writing it up right now. All of them passed away before they were 2 years of age with very, very um very, very um refractory progressive pulmonary vascular disease. So when she asked if she can include this child into the report, which obviously we did. But because of that, she, she had, we were just started her on what we call triple therapy, but we normally give them At least 1 year on this before thinking about doing any kind of surgical intervention. Uh, but given this story, we gave her 3 months, she did not really improve at all. So we went to what's called a POTS procedure, or reverse POTS where we created a communication between the pulmonary artery and the aorta to unload the right ventricle, and this child is now 8 years old. And that was one of the youngest POTs ever done in the world, um. And we did it because of knowing, knowing this genetic diagnosis and the, the terrible prognosis associated with it. Congitive heart disease, which is a big subset of the of the um. Pediatric population. What's cool about the, the, the congenital heart disease is from studies, from some terrific natural history studies, we know the natural history of this. So prep um lesions that have not only increased flow to the pulmonary vasculature, but a heart, a direct pressure head like a truncus or a nay canal or with uh unrestricted large VSD, they have a very high rate. Uh, you know, 100% risk of developing pulmonary vascular disease if they're not operated on, and they do so at a very young age. We're on the other end of the spectrum, just increased flow, but no direct pressure head this pretricuspid lesion of an atrial septal defect. This is the 20% is overstated, it's about 10%, and that happens beyond the pediatric age group, and I would argue that if we did genetic testing, a big subset of these are gonna have a genetic mutation, and they happen to have an atrial septal defect. So we, this really gives us an understanding of how mechanical forces perpetuate uh the pulmonary vascular disease. This is just a nice cartoon. That my friend and colleague Ian Atitia and Stacy Vienz uh provided me, so this is just a picture of a VSD. The red here is muscle. And so you can see that the, the muscle layer is quite thin and it's only proximal. And then, With the increased flow and pressure, the first thing you see is what's called medial hypertrophy, so the muscle actually stays proximal but gets thicker, and then the next thing, You see this um Muscularization spin to to the periphery, and then ultimately you get these pruning or loss of the small arterials, and that's been shown by biopsies um taken with children with congenital heart disease at the time of surgery by Doctor Maureen Rabinowitz. And then ultimately, um, when the resistance in the lungs becomes near equal to the resistance in the body. Instead of it being a complete left sided to right sided shunt, you start getting bidirectional shunting, so you get desaturated blood into the systemic circulation, and that's, as you know, called uh the Eisenmanger syndrome, and um, I put this up again for historical reasons, again, another 1958 article by Paul Wood, but I really recommend, this is a great read, quite honestly, and the amount of understanding that these folks had back then in terms of the physiology, etc. is really remarkable. I don't think we have any better understanding that they did back then. We have more technology and and a lot of great tools, but uh their understanding, their their insight into this disease was unbelievable. Drug and toxin, um. The big one And it's been a while now, so probably most of you don't remember this, but, um, Fen-Phen, the, um, the appetite, appetite suppressants that were quite popular, um, This was in the 90s, um 1 of the things they called mitral valve disease, caused some mitral valve disease, but it caused severe pulmonary vascular disease, and that's what, that's why it was uh pulled from the FDA in, in Europe. And then there's some that are, that are definitely associated with um Pulmonary vascular disease, and I should add to a definite methamphetamine, and it's become a tremendous, tremendous burden, uh, to the adult population, in fact, in major urban centers. About 50% of the pulmonary hypertension clinic is related to methamphetamine use. It is a very refractory type of pulmonary vascular disease, and it doesn't get better with uh stopping methamphetamine use. So this has been a huge, uh, huge problem. Estrogen is probably unlikely in by itself, but because of its thrombotic nature, we really try to avoid uh using any estrogen containing contraceptives, for example. Um, so with our, our teenagers, we, we like to provide any, you know, non-estrogen, um, contraceptives, um, because of its coagulate thrombogenic, um, Issues PPHN. This is a classic changes at the transition at birth that um Doctor Rudolph. Um, described here at ECSF and you can see this is the time of birth where there's a dramatic fall in pulmonary repression that's associated with an increase in pulmonary blood flow and a dramatic fall in pulmonary vascular resistance. I think one way to kind of generically define PPHN is the failure to transition from the fetal to the postnatal pulmonary circulation. And I, what the way I find it to be helpful in terms of thinking about it is There's the irreversible type that are just, you know, developmental lung diseases that you can see here. There's the hypoplastic type, like congenital diaphragmatic hernia, where there's a lung hypoplasia. Um, and that with that comes, um, vascular hypoplasia, so the resistance is high because the vascular bed is underdeveloped and small. Then there's the maladaptation where there's the pulmonary vasculature itself is normal, but something happens around the time of birth, whether there's aspiration or RDS or pneumonia, sepsis, and then the associated acidosis and um and or hypoxia can cause um the pulmonary vasculature to remain elevated for a period of time. You can imagine that this is quite amenable to therapy such as oxygen with or without intubation, with or without inhaled nitric oxide. And then there's the mild development where if you actually look at the pulmonary vasculature, it's quite remodeled at the time of birth, and that's usually related to some in utero uh stress event, um, you know, placental insufficiency causing hypoxia, um, ductal patent uh ductal ductus arteriosis constriction, even for about a, a week prior to delivery, it can cause significant remodeling. That's obviously why non-steroidals. Are avoided uh in pregnancy and so that you can imagine maybe the type since there's a lot of muscle there that needs time to regress that that may be diff more difficult patient initially and those patients that subset may in fact need some emo support so that's kind of one way I think of uh. Of thinking about it, our colleague Martina Steer at ECSF showed that PPHN, which is kind of thought to be completely reversible, and then you'll go on and lead your normal life, isn't necessarily that, in fact, that they looked at the first year of life, the readmission rate for patients with PPHN, this is a California database, was 29% versus uh 10% if you didn't have PPHN. Readmission for a respiratory cause was threefold higher if you had a history of PPHN. We're doing some work now using large databases and, and finding that if you look at patients who are um teenagers for childhood, teenagers, young adults that have present with pulmonary vascular disease, that there's a much higher incidence of a history of PPHN than the general population. So when PPHN persists, you know, when this is something we get called to the NICU about the kids, you know, had PPHN for a week, you know, is this PPHN that's gonna be resolved, or do we need to do more things, look for more things like alveolar capillary dysplasia, pulmonary interstitial gycogenosis, some of the interstitial uh lung diseases, developmental lung diseases, because those take an evaluation, including a a CT angiogram. Genetic testing, and if that doesn't reveal anything, even a lung biopsy, this is where a biopsy can be helpful. So this is an important decision tree for us, um. And Stephanie Choi, which is one of, one of our trainees, we actually have a NIH training grant for pediatric pulmonary hypertension research, and she's one of the first ones, and she looked back at our patients that have normal kind of perinatal PPHN which is felt to be reversible versus fetal developmental type, which is developmental lung disease, etc. and looked at time of Nitric oxide discontinuation, ECLS decannulation, echo resolution of PH timed extubation, and kind of the sweet spot there was about 10 days in terms of differences where the kind of the usual PPHN where they're gonna go on and get better. They, these things are much better by about 10 days in terms of coming off of ECO, being off of NO, echo being much better, being off the ventilator. So, we, we generally think that around 10 days of life is um If things aren't getting better, then we may up our game and start getting genetic testing, imaging, etc. I'm looking for something beyond the normal PPHN. So let's do a little bit about outcomes. So the, the, the therapies for this began back in 1995. So prior to 1995, The average time from diagnosis to death in a pediatric patient was 10 months. The median survival for adults was 2.8 years. Median 5 year survival was less than 40%. Bad disease. Still a bad disease, but we're doing much, much better. These are the three, pathways that we, we, um, target. So nitric oxide, as many of you know, it's really, really important for vascular homeostasis. It's continually made by blood flow, the sheer stress along the endothelial cell causes nitric oxide to be made, and it, it increases like a GMP causing vasodilation, and inhibits the muscle cell proliferation. And we can go after this, and there's a lot of evidence showing that there's deficiencies in nitric oxide production. Um In pulmonary vascular disorders, we can Given how nitric oxide, we can activate the enzyme that makes nitric oxide. We can prevent the breakdown of cyclic GMP by phosphodiesterase type 5 inhibitors. We can even give the precursor arginine in some circumstances where there's an arginine deficiency, for example. Many different treatments we can do to augment this. Prostacyclin, as you know, is from arachdoinic acid, and that's also been shown to be deficient in, in pulmonary vascular disease that works through cyclic AMP. And we can give prostacyclin uh either prostacyclin derivatives or prostacyclin receptor agonists as therapies. And the thelin is the yang of that and the thelin is a very potent vasoconstrictor, one of the most potent vasoconstrictors known to man in in in human vasculature, both systemic and pulmonary, and our treatment approach is to block the receptors for endothellin. So this gives you kind of a timeline in terms of FDA approval. Before 1995, we had calcium channel blockers, anticoagulation, digoxin, and diuretics. The first Flolan or first prostacyclin was in 1995. Hald nitric oxide, one of the few drugs ever. First, um, approved for not only pediatric use, but neonatal use was in 1999. 1st endothelial receptor antagonist was in 2001. The suspension was actually approved for kids in 2017. Um, sildenafil, which is the PDE5 inhibitor, was 2005, and I need to add that actually in 2023, the sildenafil was approved for children. But these, all these greens are protacyclin. What, what's happened is we've, you know, different formulations have made it much better. The pills for the endothelial receptor antagonists have gotten more selective. Instead of twice a day, three times, twice a day, it's once a day. Um, so dental fills that are three times a, three times a day, tadalafil is once a day. So a lot of improvements, but all three, still just these three cascades, all endothelial based. Until very recently, so Tattercept. Is a protein ligand that actually targets the BMPR2 cascade, that's an infusion, a multiple, uh, kind of, you go to the infusion center and get it every couple weeks. Just starting a pediatric trial and this was approved a few months ago for adults. Very exciting cause it came up, came out of understanding the biology of the genetics, and it's the first thing, first drug that's non-endothelial based that it actually goes after your focus on the smooth muscle cell. So very exciting and more to come with these type of drugs, we hope. So this is just some registry studies uh prior to kind of the targeted therapies, and then if you superimpose, again these are still late, uh, you know, several years ago, but I think you get the idea that There is no question that these drugs make these patients feel better, and they can live longer, but the, the, you know, short of a uh uh a few exceptions. These diseases are not reversible, and so you're talking about medication for life with ultimately a target of lung transplantation if needed. And then, to end, I just want to talk about our, our treatment strategy. This is not, I feel very strongly that this is not a disease. Where you dabble. People feel comfortable with sildenafil, it's easy, um, you know, it's given sildenafil was first studied in heart failure for adults and where um was shown to not be effective, but it was effective for the subset of patients that had erectile dysfunction that became the billion dollar industry, multi-billion dollar. And people feel comfortable with it, etc. but it's really the field is much more than that, and we feel like being very aggressive up front is the way to go, and this was a uh emerging data shown this was the first study uh by Berkeley, where they looked retrospectively, so they had almost 1000 patients that were started initially on one drug, usually sildenafil, two drugs with a lithion receptor, and then uh 76 were on triple therapy that included a process cycling. So these are risk criteria, so. The green is is for low uh low risk criteria and um You can see, not surprisingly, that there was selection bias that the, this is zero risk low risk criteria, so 60% of the patients had had no low risk criteria. In other words, these were sicker patients, so not surprisingly, and retrospectively, the patients that received upfront triple therapy were in fact sicker. But then with first follow up, you can see that the patients that in fact received triple therapy, besides being sicker to begin with, actually did much better, and that's the approach that we've always taken. And we feel like lowering the pressure, we know from congenital heart disease that pressure itself is probably bad for the pulmonary vasculature. So let's be aggressive and lower that pressure. And now there's emerging pediatric data also showing that you have to be, you really should be very aggressive, and if you're on sildenafil for 6 months, and then you add Basantin for another 6 months, or a year before you send some send to a pH uh center to start getting cross the cyclin, you've really, you, you know, you've really um Lost a couple of years, which is really unfortunate. And then this just speaks to the, uh, you know, uh, the importance of, of pulmonary hypertensive centers. We have multidisciplinary center including neonatology, cardiology, critical care, pulmonology, etc. with dedicated social work. And this is a nice study of adults from Boston from Pittsburgh where they have over 50 centers, you know, community hospitals, etc. About half of them have designated pulmonary hypertension centers, and they look back. And all these centers, and what they showed is if you went to a hospital in within their group, Under the University of Pittsburgh, if you went to one of the places that had a PH center, you uh had a lot more stuff done to you. In other words, you had more cats, more imaging, etc. but you had a uh improved survival. So we think it's important that you go to a special specialty care center for this disease. So, Um, in summary, pediatric pulmonary vascular disease represents a spectrum of diseases with diverse etiology and likely diverse path of biology. There have been dramatic advances in our understanding of the underlying biology. Endothelial-based therapies have markedly improved the quality of life and outcomes for these patients. Multidisciplinary PH programs have resulted in improved diagnosis and treatment approaches. What we need to do better. Our treatment is currently based on disease severity, not individualized, uh, to bio biology and um. We need to get to more personalized medicine. I'll stop there. Um, we have a 24/7 pager, but if you have any, um, non-urgent calls, feel free to call this number, and one of us will be happy to talk to you at any time. As you can see, this is um a large group that's all dedicated to pulmonary hypertension, including our research folks, etc. um, dietitians, social work, pharmacy, um, etc.
