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. 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 ideology, congenital heart disease and some of the drug toxins and then a little bit about persistent pulmonary potential 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 ways to find now and this is recent for for decades, it was a mean pulmonary pressure of greater than 25 millimeters are at risk 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, but with mean P A pressures between 2025 actually have adverse outcomes, uh worse, uh higher mortality, increased risk of cardiovascular events, et cetera. What that means for the pediatric population right now is unclear what we're gonna do is a pediatric group. In terms of whether we treat these patients or not is still kind of evolving. Then the calculated resistance of three 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 woman here. And then this uh red layer 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 small muscle cell becomes thick. You can get some inflammation in and internal uh hyperplasia. And ultimately, in subset such you get this plexiform 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 uh 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 six 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 di 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 ideologies where pulmonary 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 fallout was 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 why 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, et cetera, 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 heart of heart failure. But as you can see here, they are 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, et cetera. Uh syncope will occur in about 20% of patients in pediatric patients compared to about 10% of adult rarely. Do you see the leg swelling? But you can see some hepatomegaly from the right heart failure. Um million advanced forms, you see dyspnea at risk, but what brings them to, 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 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 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 seven. 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 puma 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 pathologies. 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 is 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 pro psychotherapy 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 inside group, one is P your 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 any uh secondary cause hereditary where there's a family history and other genetic no um causes which will talk about drugs and congest con congenital heart disease as well. Um Left heart disease is group two, much more common in adults um than in pediatrics group three lung hypoxia disorder. So, uh altitude, for example, but the emerging pediatric population is the ex premature baby with chronic lung disease. Uh chronic thromboembolic pulmonary hypertension is group four I again, not very particularly common in Children. And then group five 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 por hypertension. So adult medicine is obviously is is certainly uh simpler than, than pediatric medicine. So their epidemiology is group one is the most common, followed by group two, followed by group three. Ours is not that that uh simple. So group three actually, particularly with the bronchopulmonary dysplasia population emerging has actually become the most common type of pediatric pulmonary hypertension followed by group one. And then you can see that group 24 and five are really much, much smaller. Um And I just wanted to say that the pa the the ideologies and the epidemiology can vary by, by country and this is obviously a worldwide problem. Um And you can see the different uh epidemiologist 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 Pulmy 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 a 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, you 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 ideologies like co vascular disease, destructive sleep apnea, for example, et cetera, et cetera. HIV, scleroderma, et cetera, um congenital heart disease. But obviously, we need to get to this echo because 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 E CE CG which may show RV strain or RVH if it's been going on for a while. And in chest X ray, you may say 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 work up um that we do, let's talk a little bit about the, the family, the hereditary group because the genetic ideologies 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 ideologies 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, a patient that has a family history of pulmonary hypertension, greater than 70% of them will have um a mutation in BMBM PR two. And that's part of the uh TGF beta uh super family 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 TB X four, which I'll, I'll talk about. It's an interesting story and it's emerged as the second most common pediatric form, Fox F one for alveolar capillary, dysplasia, mela and Pulmy veins, which is a fatal um um developmental lung disease. So, getting a gene genetic panel can help with that et cetera and the list goes on and on. But T max four 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 TB X four 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 pulmon hypertension as a neonate or a child. And then as a unit, 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 pulmon 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. Then with the whole genome sequencing in about 150 pediatric and 250 adult pah. And you can see that if you're gonna get pul hypertension from TB X four, it's gonna be early on. It rarely presents as an adult with Pulma hypertension. It's an interesting phenotyping where the BM PR two can present kind of throughout the spectrum of ages. So it's been very helpful to us at A I DS and 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 com it, if we have an ideology, genetic ideology, 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 and guiding treatment strategy. So for example, we know that BM Pr two mutation, uh pulmonary hypertensive patients have a worse outcome. They have a more aggressive disease than non BM pr two. So if we get a BM Pr two mutation back, that'll guide us in terms of being more aggressive with our therapy. A and identifying mechanisms of the disease. This is that whole story would be M PR two, the TGF beta family. So clearly aberrations in that cascade are are causing como vascular disease and we now have a new drug targeting that and hopefully, that'll be more, more to come. And again, aid in 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 a, an, an interesting story that I think speaks to the previous slide. So this is written up by my colleague, Elena Ammon and uh in our group at U CS F. So we care for AAA 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 prostacyclin 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, et cetera, we ended up doing the cardiac cath. Uh the echocardiographer 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 screened for a year every year we screened her in six months later, she was completely fine normal, physical normal echo. She went to Europe for the summer before college and started college. Nine months later, she starts having uh dyspnea with exertion and had a Singapore episode and she had advanced pulmonary vascular disease. So this was um this was kind of a, a report of how pro 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 ma 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 a Columbia and she still does it. She's a leader in, in, in genetic uh pulmon 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 A TP 13, a three and it said um unclear uh meaning, you know, in terms of the report. So I showed it to her on the phone when she was sitting in, in the audience and she said, Jeff, we have four of these patients. We're writing it up right now. All of them passed away before they were two years of age with very, very pro um very, very um refractory progressive Pulmy vascular disease. So once she asked if she can include this child into the report, which obviously we did. But because of that, she, she had, we, we just started her on what we call triple therapy, but we normally give them at least a year on this before thinking about doing any kind of surgical intervention. Uh But given this story, we gave her three months, she did not really improve at all. So we went to what's called the 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 eight 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. Con 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 pre pa um lesions that have not only increased flow to the pulmon vascular, but a ha a direct pressure head like a trunk is or a navy canal or what uh unrestricted, large VSD. They have a very high rate that, you know, 100% risk of developing pero vascular disease if they're not operated on. And they do so at a very young age or on the other end of the spectrum, just increase full but no direct pressure. Had this pre tricuspid i lesion of an atrial septal defect. This is the 20% is overt, 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 pulmo vascular disease. This is just a nice cartoon that my friend and colleague Ian Aia and Stacy Obi ends 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 it's called medial hypertrophy. So the muscle actually stays proximal but gets thicker. And then the next thing you see this um muscular organization 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 it with Children with congenital heart disease at the time of surgery by Doctor M Maureen Rin. 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 Eisenman 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, et cetera 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, in 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 Fen, the um the appetite, appetite suppressants that were quite popular. Um This was in the nineties. Um one of the things they called mitral valve disease caused some mitra valve disease, but it caused severe pulmonary vascular disease. And that's what that's why it was pulled from the FDA in, in Europe. And then there's some that are that are definitely associated with um pulmon 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 Palmer hypertension clinic is related to methamphetamine use. It is a very refractory type of pulo 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 and 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 quite a thrombogenic um issues. Pphn. This is a classic changes, the transition of birth that um Doctor Rudolph um described here at U CS F. And you can see this is a time of birth where there's a dramatic fall in pulmonary pressure that's associated with an increase in pulmonary blood flow and a dramatic fall in pul vs resistance. I think one way to kind of generically define PPHN as the failure to transition from the fetal to the postnatal pulmonary circulation. And IW 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 a hypoplastic type by con gel, diaphragmatic hernia where there's a lung hyperplasia. Um and that with, that comes um vascular hyperplasia. So the resistance is high because the vascular bed is underdeveloped and small. Then there's the maladaptation where there's the pul vascular itself is normal, but something happens around the time of birth, whether there's aspiration or R DS or pneumonia, sepsis. And then the associated acidosis and um and or hypoxia can cause um the Pulmy vascular 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 maldevelopment 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 stress event. Um you know, placenta in sufficiency causing hy hypoxia, um ductal con pain, uh ductal ductus arteriosus constriction, even for about 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 a diff more difficult patient initially and those patients that subset may in fact need some ECMO support. So that's kind of one way I think of uh of thinking about it. Our colleague Martina Ster at U CS F showed that PPHN, which is kind of thought to be completely reversible and then you will 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 respiratory cause was threefold higher. If you had a history of PPHN, we're doing some work now using orange databases and, and finding that if you're gonna get patients who are um teenagers for childhood, teenagers, young adults that have to 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 Alvear calculator dysplasia, pulmonary interstitial vaginosis, some of the interstitial lung diseases, vital lung diseases because those take an evaluation including ac T 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 C Choy, which is one of one of our trainees. We actually have a NIH training grant for pediatric P 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, et cetera. And looked at time of nitric oxide discontinuation, ecls, decannulation, echo resolution of ph time extubation and kind of the sweet spot. There was about 10 days in terms of differences where they're 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 a como 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, et cetera. 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 uh median survival for adults was 2.8 years. Median five 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 psycho GMP causing vasodilation and inhibits with 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 poo vascular disorders, we can given how nitric oxide we can activate the enzyme that makes nitric oxide. We can prevent the breakdown of psycho GMP by phospho Aase type five inhibitors. We can even give the precursor arginine in some circumstances where there's an origin arginine deficiency. For example, many different treatments we can do to augment this prostacyclin, which you know is from Zoric acid. And that's also been shown to be deficient in in pulmonary vascular disease that works through psycho A MP. And we can give prostacyclin uh either prostacyclin derivatives or prostacyclin receptor agonist as therapies. And the feeling is the yang of that and the feeling 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 endothelin. So this gives you kind of a timeline in terms of FDA approval. Before 1995 we had calcium channel blockers, anticoagulation, di digoxin and diuretics. The first Folland or first Prosy Cyclone was in 1995 held nitric oxide. One of the few drugs ever first um approved for not only pediatric use but neonatal use was in 1999 1st endothelin receptor antagonist was in 2001. The suspension was actually approved for kids in 2017. Um Sildenafil which is the PD five inhibitor was 2005 and I need to add that. Actually in 2023 the Sildenafil was approved for Children, but these, all these greens are pros cyclin. What what's happened is we've, you know, different formulations have made it much better. The pills for the end of the interceptor antagonists have gotten more selective, set up twice a day, three times, twice a day, it's once a day. Um So then a film set it three times, three times a day to do fills once a day. So a lot of improvements, but all three still just these three cascades all in Ethereal based until very recently. So tater is a protein liga that actually targets the BM pr two cascade. That's an infusion, a multiple uh kind of, you go to the infusion center and get it every couple of weeks just starting a pediatric trial. And this was approved a few months ago for adults. Very exciting because it came out, came out of understanding the biology of the genetics. And this is the first thing, the first drug that's non end thether based, that it actually goes after your focus on the 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 month, you know, short of a AAA 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 soil, it's easy. Um You know, it's given soil was first studied in heart failure for adults and where 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, multibillion dollar and people feel comfortable with it, et cetera. But it's really the field is much more than that. And we feel like being very aggressive upfront is the way to go. And this was a uh emerging data has shown this was the first study uh by Bulkley where they looked retrospectively. So they had almost 1000 patients that were started initially on one drug, usually soil two drugs with a and the, the receptor. And then uh 76 were on triple therapy that included a process cycling. So these are risk criteria. So the green is is four low uh low risk criteria. And um you can see not surprisingly that there a 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 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 the general heart disease, that pressure itself is probably bad for the Pulmy vascular. 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 senna for six months and then you add Bosin for another six months or a year before you send some send to a PH uh center to start getting prostacyclin. You really, you, you know, you've really um lost a couple of years, which is really unfortunate. And then this just speaks to uh you know, the importance of, of Pulmon Hypertensive Centers. We have multidisciplinary center, including the Natal cardiology, critical care pulmonology, et cetera, dedicated social work. And this is a, a nice study adults from Bos from Pittsburgh, where they have over 50 centers, you know, community hospitals, et cetera. About half of them have designated P 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, et cetera, 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 p vascular disease represents a spectrum of diseases with diverse ideology and likely diverse pathobiology. There have been dramatic advances in our understanding of the underlying biology and ethereal based therapies have markedly improved the quality of life and outcomes for these patients. Multidisciplinary ph programs are result of improved diagnosis and treatment approaches, but we need to do better. Our treatment is currently based on disease severity and 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 pulmon hypertension, including our research, folks, et cetera, um dieticians, social work pharmacy, um etc.
