Pediatric critical care specialist Jeffrey R. Fineman, MD, breaks down a complex condition with wide-ranging symptoms in babies and children. Numerous PH therapies now have the potential to extend and improve life, so it’s important to understand risk assessment, diagnostic pitfalls, associated genetic syndromes and the value of aggressive early treatment.
mm. Um unfortunately I have no uh significant relevant financial disclosures uh related to hypertension or UCSF's pediatric ph service does participated industry sponsored clinical trials but nothing relevant to this. Talk first. I would just kind of introduce you to the field which is growing rapidly. Talk a little bit about the clinical presentation that genealogy, the evaluation classification, the importance of genetic testing which we're doing more and more now. A little bit about the two more common uh ideologies of primary pretension, PPH N and congenital heart disease. And then just end with kind of the emerging therapeutic options and the changes and outcomes that are being achieved because of these things. So, first of all, as opposed to the title where I say, palmer hypertension, it's probably better to call it pulmonary vascular disease or from a hypertensive vascular disease because the definition of pulmonary hypertension, It's really just a human dynamic definition. It was greater than 25 mm of mercury at rest and greater than 30 of mercury and exercise. But the recent World Congress was actually think agreed to make it That the threshold be not 25 but 20 because there's a lot of clinically very irrelevant Vascular disease that doesn't quite meet this old definition of 25. And then if you calculate the resistance, It would be greater than three woods units. And as many of you know, this is both a structural disease of the vasculature with vascular remodeling, which we'll go over there is also a functional disease of the vasculature where they have this increased propensity to looking strict and an impaired ability to relax. Yeah. Mhm. There we go. Sorry. So this is just a cartoon of the normal blood vessel. This would be a pulmonary artery for example. And you see the blood internally and it's surrounded by very important and ethereal cell layer and then followed by a smooth muscle cell layer with an internal and external elastic landowner surrounding the smooth muscle lawyer. And as many of you know, the imperial cell is exposed to this flow and the mechanical forces associated with the different flow. And it makes a variety of different things that not only affect the tone of the blood vessel but also the smooth muscle cell growth of the blood vessel. Nitric oxide probably being the most famous per se is locally produced with flow going by the end of the year we'll sell that's a very important vis a dilator and inhibits muscle cell proliferation as well as process cycling similarly and the feeling and thrown boxing on the other hand, there kind of the yang of that where they promote very intense from where there's a constriction and promote smooth muscle cell growth. So yeah, first of all we're gonna talk when we talk about hypertension as the spectrum of different diseases, like talking about cancer. But I'm gonna try to talk to general themes um in many of the ideologies, the initiating um paleobiology appears to be and ethereal cell injury and dysfunction where you have an impairment of the nitric oxide across the cycling and that you have an up regulation event the feeling and thrown back and thrown boxing and that results in basal constriction as well. As you can see here smooth muscle cell um proliferation, an internal fibrosis really causing narrowing of this vessel aluminum. Ultimately you can get inside your thrombosis plexi form regions which is uh um probably clonal proliferation. Again, the feeling of cells and as you can imagine, ultimately vascular occlusion of the distant materials, there's different grading systems. The most common for the pathology would be heathen Edwards who published this landmark paper in 1958 and they go through different grade ing's of the history pathology of pulmonary vascular disease with initially mild mediocre thickening to complete occlusion of the vascular bed. As you can see some better examples there. Right? But ultimately this disease becomes one of right heart failure. So a patient isn't symptomatic and doesn't die because the pressure is X. Or their primary vascular resistance calculates to why they are symptomatic or or die because they're right part can no longer compensate for that increased afterward. That increased resistance. So this is just a cartoon of a progression of disease where the pressure goes up. The vast resistance continues to go up. They're not symptomatic at this point. But the cardiac output then starts to fall and they become symptomatic and or decompensating as their cardiac output falls, pressure actually, sorry pressure actually may decrease because the output is low. But the calculated resistance continues to go up. So this becomes a disease of right heart failure. And in fact, if you look at outcome studies time and time again, you don't. The mortality risk isn't because your resistance is calculated over a certain percentage. Certain woods units. It's the indices of right ventricular function that are the best prognosis for a long term pulmonary hypertension. These are just a couple of different eco parameters utilized to characterize RV function and and the prognosis of pulmonary hypertension. And so clinically what you're seeing is signs of heart failure, right? And in infants, its failure to thrive, decreased activity differences or inability. Um older Children, it's disappeared, particularly on exertion, exercise intolerance, fatigue. I can't tell you how many times the teenagers presented and the parents say, I just thought that he or she was lazy late symptoms or cyanosis with exertion, chest pain makes swelling, etcetera very uncommon to have leg swelling in the classic right heart failure that you see in adults, About 20% present with Sync Api um and dismay at rest. Very, very often a very common theme is that they have a history of being diagnosed with a history of reactive airway disease. It's not uncommon to hear that they have been excused from uh from p E. Class for years because of so called reactive airway disease yet. You don't get a history that a puffer really helped and they've never had an emergency visit for for asthma exacerbation and what we're seeing is misdiagnosis of heart failure as reactive airway disease. And this is a nice study from our colleagues internationally where they looked at the clinical features of Of pediatric pulmonary hypertension. 362 patients. The mean age was 7.1 year and you can see that dispute with exertion was the most common presenting sign. As I said, sync up in about 20% of patients. Okay. And this is very very important time from onset of symptoms to diagnosis Was 17 months. And this is what we unfortunately see in the hospital or in the clinic. Many of our patients have been symptomatic for for much longer than that quite frankly for a couple of years is very very common. So again a spectrum of disease um under 11 umbrella of pulmonary hypertension um it is the most updated is now seven years ago. So I guess it's time for everyone to get together and updated again. But there's there's five large groups. One is our pulmonary arterial hypertension where the problem tends to be on the arterial side of things and that's where the so called idiopathic or we used to call primary primary attention patients are the ones with genetic defects are or have a family history. The drugs usually are arterial connective tissue disorder. HIV portal hypertension. This is where congenital heart disease comes in. Just a psoriasis, probably the most common cause of primary vascular disease worldwide. And then a couple others that will be talking about, you know, inclusive disease and P P H. N. Is a one double prime because we don't really know where to put it. Um, Group two is really related to left heart disease. Much more common in the adult population with either mitral valve disease or left ventricular dysfunction. Group three is the longer or hypoxia really emerging population in pediatrics. So kids with chronic lung disease, Bronco pony displeasure, the sleep disordered breathing, interstitial lung diseases. The Classic one is high altitude and induced pulmonary hypertension. Group four is si te for chronic formal symbolic hypotension, which we'll talk about very important to diagnose because much more amenable to therapy to a different type of the therapy. And one of the one of the curable ones. And then group five is kind of a hodgepodge of things where we don't know where else to put them. So this is the epidemiology from our PPH net registry. We have 13 academic centers North America. Our 1st 1500 patients. Let me just tell you that in the adult population Group one is the most common, followed by group to which is left heart disease, followed by group three, which is a long disease. You can see that in pediatrics is very different. In fact, group three with particularly with the BPD population Is the most common, followed closely by group one with P PHN and congenital heart disease being major players in group one and then group too four and 5 are much much lower on the list. So path of biology promote vascular diseases probably multifactorial. And unfortunately many of the patients present with heart failure already. That's what brings them to come to the to to medical attention. So we don't understand the underlying initial insult which makes it difficult but clearly in the material injury either by mechanical forces with control heart disease for example or toxin, certain drugs, inflammation for example, schistosomiasis, alterations, metabolism, hyper equitable states such as with chronic crumble involved disease and genetic previous disposition will talk a little bit about because I think it's really emerging in the pediatric population. So this is just to give you an idea that when you have a patient usually what we're going to end up calling an idiopathic or something where it's not really clear. They don't have, you know, they're not on a ventilator with chronic lung disease. They don't have an unrepaired large BSD. You've got to start from scratch because you really can't. You have to you can't miss anything and there may be multifactorial. They may have a genetic predisposition but they also have obstructive sleep apnea. So if we don't fix the obstructive sleep apnea. We're not going to be able to make things as good as possible. So you really have to do a thorough thorough evaluation starts with a history and physical and then we're going to do a variety of different tests. The gold confirmation of the diagnosis and Sahim a dynamic definition is to do a cardiac catheterization. These are just some of the tests that we do and we'll go through that in a little bit. But we send off a slew of blood test to make sure they don't have HIV paddle pulmonary disease. You want to make sure they don't have Colin vascular disease. You want to make sure that they don't have obstructive sleep apnea. We usually do a chest cT which we'll talk about to rule out clots. We start with an echo for screening and ultimately do some functional testing with a six minute walk or or more more detailed exercise testing. But we end up doing cardiac catheterization. So let's talk a little bit about the creditable forms. So there there's a family history very, very important. Um Let me just say that now that we're testing more in the pediatric population, We're roughly 50% of patients now have an associated genetic mutation as opposed to 20% in adults. And I just think we do a better job of screening. But by far and away if you have a family history of pulmonary hypertension. Greater than 70% results from mutations in the BNP are too which is part of the T. G. F beta uh family. Um Then the variety of other genes once associated with H H. T. Um the I. F. Two AK four is important because it's associated with this palmerino acoustic disease which we'll talk about, which is not amenable to medical therapy. So the only only therapeutic option is transplant um socks 17 is interesting because it's associated with congenital heart disease. TB X four, small patella syndrome in adults, but in neonatal and young Children, it can actually present as pulmonary hypertension or new NATO lung disease. And it's getting very close to emerging as a major form of neonatal pulmonary hypertension. Then Fox left one associated without your capture dysplasia which is a lethal form that so if we can diagnosed um hmm diagnosis gene mutation and perhaps that that can inform care. So the importance of identifying genetic syndromes syndrome, IQ associations, obviously it AIDS and identifying and ideology and or the diagnosis and importantly I think it AIDS in identifying the mechanism of disease and that may in fact guide your treatment strategy right now, for example, we may know that certain genetic mutations have a much more aggressive course. So we may be more aggressive with our therapy up front. But more or as importantly, for example, show you towards the end and now we're starting to get drugs that that target particular um mutations. For example, there's a new drug which we'll talk about at the end that Goes after the BNP are two single and cast eight. So and then ultimately where we want to be as identifying potential novel individuals, therapeutic targets Fox F one is the one uh where 40-80% of all of your capital displeasure cases are associated with it. Um T. BX four told you that the mutations in adults are associated with small patella syndrome, mutations in childhood can be ph and mutations in the DNA are ph and respiratory failure. And Down syndrome is probably obviously one of the most common genetic problems that are associated with pulmonary hypertension. It's probably it's well known that they have an increased risk of pulmonary hypertension but it's likely multifactorial and one is that they have a very high incidence of congenital heart disease. Another is that they often have start to sleep at another is that they have the long pulmonary and vascular hyperplasia. In other words, they have recurrent respiratory infections, as you know, interestingly they have an up regulated et one cascade which is a vase a constrictor um increased from boxing and decreased process cycling. They have increased oxidative stress or an inability to um take care of oxidative stress often have thyroid disease and displeasure. So there's many reasons why there are at an increased risk of pulmonary vascular disease. Let's just talk a little bit about persistent pulmonary hypertension of the newborn. This is the the normal fall in pulmonary vascular resistance and increase in pulmonary blood flow that occurs at the time of birth. This is a Cossack side by a Rudolph and PHN kind of globally is defined as the failure to transition from the fetal to the post natal type of pulmonary circulation. I always think it's kind of uh a nice way to look at it is to divide it into three different ways mala adaptation, mall development and hyper developed. Hyper development is where it's where the vasculature and along itself are hypoplastic. And so because there's a small vascular bet the resistance is going to be quite high. And the okay, The classic one would be congenital diaphragmatic hernia, the mala adaptation and is where generally someone's that associated with the one disease. But but the vascular itself is normal so that maybe meconium aspiration syndrome, RDS or pneumonia. But there you can imagine or acidosis and you can imagine where um correcting these abnormalities. Since the underlying the vasculature is normal, they may respond well to oxygen. Sometimes mechanical ventilation and held nitric oxide, etcetera mall development. Is that something in utero has happened. Um um for example, a doctoral construction from maternal non steroidal use for example, you can remodel the plumber desk which are just within a week of that of doctoral constriction. And so those you can imagine where the vasculature is actually abnormal. They may take some time to remodel. So that that may be the set of newborns where they don't respond right away to oxygen ventilation. Um And how nitric oxide and those are the kids that may end up on ECMO for a few days while their primary vast which are normalizes and then there's irreversible forms Albiol capital dysplasia surfactant protein problems and pulmonary with and yet practices. So one problem that we come up with quite a bit is when P PHN persists. So it's not resolving what do we do And we have to think about kind of up our diagnostic. We have to think about all the old copper dysplasia something called premier interstitial barca geonosis T. V. X. Four surfactant payment of inject this and there we need to get we often get C. T. Angiograms to look for some of these things do genetic testing and ultimately we may need a lung biopsy and this is probably the only place in pulmonary vascular disease where along biopsy can be very helpful. I want to pass on this and let's move on to drug and toxin induced disease. This is A report from many years ago now, 1997. Uh huh. Where showed methamphetamine Finn Finn the appetite suppressant not only cause micro valve disease but also caused marked pulmonary vascular disease. And that's why in fact fen fen was removed from excuse me from the market and then there are many drugs that are likely or I would say methamphetamines is definite benefit etcetera and then others that are possible and others that are unlikely. And again the ideologies of these are not particularly clear when were you know, inclusive disease is a rare disorder or its home Captain Nemanja mitosis is kind of on the same spectrum. Um But the problem is this is on the venus side. It's an an atomic problem. Um It can prevent present at any age but it usually presents. Um And teenagers. The problem with it is that if you give them a plumber visa dilator which we often do with the catholic will give him in hell nitric oxide. Just to test they can get forward. Palmeri Demon. This was one of our patients. This was a chest X ray before I'm going to the cath I this was after 10 minutes of of inhaled nitric oxide. And um so this diagnosis is very important to make. And the way you do it short of getting a biopsy is to do a CT angiogram and a talented radiologist to make this call. Important to rule out before you start any kind of drugs see tap a chronic problem bolic disease. Very very important because it's curable and it's not curable by giving them the drugs that we normally give them. It's curable by anti coagulation and or intervention. Um Adults usually start with a VQ scan but for other reasons we get C. T. Angiograms. So we always get a C. T angiogram on any patient that it's not clear what the ideology is and here's a an image and this is what it looked like after surgery where it and this is a recent patient just from the last three weeks came from Mexico with a long term respiratory symptoms and ended up having quantifiable abolished disease. And this was the cast that was removed from his pulmonary orders, an excellent prognosis um with long term anti coagulation and sometimes some oral agents but from pulmonary hypertension. But often this is curable, this type of so homer hypertension associated with congenital heart disease. Um, one of the more common ideologies in paediatric population. And we've learned a lot from the natural history and here we know that patients that that have defects that result in a high pressure head as well as increased flow to the pulmonary circulation, have a very high risk of developing irreversible vascular disease without corrective surgery. And they do so very young on the other side of the spectrum and asd where it's pre trial custody, there's not a direct pressure head. Um, their risk of cardiovascular disease is much lower and it occurs much after many, many years. Um, so we've learned a lot from this and my particular research is interested in this in terms of the lessons we learned from these natural history studies. Um the differences in mechanical forces associated these visions and what genes are turned on and off related to that. And I think that there, if we can figure that kind of stuff out, we may be able to tailor our therapies within this particular subgroup, but that's for another whole other talk. So this is a cartoon of a ventricular septal defect. The red here is the muscle layer. So in the normal postnatal phenotype, the muscle layer is quite thin and it it is very proximal. So here's the blood going left to right through the VSD. And the first thing that you'll now see is what we call medial hypertrophy, where this muscle gets thick. The next thing you see is abnormal extension the muscle down to the periphery where it normally is not. And then ultimately, you get this so called pruning or occlusion of the distal small pulmonary arteries. And then ultimately, when the resistance in the pulmonary circulation begins to equal that of the systemic vascular resistance that flow that's normally from the all from the left side to the right side, then starts to go bi directional or right to left. And then you get cyanotic, and that is called the Eisenmenger syndrome, which many of you know, and I would really recommend this classic landmark article by paul would describing this, um This syndrome in 1958, it's remarkable the insight that they had back then. If you look at palmer hypertension associated with congenital heart disease, they actually do much better than other forms of pulmonary hypertension and why that is is not clear. But part of it is because they have this whole that allows the RV if it's going to fail to just pop off and go right to left. So they get blue but they don't have acute heart failure but there may be other things intrinsic to the right ventricle that's been exposed to these abnormal flow patterns. That makes it more adaptive. And I'm going to skip the next few sides greater tonight. So as I talked about the the multitude of pathum biology's and highlighted material injury because as we transition to um therapies, all of our therapies to data based on Products made by the end of filial cells. So here are the three treatment pathways, the one that's most known to everyone as the nitric oxide pathway. Nitric oxide is made by arginine. It works through increasing psycho champion this muscle cell, you can break down segregation. P by giving by This enzyme passport data stressed type five. Um If you inhibit that with something as you may notice, sildenafil, you can augment that cascade. You can give and help nitric oxide to augment this cascade etcetera crossed. And it's known that nitric oxide is deficient in palmyra basket is similar across the cycling is deficient in homer vascular disease. That's made from ironic acid. Um And it works through psycho KMP and then in the feeling which is up regulated and put my vascular disease has a couple of receptors that you could potentially block therapeutically. So this is kind of the FDA timeline. Um I think it's quite impressive How many different drugs have emerged over the last 20 years or so. So before 1995, we had calcium channel blockers and a coagulation digitalis and diuretics. The first process cycling or flowing animal crossing over was in 1995 and held a nitric oxide circle because it's actually approved was approved for Children union respiratory failure was in 1999. The first and the feeling receptor blocker was in 2001 and then it's really just been um different formulations of these three cascades that have been helpful. Don't get me wrong, you know, instead of twice a day or once a day instead of three times a day pills once a day, suspensions for example, bo Sandton for pediatric suspension was recently a privilege. Um Oral process cycling's particularly the CeleXA pick really has promised. So things that um we only impact our patients daily lives, but the reality is it's just been the same three cascades that have been targeted. So, nitric oxide as many of you know, inpatient setting only and has really been the mainstay for acute pulmonary hypertension. The other way you can augment this cascade downstream is with oral agents, sildenafil Or to Dow fell, which is once a day so that it fills 3-4 times a day. And then downs Uh huh the enzyme that increased the psychic GMP is going to make side place for your sick watt has been approved for adults with Cf, we really don't have much use for currently in pediatric disease and the feeling as I said we bought the receptors of santa. Trade clear Comes with pills or suspension is given twice a day. There is about a 5% incidence of increased liver enzymes. So we have to monitor the monitor monthly with blood tests it's totally reversible. If you decrease or stop the medication it can cause some anemia. So point here is you have to draw blood on these patients percent and is a pill only um the incidents of liver function every melodies and much less and message to town is also um a pill with even less issues related to deliver. Then the process. Cyclones. Uh huh. A proportional is full and it was the 1st 1st 1 the mainstay and then a military is um one that's stable at room temperature fall and how to be in a cool cool pack. But this one can be at room temperature. It's mostly given I. V. But you can inhale it. Um, Trespass tunnel is a longer acting agents. Full land has you know half five minutes of patients would get um short of breath just with changing the cartridge and Kind of with a rebound effect of proximal has a half life of 2-3 hours. So it avoids that type of stuff. And the other thing for us is it can be given either ivy or sub Q. Which is what we use predominantly pediatrics similar to an insulin type pump. And this really reads our need for essential lines and the associated infection thrombosis etcetera associated with that. So we tend to start with sub Q. And if that fails because of site reactions etcetera, then we'll switch to ivy have a process and in held agent that we used in the ICU quite often. And CeleXA peck is the one oral agent, its receptor analog that we're using more and more. Um and I think it's really been very useful to get them off of these ivy and sub Q. It's not nearly as good as continuous therapy. Um, but it's not terrible and can really be in terms of quality of life. A nice alternative to cementing process. Acres the historical data Before it currently available treatments. The adult data was the median survival was 2.8 years With a mean five year survival was less than 40 Pediatric data. The average time from diagnosis to death was approximately 10 months of dismal dismal outcome. Let me show you the one drug that we have actually long term survival data and neuropathic former hypertension is ivy, Fulham. It's really the one drug where you can see A survival benefit. All the other drugs are studied and approved over four months with improvement in either pulmonary human dynamics or functional class or six minute walk etcetera but not survival. This is the one that has been studied and has survival, But I hope this gives you some some idea of what's been going on. These are registry um survival studies prior to 19 prior to 2000 a couple of days in 1999. And then if I superimpose the more recent survivals. Mhm. Registry studies with more of the aggressive therapies, I think you can see we're doing better. We're not curing these patients by any means, but we are making them feel better. We're making them live longer. Um And I think the field is really growing exponentially over the last decade. This is an interesting study recently where this was an adult study. We talked about starting one. Here's the problem as opposed to Cancer where a 75 year old man with prostate cancer in a 40 year old women with breast cancer are not labeled both with the same cancer and get the same medication. That's what former hypertension is unfortunately. So it's not based on any biology, it's just based on severity of disease. So it's kind of like if you only have mild disease, you get one drug and it's usually an oral drug. If it's modest disease, you get to drugs the two world types of two cascades. And if it's really bad disease and we get we had across the cyclone, it's called triple therapy. So it's barbaric. And hopefully we'll get you know, well start dealing with this drug like cancer does and really get to more personalized care. So this was a study where they used dual therapy. So they started patient was diagnosed. We weren't weren't on anything, they got to drugs which is considered pretty aggressive. We tend to just start with three drugs. But anyway at six months, Only 1/3 of the patient's got a 25% fall in pulmonary vascular resistance index, which is really not particularly gratifying quite frankly. So the point of this study is that um really combination and I would say probably more aggressive combination with triple therapy adding across the cycling up front is probably the best way to go. And I just want to um touch base. This is a a recent article in the New England Journal. This is an agent that actually normalizes BNP are too um Cast a this was patients of all kinds of video paths but they didn't necessarily have to have the NPR two mutations and they were already on therapy and then they added this and there was a significant improvement. So you can imagine probably the next trial is going to be on patients would be impure to mutations and I think this type of person more personalized or directed care therapy is really the future of the field. And in terms of surgical interventions you can create communications between the right and left side if there is none because as I said, prevents fainting, it prevents right heart cute, right heart failure, just get blue um something that we're doing is bringing back an old palliative care uh surgical procedure from for congenital heart disease. That's called the pot shunt where we create a communication between the left home my artery and the descending aorta. Um to offload that right ventricle. And this was the 1st 24 patients reported in France. And then this is just came out of 110 worldwide patients. And they had about a 35% overall mortality. But again these are patients that have been generally on triple therapy have failed medical therapy and have no other option except transplant. And so The one in five year rates of freedom for death or lung transplant was 77 and 58%. And for those I got home so they got past the peri operative period was 92% at one year and 68% For those discharged home with the meeting survivor of 12.5 years. I think this is a promising therapy. You really have to have a good team to do this. This is not or benign operation in a very high risk patient today. To UCSF we've done three dr ready does it? We have the one anesthesiologist that's done all three. Um The same. ICU team that's done all three and all three have done remarkably well there they were been excavated in the operating room after the procedure. They have Gone home within six days of the procedure. And all of them have had marked improvements in their exercise tolerance, been able to come off the continuous process cycle. And their echoes look, there are being looks much, much improved. In fact, one of the they were all teenage girls, One of them was in a wheelchair and now runs five miles a day. So I'm not not a cure. But you know, I think if you can hold off lung transplantation, particularly young patients since the results are not particularly great from translation transplantation currently, um this this procedure maybe something really worth considering in the right hands. And then this gets along to something that I feel very strongly about. This is not a disease, that it's a rare disease and it's not something that people should be dabbling on. This is I hope you can get the impression that this field is really dynamic and changing all the time. And there are specialized care centers were lucky enough to have both an adult and pediatric one within the CSF community were both approved by the Player Hypertension Association is Comprehensive care centers. This was studied from Pittsburgh where they oversee 40 different hospitals. And they some of them have specialist care centers for preventive detention and some of them don't. And then they they they retrospectively looked to see what the outcomes were and what they found was That if they were in one of the specialty care centers of the 40 institutions, they oversee the patients got more interventions, patients got treated more aggressively. And as you can see on this graph in blue that the patients had a better survival. So I think it's really important and I think the pediatric population is doing a great job of really working together. We have again this network of 13 North American centers That includes two Canadian centres and we do a lot of studies together. We do a registry together and we're learning a lot from each other. So in conclusion the neonatal and childhood trauma hypotension spectrum of disease with diverse path of biology. Understanding the role of industrial dysfunction is that the therapeutic targets that have markedly improved our outcomes identification of the spectrum of mechanisms related to different forms of ph may identify new therapeutic targets and guide individual therapies aggressive upfront therapy we think may be beneficial and specialty care centers we think improves outcome. And there's finally some adult data to back that up. I'll in here this is uh this is our team, it's a large team. It's so great to go to work every day because of this team. So we have our own you know specialist pharmacist um we have a pulmonologist, here's our nurse coordinator, there's r research coordinator. I mean our social worker Elizabeth is one of our great nurse practitioners doctor title run the division of cardiology is one of the initial interventional to see. He and Elena who's um a younger cardiologist, they do both of our they do all of our cardiac catheterization. So every ph patient is seen by the same uh pulmonologist, by the same interventional cardiologist, Claire Parker's or other nurse practitioner hiking the way, too is our Imager. He reads every single one of our echoes either officially or unofficially as well as these patients in clinic. This is our dietician And Roberta Keller's are neonatologists that we're so lucky. She started the program with me in 2012. And so we're very proud of the committed multidisciplinary team that cares for these patients because this is a multidisciplinary problem. And with that I'll stop and thank you for your attention.