Thank you for the invitation and the nice introduction. I appreciate it. I am local, so I'm on a meter, so I have to hurry up. So I've been given the task to talk about varied aspects of pediatric pulmonary hypertension in 15 minutes, so here we go. I have no disclosures that are relevant to this talk. I'll talk a little bit about the new definition of pulmonary hypertension, which is both adult and pediatric, but all the data is in adults. Go over a little bit about the classification and how that probably should be different in adults and pediatrics. A little bit about the pediatric epidemiology and some outcomes, and then I picked a few emerging issues related to pediatrics. We do a lot more genetic testing. And the emerging population of ex-preterm babies and then in congenital heart disease, where we're taking kids that were previously felt to be unrepairable because of their elevated pulmonary vascular resistance and then going ahead and treating them up front and then repairing them. So, as you know, the hemodynamic definition of pulmonary hypertension is a mean pulmonary pressure. It used to be, up until very recently, of 25 millimeters of mercury at rest and 30 millimeters of mercury at exercise, and a pulmonary vascular resistance calculated at three woods units. So recently, it was changed to 20 millimeters of mercury. This is the proceedings of the Sixth World Symposium, where they made that change. You still need a wedge pressure less than 15 and a pulmonary vascular resistance calculated greater than three. But I just want to go through why that happened. First of all, if you go through some very, very nice studies, the upper limit of the normal mean pulmonary pressure appears to be 20. In fact, these are things that came out of world congresses in the 1960s and 70s. They had these joint statements. And if you look, the mean pulmonary pressure is actually 14, and this goes throughout the pediatric and adult patients. A mean pulmonary pressure of 20 is a biomarker of worse outcomes in several different settings, including mortality and exercise-induced pulmonary hypertension, and this has only been shown in the adult world. So most of this data is derived from secondary forms of pulmonary hypertension in adults, not idiopaths. How this translates to the pediatric world is unclear. What we should really do with this in the adult world is also unclear. Do we need to look at these values of wedge less than 15 and a PVR greater than three? Do they need to be reexamined as well? How much will the number of patients that we actually see now and treat change based on this new definition? How often, when should we see these patients? And how will this affect clinical trials? These are all unanswered questions right now, but this is a relatively new thing in the field, so I thought it would be important to mention it. As you just saw in the previous talk, this is a classification. There's five different groups. In the pediatric world, it's kind of, we use the same classification, unfortunately, but then we have like one double prime, which is persistent pulmonary hypertension in the newborn because we have no idea what to do with that within this context. And as you probably know, epidemiologically, in the adult world, it's easy. Group one is the most common. Group two is the second most common, left heart disease. And group three, lung hypoxia disorders, is the third most common. So in pediatrics, obviously, we see PH within the context of chromosomal genetic syndromes much more commonly, issues related to developing and growing lung developmental abnormalities in lung hypoplasia, et cetera. So this, although we use this classification, it really, we struggle with it within the pediatric world. We've come up with different classifications. This is the Panama, and we probably, this was over 10 years ago now, so we probably need to re-look at this. But it includes prenatal or developmental pulmonary vascular disease, PPHN, which would be perinatal pulmonary vascular maladaptation. Obviously, pediatric cardiovascular disease is a big subset, not left heart. Bronchopulmonary dysplasia, the ex-preterm babies, et cetera. So we are, just to tell you that the classification is suboptimal for pediatrics, probably suboptimal for adults. And we are trying to alter it a bit. So this is the epidemiology of pediatric pulmonary hypertension. So it's quite different, actually, than the adult world. This PPHNetwork is a group of 13 academic North American PH centers, and we have a registry with over 50, now it's over 2,000 patients, but the first 1,500 patients. We just looked at the epidemiology, and as opposed to the adult world, where group one is the most common, actually group three is the most common in pediatrics, and that's most likely related to the emerging population of ex-preterm babies with chronic lung disease and bronchopulmonary dysplasia. Group one being the second most common, and they're pretty close with 43%. But as you can see, group two, left heart disease, is not very common at all, and similar to the adult world, group four and five are not common. These are some, just to give you an idea of the pediatric outcomes, this is Robin Dunbar-Ivey. These are some old survival studies in pediatrics prior to the advent of advanced PH therapies, and then if we just overlay some of the newer registry trials, just to give you the idea that we are improving survival in these pediatric patients, but similar to adults, at least with the idiopaths, you know, this is a lifelong disease. The kids with BPD, as they go through years of lung growth and vascular growth, they can come off medication, but for the most part, it's similar. So we can make them feel better, we can make them live longer, but to date, we're not curing them. Just to give you an idea of what BPD is, histologically, people talk about the old BPD, and this was related to the, they weren't as premature, but we used to really damage their lungs with aggressive ventilatory strategy. The new BPD, they're much less, they're much more premature, and the neonatologists take a much gentler approach to ventilation, so the histology is different. The definition is actually assessed at 36 weeks of gestational age, and they have to be treated with oxygen for at least 28 days, and if they're at 36 weeks, if they're on room air, it's considered to be mild. If they're on less than 30%, oxygen's felt to be moderate, and if they are on greater than 30%, require positive pressure ventilation, then it's considered to be severe disease. And this is a nice study of about 1,600, 1,700 patients, some with no BPD and no pH, of all BPD, no pH and pH, and you can see, basically, that on every category, if you have pulmonary hypertension associated with BPD, they do much worse. So their mortality is four times as high, remains hospitalized at one year corrected age is five times higher, et cetera, et cetera. The need for tracheostomy, ICU admissions, mechanical ventilation are all much higher if you have pulmonary hypertension. So these are the pediatric guidelines, and we actually treat these young infants just as aggressively as we would treat a 17-year-old with idiopathic pulmonary hypertension. We cath them frequently. We treat them aggressively with triple therapy, et cetera. So we treat them very similar to older kids. This is one study, maybe for this audience, it's not necessary, but in the pediatric world, we argue about whether doing cardiocatheterization is safe in these small babies. And there's many studies showing that utilizing ECHO is reasonable for screening these babies, but in terms of making management decisions, we believe pretty strongly that there's so much, so many false positives and false negatives that they really should be treated like other pH patients and have a right heart cath. The other thing is, these in the recommendations, the reasons to include a cardiocatheterization is because they can often have left ventricular diastolic dysfunction associated with the disease, anatomic shunts, pulmonary vein stenosis, which is a big problem, and systemic collateral. So we believe that you need to treat them, evaluate them aggressively. This is just one study showing prematurity in the incidence of pulmonary vein stenosis. It is frequent in those that have multiple veins involved, you're obviously much worse. And in this particular study, ECHO diagnosis was made in only 56% of them, and there was a median of five ECHOs needed before they made the diagnosis. So this is another reason why we do a cardiocatheterization in these patients. I wanna touch briefly on the genetic component of the disease as of now, if you look at the pediatric pH world, about 40% of these patients will be able to identify some genetic underlying issue relevant to pulmonary vascular disease, where in the adult world it's currently about 20%. I think it's in part because of the epidemiology, but I think in part because the pediatric population, we tend to try to do genetic testing on almost every baby now. So these are some of the genes that are associated with increased risk of pulmonary arterial hypertension. This list keeps growing. There's a second slide, because I can't fit them all. But I'll just mention a couple, BMPR2, which you know is the most common, both in the adult and pediatric pulmonary hypertension. And greater than 70% of hereditary pH is related to BMPR2. SOX17 is actually more frequent in kids with congenital heart disease that have pulmonary hypertension, irrespective of the lesion. FOXF1 is an important one for neonatal collies, because it's associated with alveolar capillary dysplasia, which is a fatal developmental lung disorder. So making that genetic diagnosis in the setting of severe pulmonary hypertension and respiratory failure is important. TBX4 has really emerged as an extremely interesting and important genetic mutation. In adults, if you have a TBX4 mutation, you present with small patella syndrome. So you have knee and hip problems, and you can have that classic toe spreading. In neonates, they present with severe neonatal respiratory failure and severe pulmonary hypertension. In adolescents, they can present with pulmonary hypertension. But adults do not present with pulmonary hypertension with TBX4 mutations. And this actually emerged as a second leading genetic mutation in pediatrics, with BMPR2 being first. So I will tell you that whenever we see a new young pediatric patient, we talk to the family about whether they have knee or hip problems, and we ask them to take off their shoes and socks and look at their feet, because it's really emerged as an important etiology. Okay, so these are just some more genes. This is a nice paper by Zhu et al, looking at exome sequencing, just showing that BMPR2 is most common and familiar with pediatric and adult. These are some of the genetic syndromes that we see that are associated with pulmonary hypertension in childhood, and there's a tremendous amount, as you can see there. But I really think it's been very, very important for us to identify these genetic syndromic associations. Obviously, it aids in identifying an etiology and or diagnosis. If they have a BMPR2 mutation, you kind of know what you're dealing with. Aid in identifying mechanisms of disease. Aid in guiding treatment strategies. For example, we had a patient with a rare mutation, Wendy Chung, who was at our meeting, was about to write up five patients with this mutation. They all died within the first two years of life, and we, with that knowledge, went ahead and treated her extremely aggressively. Besides triple therapy, we went on and did a surgical procedure to what's called a reverse POTS procedure, which, unfortunately, I'm not gonna talk about today, but it unloads the right ventricle by creating a left pulmonary aortic to descending aortic shunt. Purely knowing the course of that particular genetic mutation. And then aid in identifying potential novel individual as therapeutic targets, and there's an exciting new drug coming out that's related to stabilizing the BMPR2 cascade. So I really think once we get towards more personalized medicine in this field, this is gonna be one of the leading ways to get there. And then lastly, switching to congenital heart disease, which is a big subset of our patients. Many of you know that at some point, with these left to right shunts, the pulmonary vasculature is exposed to abnormal mechanical forces related to increased flow and pressure head. And at some point, if they get too old, or the resistance gets too high, the remodeling is too much, if you close the holes, you may get them through the perioperative period, but they're gonna reemerge with bad pulmonary vascular disease. And we have weekly cardiac catheterization conferences where there's always one patient that we're talking about. Was it safe to go ahead and repair them, or should we leave them and have them go on to be Eisenmanger syndrome? So this is a big question in our field, and it's an important one. This is a study by Maines et al in their clinic. They looked at different groups of patients, and as you probably know, Eisenmanger's patients have a lot of morbidity, but they live very long. That's the top group there. The pulmonary hypertension with systemic pulmonary shunts, where you have enclosed that are kind of pre-Eisenmanger's, they too, 87% survival at 20 years, and 86% survival at 20 years. Small defects, these are the small ASDs, which are probably not really related to the congenital heart disease. They're probably idiopaths that happen to have a small ASD. Their survival is similar to idiopaths, 66% at 15 years. But if you look at the subset of patients where we made the wrong decision and decided to correct their defect, and they actually didn't have reversible disease, they have the worst survival of all of them with 36% at 20 years. So it's a very, very important decision whether or not to close these. And we've come up with consensus statements, et cetera, but it's really kind of not, we don't really know what it's doing. One thing is clear, there's no absolute pulmonary vascular resistance at cath, which makes them a good candidate or a bad candidate. And when you kind of tease out the data, even biopsy studies, et cetera, age is the thing that comes up. The older you are with a high-risk lesion, the more risk it's gonna be. The AHA-ATS guidelines said repair should be considered if the PVRI is less than six or the ratio is less than 0.3. And then if it's greater than that, but with acute vasodilator testing, you can get it lower, you should consider repair. But if you can't get it lower, it's reasonable to implement pH therapy followed by repeat cath. And that's an important thing. We're doing it quite a bit now where we treat them up front with what we call triple therapy, something that augments the endocyclic GMP cascade, blocks endothelium and endoprostacyclin, and bring them back. And they've had very, very good results because pretreatments can reverse vascular remodeling. There's good animal data and some adult data that they not just dilate you, but they can reverse vascular remodeling. They can decrease the perioperative risks. And are they safe? Yes, if we're lucky enough to get them to develop a big pulmonary overcirculation, we can treat them with diuretics and then bring them back and cath them and then repair them. It's just one of many studies showing good outcomes with these treatment repairs. There'll be short-term outcomes, long-term outcomes, we don't know yet. And let me just end with this concept of upfront aggressive triple therapy because I think it's important. It's something we've been doing in pediatrics for a while. Of course, the adult world was great in showing it. So this is a really nice study from Bulkley et al where they look retrospectively at patients that were treated with monotherapy, almost 1,000, 984, dual, 551. So those are oral therapies. And then triple where they add a prostacyclin is only 76. But if you look at their first follow-up, which was on average about five months, so the green would be low-risk patients. Now this is retrospective, right? So there is definitely an inherent bias that the patients that were sicker got the more aggressive therapy. And you could see that in the baseline bar. There's very little green low-risk patients there or none actually getting the upfront therapy. But at first follow-up around five months later, you can see that that triple combination therapy is actually doing much better. And the triple five-year survival was 91% versus 61%. And we think coming from the congenital heart world that decreasing pressure and minimizing those bad mechanical forces probably has a lot to do with that. I'm gonna end there. If you wanna come back in San Francisco in March, I guarantee no more rain. If you're interested in neonatal and childhood pulmonary vascular disease, thanks very much.

pediatric pulmonary hypertension

new definition

classification

epidemiology

treatment and outcomes