Dr. Ryan Callahan and Dr. David Hoganson - Pulmonary Vein Stenosis

I think we're gonna go ahead and get started here. So we have 2 speakers today. Ah thanks. We have 2 speakers today, um, Doctor Ryan Callahan and Doctor David Holkinson, who will be speaking to us about pulmonary vein stenosis. Uh, Doctor Callahan did his undergraduate studies at Pennsylvania State University, and attended, attended medical school at Drexel. Uh, he then came to Boston Children's for his pediatric residency and then went on to do pediatric cardiology and pediatric and interventional cardiology fellowships here. Uh, he's currently attending in the division of cardiology. His research interests include coronary artery disease, anomalies in pediatric and young adult patients, and fetal interventions in children with congenital heart disease. Doctor Hogenson uh did his undergraduate studies in electrical engineering at Grove City College in Pennsylvania and then attended Temple Medical School. Um, he then did a surgical research fellowship at MGH and then went on to do a general surgical residency and cardiothoracic, uh, surgical fellowship at Barnes Jewish Hospital in Saint Louis. Um, in 2014, he moved back here, uh, for his pediatric cardiac surgery, uh, fellowship and, uh, has been attending in cardiac surgery since. He has been principal, principal investigator on several grants and has over 15 patents and several additional patent applications. Um, today, Doctor Callahan will be, uh, discussing the current approach involving the diagnosis, diagnosis and medical and catheter-based treatments. Pulmonary vein stenosis and then Doctor Hoganson will present the surgical treatment options and also his research, uh, investigating, investigating the potential role of left atrial transplants as a novel therapeutic option for pulmonary vein stenosis. Uh, please join me in welcoming our two speakers. Good morning. Thank you for the opportunity to speak today. Thank you for letting us, uh, double team this. Super straightforward topic. Um, all right. So, uh, we've no disclosures. Uh, so, we're talking about the pulmonary veins. Um, the four vessels typically that bringing back, that brings back oxygenated blood, uh, from the lungs to the left atrium. Uh, there's a few variants, but in general, there's gonna be two right-sided veins, 2 left-sided veins. So, not all narrowing or obstruction, uh, is gonna give you, uh, this true, uh, PVS, uh, which we'll go into much more detail. Um, some of the other mechanisms of, uh, pulmonary vein obstructions, uh, can be seen, uh, in children that's had, um, congenital heart surgery, for instance, uh, typically, the total anomalous pulmonary venous repair. Uh, other children can be Born with anatomic substrates that uh look like true PBS but may just be uh a kink, uh, as the vessel uh enters the LA. Also, each vein has different surrounding structures, which David will go more into. Uh, and it can, these vessels can be externally compressed, uh, giving you gradients by echoes, but not necessarily true PVS. And, uh, the adult. deal with post-op, um, post- atrial fibrillation ablations as well. But really, what we're gonna talk about today is intraluminal, uh, pulmonary vein stenosis, which has an incidence of 1 out of 50,000. Now, all these other mechanisms can lead to turbulence, which can then lead to intraluminal PVS, um, but it's important to identify the mechanism prior to going down, um, the treatment. Uh, pathway. And so, what is intraluminal PVS? So, here we have a, a normal vein with thin layers, particularly the thin intima and medial layer here. And then, uh, intramal PVS is neoinimal hypoplasia. So, thickening of the intial layer here. Uh, it begins at the veno atrial junction or where the pulmonary vein connects to the left atrium, and it can extend distally into the, in the vein into the lung. And this ultimately can progress to complete lumen obliteration and atresia. So what are these cells here? So when we've done biopsies on every single one of these pulmonary veins, um, they've all demonstrated these myofibroblast-like cells, um, that are depositing extracellular matrix and taking up space. So, why does this happen? We're not quite sure yet. We have a few theories. We feel there's certainly genetic susceptibility to this. Um, we think flow turbulence, uh, is definitely playing a role and perhaps mediastinum and systemic inflammation. But there's, uh, much more research to come to identify exact mechanisms of why this is happening. So, specifically looking at intraluminal PVS, what are the types? Uh, what types of patients, uh, develop intraluminal PVS? So, you could be born with it. You have a structurally normal heart, and you can have a sibling who also develops this, so there could be a strong genetic component, component. And that can be called isolated or primary or congenital. Uh, mainly primary, uh, PVS is, uh, the most common, uh, nomenclature. It can be found in types of congenital heart disease. I mentioned, total nonous pulmonary venous return. Some single ventricles and heterotaxis as well. And then the last group are patients with lung disease. And the most common presentation for that would be premature infants who have chronic lung disease, usually have pulmonary hypertension, usually have some sort of left to right shunt like a VSD or an ASD or a PDA, uh, and usually a history of neck. Um, and so, that particular combination, we see, uh, premature children develop, um, this intraluminal pulmonary vein stenosis. So how do you make the diagnosis? So, clinical, uh, presentation. So, if you have obstruction of flow, um, from the, uh, in the pulmonary veins, uh, the blood gets trapped, uh, in the lungs causing pulmonary edema. So here you have an X-ray with significant pulmonary edema. Uh, this leads to variable levels of, uh, respiratory failure, uh, and the Increases the pressures on the right side, uh, leading to right heart failure, all of which causes failure to thrive, feeding intolerance and irritability. So that's typically how these children present. And they can certainly present, uh, an extremists, uh, following, you know, a viral illness, uh, and end up in the unit within 24 hours. So, it can be quite, uh, severe. Um, or they can present with, you know, um, gradients found on echocardiogram. So here's an example of an echocardiogram. So this, uh, image scares me, uh, for sure. So this is a peristternal short axis, and here you have, uh, your right ventricle, and here you have your left ventricle. And usually, the circle shape is actually the left ventricle cause the pressure there is much higher. Uh, and it's usually bigger than the Than the right side. Um, but, uh, here, in this patient, you have a dilated, uh, right ventricle that's dysfunctional. And then the pressure is actually higher than that of the left ventricle, um, also known as supersystemic right sided pressure, and the septum is bowing into and pancaking this left ventricle. All right. Uh, here, you have a picture of the pulmonary veins and see, here's the left upper, here's the left lower, and you see some turbulence here. Uh, and you can, uh, map out a gradient using the Doppler, and here you have a gradient of 6. So echocardiogram is usually the first non-invasive imaging modality to make the diagnosis. Uh, we also use lung perfusion scans. They're very helpful to nuclear study, requires an IV for the injection. Um, and it's paired with the echo. And so, here's, uh, it tells you where the blood flow is going, um, to the lung. So, the injection goes to the right side and flow either goes to the right or to the left. And this patient, there's no right-sided pulmonary vein stenosis. And so, almost 90% of the flow is going to the right lung. Uh, and on the left side, there's left upper pulmonary vein atresia, and there's severe left lower pulmonary vein stenosis. And so, the flow to the left side is only 11%. Uh, then they undergo catheterization and balloon dilation of this left lower vein. And now post-catheterization, the flow to the left lung is 30%. You see more black dots to the left lower lobe. There are still a few dots to the left upper, even though the left upper is a retic because that blood flow has found its way down to the left lower vein through collaterals. And so, uh, lung scans are, are can be very helpful when they're paired with echocardiogram. Uh, we also use CTs, uh, mainly outside hospitals. We do a lot more cats here, uh, but we do still do some CTs and we do review a lot of outside hospital CTs. Uh, and they give you a great anatomic assessment of the pulmonary veins, and they help us, uh, uh, delineate the amount of lung disease the patient has as well. Here, you have a right upper pulmonary vein with severe stenosis here, left lower pulmonary vein with moderate stenosis, uh, here. Uh, we also use MRI. Uh, this is, uh, a patient with no intraluminal pulmonary vein stenosis, but an example of other things that can cause, uh, compression and, and gradients perhaps. And so here's the left lower pulmonary vein, and here's the aorta and the heart. You see during diastole, there's, um, severe compression of this, uh, of this, uh, left lower pulmonary vein. So compression without intraluminal PVS. And so, catheterization. So, we also use this, um, this, uh, cath to diagnose and also provide treatment for pulmonary vein stenosis. From a diagnostic standpoint, we can assess the hemodynamics with cardiac index, right-sided pressures, etc. Um, and then a full pulmonary vein assessment. We can delineate the mechanism of, uh, obstruction, uh, identifying any type of, uh, intraluminal, um, pulmonary vein stenosis, and really, uh, determine the extent of the disease and how much healthy Pulmonary vein bed is preserved at this point. And what, and how much, um, how many veins are involved, um, and within each vein, um, is the proximal disease is going into the lungs. So a full, uh, pulmonary vein assessment. Uh, and then we can forward interventions, we'll go into more detail about our first study, um, prior to surgery, which is our typical approach, we may do some dilations to, um, open up the veins a little bit, decrease the right-sided, uh, pressure in order to make them a better candidate for surgery. Um, balloons itself in the veins help determine vein characteristics. Uh, a more diseased vein is more non-compliant and so just simply putting balloons into a lesion can help, uh, determine vein characteristics. And then, obviously, we use cath, uh, after surgery if these patients develop restenosis, which, uh, can be very common in the aggressive subtypes. So, how do we treat this disease? So, it comes down to really single vessel versus uh multi-vessel disease. Single vessel, we're much more conservatively, these children can do well even if they lose the vessel. Um, and so we're not aggressive in terms of going right to surgery to, to try to fix these lesions. Uh, here, you have a left upper pulmonary vein with two points of obstruction here as it crosses the left bronchus and here as it's entering the heart. Uh, we do balloon dilation and it opens these two areas up. Um, and that may have been the only thing we would do from an intervention standpoint. However, if the patient needs to go to the OR for additional surgeries such as ASC closure, which happened in this patient, they did, they also did fix the left upper vein. Um, but no aggressive, um, surveillance, no aggressive, uh, pharmacologic therapies, uh, and may, may not even have surgery. The Multi-vessel subtype, that's another beast that's much, can be much more aggressive, and we first make the diagnosis, we're not sure how often these patients are gonna recur, how often, how aggressive this disease is, so we kinda manage everybody the same. And certainly, if they, they could undergo one cath and one surgery, we won't see them again, and that's great. Uh, but they could be the other phenotype where, uh, the disease is relentless and it continues to recur. And so, we use this multi-modality approach to all our patients until they declare themselves that they're gonna be in the aggressive subtype or not. Um, and so, we first cath these patients. We talked about making a diagnosis and optimizing for OR, uh, and then they undergo surgery, which David will talk about and changing the anatomic substrate and removing as much disease as they can. Um, and then we give, uh, we give pharmacology, we give drugs, which we'll talk about, uh, to try to prevent this neoentomal hypoplasia, to prevent the proliferation and to slow this disease activity down. Um, The drugs don't kill these cells, but rather they try to alter their cell signaling and, and decrease cell proliferation. Uh, the families have an option of undergoing lung transplant evaluation. Um, At the time of diagnosis or later, uh, we aggressively watch these patients initially, uh, monthly with monthly clinical assessments, echo, lung perfusion scans. At least monthly for 3 months after any type of intervention. Um, if you watch them less frequently, you're, you can lose veins in, uh, in that, in that, uh, time period. Um, nutrition is incredibly important. They, they all have feeding intolerance. They all have failure to thrive. And so, um, we have to, um, get our GI colleagues involved, do a full feeding evaluation, consider GEJ tube, uh, as well. And the lung evaluation is, is critical. So, we've, um, certainly, lung disease can lead to pulmonary vein stenosis, but we've also found that patients with active lung disease, um, such as persistent chronic lung disease, persistent aspiration, uh, it can keep the pulmonary vein disease active and recurrences can, can continue to occur. And so, a, a very broad lung evaluation with aggressive therapies is, is important. And we usually anticoagulate these patients with aspirin. So now let's focus on um the catheterization, what it can provide. We talked about the initial cath for hemodynamic and anatomic assessment plus minus interventions, and then, then they go to surgery and now we're watching very carefully with echoes and lung scans. So, when do they, when do they go back to the uh cath lab? When do we suspect restenosis in these vessels? Well, it's probably a multi-factorial decision. Certainly, a change in clinical status. If they're at home, asymptomatic, and then they develop respiratory symptoms, feeding intolerance. Those are usually uh the symptoms they develop. We'll rule out confounders such as infection for sure. Um, If there's a change in echo and lung scan, that'll get you back in the cath lab or we might schedule a cath selectively based on the last cath, um, or the last surgery. Um, Uh, in order to catch you before you get too sick, essentially. Uh, so my cardiology colleagues in the room think about this a lot. This is what I think about when I'm, uh, for risk stratification, um, in these patients, uh, into the cath lab. And so, essentially, um, if they're coming from home versus coming from the ICU on the ventilator, or even worse, they're hanging out on 80s, grunting away on, on, uh, 2 L. Um, uh, that increases your risk, uh, the degree of RV failure, um, Not just RV dysfunction, but also the degree of right heart failure symptoms in general. Uh, their RV hypertension, so if they're super systemic versus subsystemic, uh, and really the amount of preserved unobstructed pulmonary vein bed, uh, and their age. So, I know a patient coming from home who has subsystemic RV pressure and good function, who's over one with just left-sided disease is probably gonna do OK with that cath. Um, but the one coming from the ICU won a ton of support with retic veins, who's under 1. It's gonna be a tough day at the office for sure. Um, so let's just look at some angiography here to get a sense of what, uh, what I see in the lab here. So this is gonna be a normal, uh, pulmonary vein here. You have a catheter going out the, uh, from the IVC going through the right heart and pushing dye into the right lower pulmonary artery. It goes through the lung and then comes back through the pulmonary vein here. This is the right lower pulmonary vein. It's good size and it's completely unobstructed as it connects to the left atrium. So, no evidence of disease there. Same patient, we're excluding the contrast from the right lower vein and it's being injected into, excuse me, the artery. It's injecting into the right upper pulmonary artery. And you see unobstructed pulmonary venous return in the right upper arm libo face here. So here's another example of external compression without intraluminal pulmonary vein stenosis. So we're injecting into the left lower pulmonary artery. You see the venous return come back here through the vein. It's good size, no evidence of intraluminal disease. You see something happens right here, the contrast kind of thins right where this pigtail catheter is, which lies in the descending aorta. This is a lateral projection, so this is the anterior chest and this is the spine. And here's that pigtail and the descending aorta. And so as the vein goes anterior to the descending aorta and posterior to this left heart, it becomes an, an ellipse or a slit. And so, that tells us there's external compression, but no intraluminal disease there. And so the full anatomic assessment really um uh tries to identify how many veins are involved in, in the, in the stage of intraluminal PVS and we'll go through each stage individually here. Um, and so here we have mild osteostenosis. So I mentioned the disease starts at the veno atrial junction. So, good-sized vein out here. Um, you can see my mouth. And then, uh, as it connects to the heart, there's some mild narrowing here, OK? So then it progressed to severe osteostenosis. Now we have a catheter inside the left lower pulmonary vein. All that vein is healthy, and good size, uh, but the, the sheath itself is completely, almost occluded occluding the flow, so severe osteostenosis right here. This is kind of a unique case. Uh, you can end up having paroxximal tresia, so the connection between the vein and the atrium is completely lost. However, the pulmonary vein bed is still, uh, healthy and preserved. Uh, this is probably severe obstruction that then clotted off and, um, severe compression rather from a large VSD and a dilated left. Heart and, uh, and ultimately just kind of clotted off, uh, without significant intraluminal disease in the vein. But you can have proximal resia where the connection between the vein and the heart is lost. Pulmonary vein bed is intact, uh, and you see some collateral, some decompressing. Blood finds its way back to the, to the right heart here through the innominate and the SVC. Uh, so now there's another lateral projection. So here, a decent sized vein, uh, out into the lung, but here the narrowing here is more lung segment, greater than 5 millimeters. So now we're starting to develop more distal disease, and severe lung segment stenosis. Now it's extending even more distally. So this was after a dilation of this ostium here. But you see how the disease causes some irregularity now into the segments of the lung, not just the left upper vein itself, but into each branch of the, of the, of the left upper. Similarly, disease extending distally into uh branches of the left upper. So good size anterior, but disease at the origin, disease creeping up into the apical and posterior segments here. Now diffuse distal disease. So just kind of spaghetti strands going way down to the way out to the lung, diffuse distal disease. We can't dilate this or make this better. Um, and the next stage here will be distal atresia. So this is a catheter injecting out into the left upper lobe way out here, and then the vein ends way out here. So a diffused distal resia. The heart's over here and it's, it's ending way out there. So, what tools do we have in the cath lab? We have balloons, conventional balloons, and then we have cutting balloons. We have blades that can come out of the, of the balloon at full inflation. Uh, we have stents, uh, bare metal stents. We have drug-eluting stents where there's, uh, these stents are coated with drugs, uh, and covered stents. And then we've been lately using some intravascular ultrasound to, to look at the integrity of the veins. So what, what works, conventional versus cutting, um, they're both effective in decreasing the gradient and increasing luminal size, um, no difference in outcomes. And we typically, typically, we use cutting balloons for, uh, resistant lesions. So, uh, here's a lesion on the left lower pulmonary vein. There's osteostenosis there. Uh, here's conventional balloon dilation. You see this is the lesion, this is the waste, it's going away with the oon. Now, the vein's unobstructed. Uh, So, this lung is floating in her pleural fusion which we tapped, but then there's a moderate osteostenosis here. And you see the conventional balloon kinda milk out, kind of a resistant lesion here. And so now we have the cutting balloon, so then at full inflation of the blades come out and this weight goes away. Uh, to cut the lesion, and now it's, uh, improved angiographic, um, angiographic improvement there. So whenever we consider a stent, it's complicated. Uh, we think about the clinical picture. We think about if there's a geometric component to the obstruction, if the veins kinked or compressed, or there's atrial tissue obstructed in the ostium. A, a balloon will just push that away and when the balloon comes down, it'll come back. And so we, uh, consider a stent. Uh, recurrent stenosis in vessels at least 7 millimeters, less likely to develop stent stenosis. I'll show you that. Um, perhaps I'll recantalize the red vessel. And then there's been some, uh, uh, recent, uh, anecdotal data and some unpublished data from Houston saying the drug-eluting stents are ideal and small stents, uh, small stents are necessary, uh, like under 5 millimeters. But the challenging of stents is that they can jail other vessels. So this stent is in the lingula vein and it jailed the upper here, that's obstructing its flow. Uh, it can develop significant instant stenosis. So, here's the vein caliber here and the stent goes all the way out here, and this is all filled with other types of proliferation. Uh, another example of instant stenosis here, the stent goes out here, but the lumen is all the way in here. Uh, so there's risk of needing additional surgery to remove these stents. The stents might not be able to go to adult size. Uh, so there's so many challenges to stents. Uh, do they work? This is where I got the 7 millimeter, uh, diameter, uh, study from, from Goff at Boston showing that at least a 7 millimeter stent is associated with freedom from, um, re-intervention and significant in stent stenosis. And the adults have shown this too in their Afib population, so even 10 millimeters would be more ideal. Um, but clinical picture, so let's think about this child. He had 4 vessel disease. Uh, the other veins had stabilized. There was no re-stenosis, and it was just his right upper bringing this kid back to the cath lab, so we decided to try something different, uh, with the drug-eluting stent. So here's a severe stenosis in the right upper vein, really occluded by the 1.3 millimeter uh, uh, catheter. After balloon dilation, still residual obstruction. So we placed the 3, 0.5, uh, drug-eluting. Uh, drug eluting stent. It's unobstructed and now the kid's been out of the cath lab for over a year. Another example of a stent, uh, this is a common vein that was reastomosed to left atrial appendage. Uh, there's some atrial tissue here, pecting the muscle. There's some, some, some mechanism I don't quite understand, obstructing this vein. Had two previous caths where balloons alone failed. Uh, so we put a, a drug-eluting stent in, jailed, these vessels, but unjailed them by putting balloons up them, and now increased flow and have kept the kid out of the cath lab. Uh, here's an example of intravascular ultrasound, where we put the ultrasound inside the vein itself. Here's the lumina of the vein, and then, and here's the outside of the vein, and here's this intimate medial layer, this, which I think is the neointima hyperplasia. Uh, and this has been very helpful in, in helping me, um, choose balloons, choose balloon types and sizes, and, and thinking about these lesions a little bit more. So, it's interesting. Um, we're busy. Uh, the number of caths we've done and the cath lab has increased. We're averaging close to 100 now. Uh, and that's because our patient population, uh, and referral-based population has increased and our, and our survival has improved. Cases are not without complications as the cardiologist in the room will tell you. Um, out of all these cases, a third of them had some kind of adverse event, level 1 through 5, and then 12% had a serious adverse event of level 3 to 5 and, and 1 death. These serious adverse events are, um, mainly arrhythmias, uh, injuring the veins that were dilating, uh, causing significant injury, respiratory symptoms like cyanosis, worsening pulmonary edema, blood in the ET tube. Uh, strokes, human dynamic instability, and cardiac arrest. So, um, Um, your, the cardiology anesthesiologist in the room can, you can share war stories for sure. Uh, so thinking about the pharmacology and, and what medications we are targeting at these, these lesions. So, uh, study done in 2006, um, performed immunohistochemical analysis on these cells, um, that we're taking, uh, from surgery and they demonstrate strong and diffuse immune reactivity to the tyrosine kinase receptors, PDGFR and VEAGGF. And so we use Gleevec to target the PDGFR and the Avastin to target the VEGF, hoping to decrease the cell signaling, decrease the cell proliferation. Um, Gleevec is by mouth, Avastin is IV. It requires a central line, so we only use that in the higher-risk kids, so most of them got Gleevec. And we gave this uh to 48 patients, mainly just Gleevec, to a single arm, um, uh, so 48 patients in a single arm perspective, FDA approved trial. These patients had aggressive disease, they're multi-vessel disease. And initially, just a feasibility study to look at how well these drugs are tolerated, and they were 1% of all the adverse events reported were definitely related to the drug. And it ended up being 16 adverse events. And that was determined by the drug, uh, the DSMB, none of which were serious. So they, they tolerated the drugs. Uh, and then stabilization, which we defined as 6 months without re-intervention or 6 months without restenosis. That was associated with patients who didn't have lung disease. So this is telling us that kids who have lung disease are still recurring and then patients who got more of the drugs, or a higher percentage of the eligible doses. So the kids that got at least 90% of the Gleevec, um, were more likely to stabilize. So there's something there. We didn't prove it. It wasn't a randomized, um, uh, you know, um, there's no control, not a randomized trial. We can't really do that in this population. Um, but there, there's some role in some kids and we're, and we're looking into that more. So these are the first patients referred to BCH, uh, uh, and then this is the results of the patients who were in the study. So 77% survival, uh, at 72 weeks, so probably, um, I think for 73 or 2 years. And, um, The first drugs we gave were more cytotoxic than blastin and methotrexate, using, using the same aggressive therapies of surgery and cap. Um, and, and those 28 patients survival was 28% and so we're doing better, uh, in the most aggressive population. Uh, so who's responding to therapy? So, patients who are discharged from the hospital, they're not going to the ICU after intervention. The intervals between cats, if they are developing re-stenosis, are spacing out, and eventually, the disease burns out at the age of about 3 or so. Um, and so you might see a kid during the first year who's going to the lab every 6 weeks, and then during the second year, every 3 months, and that continues to space out to about 3 or 4, and they're not in the lab anymore. And if they're growing and thriving, that's a huge sign if their low RV pressure is lowering. And who's not really the opposite of everything above. And that's the frequent flyers that you guys see often in the hospital. But most of our kids are doing well. So who, to predict the future, uh, I get a lot of these consults from outside the hospital. So, um, they asked me what, what chance does this kid have. So, what we know is that, um, uh, the age of presentation, so if they're less than 6 months, Uh, if they have bilateral disease, if they have distal disease in these vessels, um, and if they have high pulmonary artery pressures and RV dysfunction, these are all associated with mortality. Um, and so, um, you know, the ex-premie who's 3 kg, who's super systemic with a retic left side. And distal disease on the left is not, that's the extreme example, uh, it's not gonna make it. Uh, so I thank you and Caroline like thanks you. And so David's up next. We'll get you some questions after. All right. Thanks. All right. Thank you all for the opportunity to do, uh, to share with you today. I'm gonna switch gears and talk about the surgical approach to pulmonary vein stenosis. We're gonna talk about the current surgical approach and how we do it as part of a multimodal therapy and then, uh, at the end, talk about a, a new transplant concept, uh, for pulmonary vein stenosis. Uh, so Chris Barrett is the surgeon in our group that's really tackled this disease along with Ryan and the rest of the PBS team. Unfortunately, he's out of the country, so he couldn't be here to talk about his work in the current, um, And developed approach for surgical therapy for pulmonary vein stenosis. So I'm gonna share his results and his approach, uh, but I'm going to start off with some observation that he and others have made about potentially some of the mechanistic drivers of pulmonary vein stenosis. And really the, the concept is that there's, um, there's potentially some anatomical compression as Ryan showed some images of. Uh, within the, within the chest. Uh, you know, and, and the reality is that there's no free space in the chest and everything is next to something else. And for pulmonary veins, which have generally low pressure when they're next to structures that have higher pressure, they're subject to compression. And so Chris and others have identified um uh several uh um etiologies of this compression, pulmonary hypertension, ectasis, and high airway pressures as contributing to uh compression of these veins. So, if we go to Nedder for a second, you can see on the, on the, uh Right chest here, the right, uh, pulmonary artery is uh right adjacent to the right upper pulmonary vein. If you have pulmonary hypertension, uh, as a premature infant, you can have compression of this right pulmonary, uh, vein. And, uh, and potentially leading to narrowing or stenosis. And similarly on the left, the left bronchus is right adjacent to the left upper pulmonary vein and somewhat adjacent to the left lower pulmonary vein, we've certainly seen evidence of uh bronchus compression of the left upper pulmonary vein. And if you look at the distribution of the, of the veins that are involved in pulmonary vein stenosis, I think this is clear. Uh, so 98% of these patients have right upper pulmonary vein stenosis, and almost all of them have pulmonary hypertension. Uh, and the left upper is the next most common, uh, and left lower, both subject to compression, and the right lower pulmonary vein is the one that's most, uh, unaffected by an immediate, uh, adjacent structure. And so this, this, uh, um, looks like it very well may play a prominent role, uh, in the development of pulmonary vein stenosis in these kids. So here's a CT scan showing the right, uh, pulmonary artery adjacent to the right upper pulmonary vein. You can see some indentation and narrowing of this pulmonary vein. And the, The thought is twofold. Number one, you can certainly have some, just some anatomical compression and narrowing, uh, but the bigger issue is that this can lead to flow changes and turbulence within the vessel, changes to the endothelium. Other groups have shown that endothelial to mesenchymal transformation is the principal sort of uh driver of how the pulmon the fibrotic pulmonary vein stenosis starts. So the thought is that, is that a little bit of compression can beget flow changes can sort of incite true pulmonary vein stenosis and not just a narrowing. Uh, and that's the, uh, uh, and that's the interest. This is a CT scan showing the, uh, left main bronchus compressing, uh, the left upper pulmonary vein. And I think this is very interesting. So this is a patient with some adectasis, uh, and a little bit of shift of the, of the cardiac mass into the left chest. And with that, uh, you have the aorta here and the aorta is now compressing the left pulmonary vein as the, as the heart is just subtly shifted. And uh we've seen on patients who have a gradient on the left lower pulmonary vein and then undergo recruitment of their lungs in the ICU, eliminate the ectasis, and the gradient either completely goes away or decreases. So there's definitely a true effect. Uh, of these anatomical compressions, uh, and, uh, Chris is now working with, uh, some engineers at Georgia Tech and trying to do some computational fluid dynamics to understand the, the fluid disturbances associated with this compression and, uh, trying to understand how that can lead to, uh, uh, pulmonary vein stenosis. So this is an area of ongoing work, uh, but I think it certainly plays a role in some of these, uh, some of these patients. So we look at how we repair pulmonary vein stenosis. Uh, the, uh, conventional, uh, technique was to, uh, open these pulmonary veins in the posterior aspect, um, Uh, of the heart and then sew the left atrium right to the uh open pulmonary veins, uh, and, and try to get past areas of stenosis that may occur within the vein. This is a, a kid who was total anomalous pulmonary venous return, um, and there were, um, poor outcomes associated with sewing right to the veins and the thought was that in sewing directly to the veins, you, uh, you elicited more of this, uh, scar tissue within the veins. And so many years ago, Uh, we as a field developed this, uh, uh, and adopted this sutureless repair where, uh, it doesn't not use sutures, uses a lot of sutures, but rather than suturing directly to the veins, you suture around the veins to the edge of the pericardium, creating more of a pericardial well that the veins can then drain directly into this well and then back in the left atrium. And so this is the, the quote unquote sutureless repair that is used by most centers around the country for, uh, sometimes for primary, um. Uh, therapy, but, uh, but most often for recurrent pulmonary vein stenosis. And uh Chris has really uh modified this concept of uh sutureless repair in, in his current approach. And not only are the pulmonary veins opened, but he actually aggressively resects the pulmonary vein disease out into the first and sometimes second order branches. So it's not just opening the veins, creating a well. And having them drain into the left atrium. He actually, uh, is very aggressive about resecting the pulmonary vein stenosis, even opening atretic veins that have a, a portion of uh of uh lumen uh further out into the lung and trying to get all the fibrous tissue, uh, resected from the veins. And so some pictures here of what this looks like. So there's a patient uh on the heart lung machine, you see the cross clamp is on, the heart's been stopped, and the cardiac mass has moved out of the way and you can see the left atrium and the left pulmonary veins as they enter the pericardial space. And then the left atrium is open and these veins are opened out into the lung. Um, and, and actually now, uh, Chris is aggressive about going pretty far out into the lung to get rid of whatever uh fibrotic disease um there is, and, and often this is, uh, as Ryan said, right near the ostium, uh, in the connection left atrium, trying to resect all that disease, uh, and get back to healthy uh pulmonary vein tissue. On the right side, a very similar, uh, approach is taken where the left atrium is opened and then these veins can be opened out, well out into the, uh, into the lung itself, uh, outside the pericardial space, and the, uh, uh, the stenosis, uh, can be resected. And so the, the change in the last few years, uh, and Chris's approach, uh, from a, a standard sutureless repair has really been the concept and the observation he's had where if you can, uh, if you can get a healthy endocardium of the left atrium adjacent to healthy endothelium of the pulmonary vein, uh, his observation is that those patients have a better outcome. Uh, as opposed to just resecting whatever pulmonary vein stenosis you can and then just leaving those veins in free space to drain into the pericardium, which of course is not endothelial tissue, and so then they have to span this non-endothelial tissue, and he thinks that that's, um, uh, potentially eating. Etiology for recurrent pulmonary vein stenosis. Uh, and so his approach now is to try to resect as much of the scar tissue as possible and get out to an area where there's healthy, uh, pulmonary vein and where possible, bring that, uh, back and connect that to the left atrium, uh, a nice endothelial to endocardial connection. Uh, now, realistically, that's not always possible. So the reality is it's a bit of a hybrid approach where some veins, and some patients may have more of a sutureless approach where you actually sew around the vein, uh, to the edge of the pericardium, but when possible, he tries to get an endo, endothelial, endocardial connection, um, and, uh, um, this has been a focus over the last few years, so we'll see, uh, in time if this, uh, if this truly makes a difference and we're impacting, uh, the recurrence rates. So our volume uh for surgical pulmonary vein stenosis repair, uh, this is a partial year of 2017, uh, has grown substantially in the last several years and now doing 10 to 15 cases a year. Um. Uh, as Ryan said, the age of pulmonary vein stenosis is really focused on younger kids. Most of them are less than 2 years of age, and there's a, uh, and the majority of them are in sort of in the 3 to 8 month time frame. Um, and so, uh, once you get, uh, uh, quite a bit older, uh, as Ryan said, the, the disease tends to burn out. So the challenge here is that the outcomes are still very challenging. Um, this is our data which, which is among the best that there is and still have 44 year survival of less than 60%. And so if you think about all the rest of the congenital heart disease and our, our survival of, you know, our operative survival of, uh, you know, better than 97%, uh, you know, this remains a very, very challenging group of patients. The, uh. Uh, and the approach of the PBS Group has been a very aggressive multimodal approach with medical management, catheter management, uh, chemotherapeutic agents, and very aggressive surgery, and still we're sitting on, uh, just better than 50%, uh, survival at 4 and 5 years. And so I think this, this remains a, a significant challenge and, uh, uh, and the question is, you know, is how to Uh, how to really impact this disease process, so our survival can, can dramatically change. So I'm gonna share with you a concept that we've developed, uh, and are starting to pursue, uh, and that is a, uh, basically a new transplant, uh, therapy, uh, directed at pulmonary vein stenosis. Uh, we've called it left atrial transplant, uh, and I'll show you exactly, uh, uh, what it is. But basically, you know, the, the driver of this is the, is the fact that pulmonary vein stenosis, uh, outcomes remain very marginal. Our group has a, uh, Almost 60% survival of 4 years. Other, uh, very busy groups have 5-year survival, uh, of about 50%. Um, and, uh, these patients die from recurrent pulmonary vein stenosis. That's the, uh, the driver of their, of their clinical outcomes. Other centers, uh, use lung transplant as a primary therapy for recurrent pulmonary vein stenosis and don't do any of the chemotherapeutic, um, uh, treatments. Don't do any, uh, aggressive pulmonary vein stenosis surgery. Uh, lung transplant itself is, is a palliative therapy for PBS for sure. The short-term outcomes are excellent, but the 5-year survival is basically the same. It's in the 50 to 60%, uh, uh, range with a median survival of 7.5 years for kids. The reason kids die after lung transplant is bronchiolitis obliterans, uh, which is fundamentally the rejection of the lung parenchyma. Uh, after lung transplant, you don't have recurrent pulmonary vein stenosis, and that is not what you die from, whether you have a lung transplant for pulmonary vein stenosis or lung transplant for another reason. And so the concept of the left atrial transplant is really building on the strengths of lung transplantation, um, and the outcomes of pulmonary vein stenosis, uh, for lung transplant, but eliminate the risk of, um, of bronchiolitis obliterans and rejection of the lung parenchyma. So essentially what we're gonna do is we're gonna, we're gonna do a lung transplant without the lung tissue. So we're going to transplant the left atrium. We're gonna transplant the individual pulmonary veins, uh, as far out as we need to, resecting all the pulmonary vein stenosis and getting healthy native vein to healthy donor vein, and we're gonna leave the lung parenchyma in place. Um, so we're basically gonna, uh, try to affect the long-term positive outcomes of lung transplant and pulmonary vein stenosis and avoid, uh, the rejection of the lung parenchyma tissue. And so how we're going to do this, we're gonna, uh, we're gonna harvest lungs uh from donors who are rejected for traditional lung transplant, whether that be because there's not a suitable recipient for the age and blood type, uh, or there's marginal lung function, their PO2s are low, they have lung contusions or other, other things which we don't care about because we're not gonna use the lung tissue. Uh, and we're also going to be able to use the DCD donors. So donation after cardiac death is, uh, is a means by which many other organs are used for transplantation, including adult lungs. Many centers now are doing adult lung transplants for donors who have donation after cardiac death. Uh, in the pediatric population, we currently do not do that, uh, for pediatric lung transplantation. So this is going to open up a whole new donor pool that is not currently being utilized. The way we're gonna do it is harvest the, the lung block in its entirety, uh, just as we would do for a normal lung transplant. So this is not gonna affect, uh, heart transplant. The, the heart team will still be able to harvest the heart exactly as they normally would, uh, and use that from the donor. Um, and the whole lung block is going to be brought back and then based upon the patient's individual anatomy, uh, the, uh, the length of each pulmonary vein is going to be trimmed, uh, and utilized exactly what we need, uh, uh, to transplant for the patient. And so we're putting together an initial uh clinical trial to, um, to look at this therapy. Uh, it's a safety study to address the feasibility of a left atrial and pulmonary vein transplant. Uh, the pilot study is going to include 5 patients. Primary endpoint is going to be, uh, 30-day survival with the secondary endpoints of survival at 6 months and then pulmonary vein patency, uh, uh, gradients and right ventricular pressure. And so that we're gonna um focus on initially patients who have uh fairly focal disease as Ryan showed you, these patients can run the gamut from isolated disease right at the left atrium, uh, pulmonary vein uh connection to very focal disease way out into the lung. And so we're gonna focus on patients who have a fairly focal disease of one or more pulmonary veins, and I think eventually this therapy may be able to be used for patients who have disease a little bit further out into the lung, but it's never gonna be a good therapy for patients who have that, uh, that diffuse disease way out into the lung. Those patients are still going to be, uh, best managed by lung transplantation. Uh, there's a litany of contraindications to this therapy. Most of them are centered on normal contraindications to transplants, um, but certainly diffuse pulmonary vein stenosis, we're not going to tackle. Um, some of these patients have very significant underlying lung disease, uh, as Ryan pointed out, and, uh, those patients are not going to be great candidates for this, um, because their lung disease usually Uh, defines the overall clinical outcome. Uh, some of these patients do have irreversible pulmonary, uh, artery hypertension. Much of the systemic or super-systemic pressures are due to pulmonary vein stenosis. When you take that away, um, you can, uh, you really get their RV pressures down, but some patients have had it for long enough, uh, that that's not the case, and we're, we're not going to be able to, uh, to treat those patients. These patients are going to require immunosuppression, um, just like any other transplant, and I think that's, uh, really the, the fundamental paradigm shift here is that we're, we're going to offer patients uh, a non-solidd organ transplant. We're essentially transplanting vascular tissue, and they're going to undergo the risk of sort of full immunosuppression. Uh, but I, you know, I think you all can see that the outcomes of this disease, uh, are such that, uh, that for this patient population, I think that's warranted. Um, and, uh, the approach is gonna be to, uh, treat these patients like normal heart transplant plants. So they're gonna get the normal, uh, complete heart transplant immunosuppression, uh, protocol. Um, I think over time, we're gonna be able to reduce the immunosuppression, uh, regimens in these patients. Uh, we don't know exactly what to do, but I think that it's uh very conceivable, uh, that we'll be able to get these down to very low, uh, chronic, uh, immunosuppression, um, uh, doses. Uh, for these patients. Um, the follow-up imaging is going to be done with echo, CT, and lung scans. Uh, we're gonna reserve catheterization for patients where there's a question of the, uh, their anatomy and potential for, uh, uh, areas of pulmonary vein stenosis. Um, but unlike all other, uh, salt organ transplants, we're not gonna, uh, do any routine biopsies for immunosuppression management. You can't really biopsy the pulmonary veins to the left atrium. Uh, and so these patients are going to be empirically managed, uh, for their, uh, immunosuppression. Um, uh, certainly there's a lot of interest in developing, uh, biomarkers, uh, that can, uh, demonstrate, uh, rejection of vascular tissue, but right now we have, uh, we have no such thing because all of our solid, so, solid organ transplants have been based upon, um. Upon, uh, in total organ function as well as, uh, biopsies and, and, uh, certainly we're not gonna have any of that, uh, for these patients. So from an immunosuppression standpoint, this is a, this is a whole new world and, uh, and hopefully we're, we're gonna be able to, uh, to whittle down the immunosuppression, uh, over time. Uh, so the current status, uh, is we've, uh, just in the last couple of weeks, uh, received IRB approval after what you can expect was a very lengthy process. Um, the New England New England Donor Services is starting a separate review of this. They've been extremely, uh, supportive, uh, of this, uh, of this therapy, um, and the, uh. Uh, the National Organization that controls transplantation, Eos, uh, uh, we've, uh, had discussions with them over, uh, over the last couple of years as we've been putting this program together and they, um, They're a slow moving organization, and they said that it would typically take an expected 2 to 3 years to Uh, to develop what what is essentially an entirely new, you know, area of transplantation and a whole new waitlist and all that stuff. So, um, so we're not going to be able to, uh, roll this out as a, a therapy outside of New England, but they have provisions within, you know, so you can do regional-based, uh, research programs. And so we're going to do this as a region one research program. So all the donors and all the recipients, all the recipients will be here. All the donors are going to be within the New England region, the Region One, for the, you know, sort of national, um. Um, you know, regionalization of the, of the transplant services, um, and, and from that, uh, we'll be able to apply to Yos for, uh, uh, for making this a, a, um, a national therapy. Uh, we've been screening prospective patients, Ryan and I, for quite some time. Um, but once we have approval from New England donor Services, they'll be, uh, uh, strictly evaluated, uh, with a multidisciplinary team consisting of basically everybody, uh, heart transplant, cardiologist, and the entire extended heart transplant team, the lung transplant pulmonologist, uh, the, uh, the pulmonary vein stenosis team, and then Francis and Thompson and I, uh, will be, uh, the surgeons, uh, together for all these cases, so. Uh, it's been a huge effort. Um, there's a ton of people who have contributed and been involved, um, in getting this off the ground, and, uh, I'm very appreciative, uh, for all the effort, and, uh, it'll be interesting to see. And I think there's a lot of enthusiasm and hope that for this very difficult disease, not all the patients, but some of these patients, you know, this may be an opportunity for, uh, you know, for good long-term outcomes. Uh, thank you guys, and we'll be happy to take any questions. Ryan and David, I'd first like to thank you for your excellent presentations. This is obviously a very challenging area and with still 60% survival at 5 years, we obviously still have ways to go, but it's exciting to learn about new areas, particularly the transplant. Ryan, I have a couple of questions and then I'm, I'll I'll throw it up to the audience. So are we learning anything more about what the underlying process is that causes the intermel hyperplasia and the pathogenesis of the disease? And, and second, with your drug therapy, I noticed that you're using antiangiogenic agents, and I usually think of that as Them as preventing new vessel growth and not necessarily having an effect on internal hyperplasia, so I'm interested in, in how that's working out. Yeah, no, thank you. Thank you for your questions. Um, yeah, I think the, you've heard a few of our theories up here. I think the exact mechanism is, is, um, is, is unclear, like why, and I, uh, and it spawned. Future research studies right now, we're, we're working on doing a case control study of uh these preemies. So the preemies that we have here who've, who've developed, uh, the PBS and um compare them to those who haven't with, with this, um, um, controlling for as many things as we can and to see if, cause that, that might be a population that we could identify earlier and, and prevent. And so, I think, um, our theory is that it's coming down to an anatomic substrate, um, and looking for Um, trends that cause turbulence in these veins and looking for certain populations that might be at more, uh, more at risk, but, uh, there's a long way to go in terms of understanding, um, you know, the genetic susceptibility to this and, um, potentially, uh, and then any other unknown risk factors. So, and then we haven't, um, you know, we don't have a clear Basic scientists on our team yet working with us to kind of take a closer look at, at these cells. And I think we, um, we still have, we have a lot of samples and it might be interesting to see, you know, which, there might be more groups that will, why that some people respond to the therapies and Gleevec and why some don't. So, and then with your question for Avastin, I mean, um, yeah, it's a pretty, um, This was undertaken, this started like 10 years ago by, uh, pioneered by Doctor Kathy Jenkins. She's the one that has never really given up on these patients ever when historically, most, uh, uh, physicians and institutions have, and, uh, um, has, has pushed for more and more thought and more innovative therapies. Um, and, uh, I think we, the quick answer is I, I, I don't know. And I think we're learning more about these drugs. Not, not many of our patients have gotten the Avastin. Um, it was only Um, it was, uh, less than 15 less than 10 in our trial, um, and it's been reserved for the patients that are the highest risk. Um, and those we think are the children that have the primary PVS, the ones that are born with it with structurally normal hearts, the premature patients, and then the ones that fail Gleevec only. And so, um, I think we are only giving the Avastin to the highest-risk kids and they aren't, aren't doing as well. And so we're not clear if, uh, if that's Helping them or not at this point. Um, and then, um, but I think the, the drugs were selected very carefully with, um, Um, under the guidance of Doctor Mark Karen, an, an oncologist at Dana-Farber, and so he felt that, and Kathy felt that there was enough evidence from the pathology specimens that, uh, and the immunohistochemical analysis that they're This might block the cell signaling, might block the cell proliferation. Um, but yes, it is used in other, um, therapies and we're, um, Um, Yeah, I think that's it. Yeah. Additional questions for Ryan and David. Doctor Hickey, you deal with these nice healthy patients all of the time. The, as, as was observed by our, my colleagues up on the stage, that the patients with pulmonary vein disease and recurrent disease and uh. Super systemic levels of pulmonary hypertension are substantial anesthetic challenges as well. And since we see these patients repeatedly for echoes, for caths, and sometimes for surgery, uh, we'd, we'd love to see a real solution to this problem, to the kids that have recurrent disease, and I think. Uh, the, the concept of having a left atrial transplant with the pulmonary veins intact is potentially may get around the, the primary site of the pathophysiology. So, from the anesthetic side, we'd welcome some way to get, get, get these kids some, some relief and uh get out of this very high risk anesthetic category. Additional question, Doctor Liliha, you transplanted lungs for a long time. Uh, David, congratulations. This is really an exciting new, new domain to, to explore. I, I, uh, there are a couple of questions I wanna ask you, and, and obviously, it's tissue that's not gonna be used otherwise. So, from a, from a donor point of view, to be able to make some, some beneficial use of this is, is an exciting opportunity. Uh, two questions, uh, just, uh, anatomically. One is that Whether you have to uh match in terms of size, or whether you mentioned that most of your patients are in that first year of life, and, obviously, those are donors that, that are harder to come by, and wonder whether you could use larger donors, and, and remodel that tissue. That's number one. Number 2 is that we'd, we'd been taught, and maybe erroneously, that, that, uh, in doing the lung transplants, we didn't want to, so the pulmonary veins, more likely to re-stenosis, and that's why we did an atrial to atrial anastomosis, and I think that's part of the reason that we weren't seeing uh stenosis at that level. concerns in that regard. Yeah, uh, for sure. So, yeah, this is, uh, Tasha is correct. This sort of flies in the face of conventional surgical teaching and the pulmonary veins are sort of like the pancreas, you just don't touch it. Uh, and so, um, so I, I think, you know, they're, um, I think the reality is we don't know exactly how these are going to respond. Um, as far as the size match, I think in the beginning we'll be very careful to be within a reasonable range of matching the size, and as we learn, we may be able to oversize a little bit. Undersize is not the issue, as you know. It's not that you have lots of younger donors, it's you have donors who are a little bit older than this time frame. And for, for us, just for, um, you know, relative perspective to get a heart for a 3 month old child is typically about a 3 month wait. And so these donors are very hard to come by. Um, I think expanding it to basically anybody, um, who is, you know, willing to undergo the DCD process or uh anybody who, um, who has, uh, you know, um. Is undergoing a donor who's not using their lungs, uh, the the potential wait times are actually gonna be very short. Um, and so I think, um, and certainly, you know, we didn't talk about it, but, you know, we typically transplant lungs within 4 hours of harvest. Uh, but for these, since we're not. Using the Prechema, we've opened the time based upon some other research we've done with preserving umbilical veins to 24 hours. So we're actually going to have a 24 hour window to transplant these. So, eventually, you know, once we're open to the whole country, we can take, we can take loans from San Diego. And so I think, I think once this is open to the national. Um, you know, donor pool, we should have extremely short wait times in the order of, you know, we think a couple of weeks, uh, for these patients, uh, and get hopefully a suitable sized donor for that. As far as the pulmonary veins, um, you know, certainly the, the question is, you know, if you do an end to end anastomosis, I think we all, uh, can expect that would be a potentially dicey situation. So the plan is. Actually do a, uh, do an overlay anastomosis where we open the native pulmonary vein and open the donor pulmonary vein and overlay them. And so in the area of anastomosis, we're going to have almost a double diameter anastomosis, uh, to account for this concern about, you know, pulmonary veins, you know, scarring down a little bit, uh, in the area of the sutures, etc. Uh, we'll use, you know, 70 PDS suture. Just like Chris does for the pulmonary vein stenosis surgery. So I think we're going to try to avoid some of those by anastomotic technique, um, but I think, I think that's the, that's the million dollar question in this, in this therapy is, are the pulmonary veins going to be able to heal and remodel in a way that doesn't scar down and that anastomosis stays open. I think, you know, I think once we get through that initial period of time and things stabilize, we're going to be fine. So, but hopefully, you know, increase in the size of that anastomosis will, uh, will do just that, so. We'll see. There's no questions, Doctor Fishman. I'm not smart enough to ask that question, just a comment, um, given his, his belief that angiogenesis and the biology. Related to that would go well beyond cancer. I'm pretty sure that the grin in Doctor Folkman's uh picture got a little bit wider during this presentation. Any additional comments or questions, Doctor Holtzman. Thank you very much for this glimpse at the, at this very complicated future. Um, that was just an outstanding presentation. I have a corollary question to Craig's, which is, um, assuming part of the difficulty with this is in the cell signaling process, even if we don't know what the mediators are, has there been any thought to immunomodulated uh xenografting? Um, you know, I think, I think that's a, um, The short answer is no, but, um, you know, the, the solid Oregon teams that have approached stenografting, uh, still, um, have had a lot of challenges. But could you overcome that for just vascular tissue? I think, I think potentially. Um, and I think, you know, the other question is if it's, if it's purely um. Uh, you know, looking for a healthy endothelial surface. Um, my background's in tissue engineering, one could, one could theorize you could actually build a atrium and pulmonary veins that, uh, you could match these patients, see them with your own endothelial cells. I think that's a, another sort of, you know, in the xenotransplant category of sort of a far out therapy that potentially would make sense. So, I think, I think if this works with standard allogeneic transplant and. Suppression, I think it's maybe gonna open, open the question of, you know, are there other ways to do this, uh, if, if really the goal is, is essentially healthy vascular tissue, and that's what we're aiming for. The back, left atrium, I think could be anything. I mean, currently it's muscular tissue doesn't really contract and contribute a tremendous amount to the atrial function. So, um, so I think it's going to open the door for a lot of, a lot of possibilities. So that's an interesting thought though. Well, Ryan and David, thank you much more once again for your excellent presentation.