Rajeev C. Mohan, MD, explains the pathophysiology of Pulmonary Arterial Hypertension versus Pulmonary Venous Hypertension, and reviews diagnosis and treatment options.
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good. All right. So we're going to move on to our next speaker in the conference. This is Dr Mohan Raj Mohan. Who's going to talk about pulmonary arterial hypertension? Its lungs. Uh, Dr Mohan came to us from Philadelphia. He did are the cardiology fellowship here. And I recognized a great clinician and scholar when I saw one. So I lured him into the world of heart failure and pulmonary hypertension. Uh, he went to Cedars Sinai and in a fellowship in Advanced Heart Failure, and then came back here and has really been a star at scripts in the years that he's been here. He runs our cardio oncology program and also our cardiac amyloid program and is the director of quality for Scripps Memorial Hospital here. So he's accomplished a lot in a few short years and has a lovely young family as well. So, Araj, tell us about the lungs and pulmonary hypertension, please. All right, well, thanks for that introduction, Dr Heywood. I appreciate that. Mhm. All right, so we're gonna be talking about pulmonary arterial hypertension, and as Dr Heywood mentioned, it's really key to kind of differentiate between Paul Marie arterial hypertension. What we call pre capillary hypertension versus probably Venus hypertension or post capillary hypertension. So one thing to take away from my talk today, I think, would be, um, to always ensure that there that you have a clear idea of whether or not, uh, whether it's pre or post capitalist hypertension, because the treatment strategy is going to be very different. Um, but we're going to focus more so on our on pre capital hypertension today. Let me just make sure I can advance the slides that right. So objectives for today who to treat. So we'll quickly review the W H O classification of falling hypertension. We'll review how to diagnose pulmonary pretension and compare and contrast the path of physiology between arterial and venous hypertension. Talk about when to treat review guidelines for initiating treatment specifically geared towards early intervention to prevent Harvey dysfunction and then how to treat. So what are the treatment options based upon wh group and a lot of this. You know, some of this will will be reviewed from what Dr Heywood said, and you'll also hear more about this in the talks to come. But I think it's important to help solidify this this information by hearing a couple of times a day, so we'll start off with the case presentation. So this is a 56 year old woman with a history of hepatitis C with cirrhosis who was referred for evaluation. She began to experience shortness of breath and was evaluated by her primary care physician. Had several months of progressive dismount exertion. She had been treated for hep C before uh, and had been cleared of the virus but did develop cirrhosis. She had a PE ruled out, as that was. One of the first thoughts is the cause of her of her shortness of breath, Um, and then an echocardiogram, and that showed RV enlargement with pay pressures that were elevated. And so she was referred to cardiology so that echocardiogram revealed at a pressure of 75 with a mean pressure of 45. So here's what that echocardiogram looked like, and you can see here both in the short axis and the long axis. The RV is enlarged. The LV is kind of impinges, unable to squeeze as well, and any time we have evidence of RV enlargement, Anara enlargement, where it's bigger than the left side of the heart, and we know that there's significant RV dysfunction and there's significant elevation in the pulmonary pressures. So this is the short axis view here, and this is looking now at the mitral inflow, which suggests that the left atrial pressure is probably relatively normal. So that's another clue that we use to help differentiate between pre and post capillary hypertension. So she underwent right heart catheterization, which showed a significant elevation and implement pressure. Um, up to 79/33 wedge pressure of 13. So here already, we've made the diagnosis. Now pulling arterial hypertension or pre capillary hypertension, Um, and you can see some other human dynamic parameters there. Her cardiac output and index were quite low and are PVR polio. Vascular resistance was quite high. 10 woods unit. So we're going to review all of that in the coming slides here. So to go back, how do we classify Palma hypertension? W H O classification kind of separates it into five general categories. Group one, Pullman Hypertension Is that due to pulmonary vascular disease, some of the things that can cause this or connective tissue diseases, Dr Keating is going to be reviewing this a little bit later. Liver disease or Puerto pulmonary hypertension? We see a lot of we work very closely with our culminate with our liver transplant team, and so many of those patients have to be evaluated for elevation. And they're pulling pressures as this is a contraindications to liver transplant. Um, and so we, in conjunction with them, help manage their port of Palma hypertension in order to make them eligible for liver transplant. What we're seeing a lot more of now is Pullman hypertension related to toxins, specifically methamphetamine. Um, it's becoming a plague here in Southern California, with many people developing Pullman hypertension related to methamphetamine use but also cardiomyopathy related to methamphetamine use. So we're seeing much more of that. But there are some other, um, uh things that can cause, uh, this, including certain chemotherapeutic drugs used for a variety of different cancers may also be idiopathic, and there are some forms that are heritable. It's thought to be related to remodeling of small vessels, and we'll talk a little bit more about this in a minute. Um, group to Pullman, hypertension is due to left heart disease, So this is all post capillary hypertension, and that could be for a variety of different cardiac reasons. Reduced EF Heart failure, preservative heart failure, restrictive cardiomyopathy, valvular disease. You can see the echo on the left is somebody with reduced. You have heart failure, and their pulmonary pressures may be elevated as a result of elevation in their l G D. P and left atrial pressure. Same thing for the echo on the right. This is somebody with cardiac amyloid that has very stiff left ventricle, and that's caused an elevation, the left atrial pressure and thereby an elevation in the pulmonary pressure. So that, of course, is all group to cardiac related Group three. Uh, this is due to lung disease, and Dr Fan is going to be reviewing this a little bit later. Um, this can be related to COPD obstructive sleep apnea, interstitial lung disease, pulmonary fibrosis, all kind of lung prank camel Um, uh, disease diseases that can ultimately lead to hypoxia and vessel constriction. Leading television and polling pressures. Group four Uh, this is related to chronic thrombosis, bolic disease, or CTF. So patients who have ongoing issues with V T E can develop Palma hypertension as a result of this because of the chronic embolization to the lungs. We've seen a fair amount of patients with this as well. So to review Group 11 large category that I left out here for Group One is, uh, congenital heart disease. And of course, doctor, I'll show up. They will be reviewing that a little bit later. So in addition to congenital heart disease, the most common things that we see are either liver disease or connective tissue disease. And then again, toxin related specifically methamphetamine group to kind of differentiating these colours, mostly to help differentiate between pre capillary, which are in the blue, and then post capillary, which is the heart related elevation pulling pressures due to heart failure. Um, Group three again due to lung disease Group four due to chronic metabolic disease. And then there is a Group five, which is sort of multifactorial disease, a variety of different human logic disorders. Sickle cell anemia. Uh, hemolytic anemia is can cause Pullman hypertension as well as sarcoidosis. There's a sort of hodgepodge of different things that's all in Group five. How do we make the diagnosis of Palma hypertension? This is often diagnosed as part of an evaluation for shortness of breath. Um, and the destiny of work up should always include an echocardiogram. And Dr Heywood kind of alluded to the importance of that already provides information about the overall LV. An RV function provides an evaluation for structural heart disease and really provides an estimation of pressures in the heart. And that's really the key component of cardiac dismisses. What are the filling pressures inside of the heart? So when we're reading echoes as part of our kind of assignments that we get over the course of a month, I always look to see what the reason for the study is. And if it's shortness of breath as the cause of or the reason for the study, that kind of hones us in to know to look for filling pressure, abnormalities and, really, you know, ensure that we're doing an assessment for what the pulmonary pressures are. So what are the things that we're looking for? So wall motion abnormalities, If there is ischemia presenting a shortness of breath that would obviously be concerned if there's obviously a change in ejection fraction or evidence of some sort of cardiomyopathy? Certainly that could cause shortness of breath, valvular disease and human dynamics arrangements that can happen as a result of that aortic stenosis. Much regurgitation, of course, that can all cause shortness of breath. But really, what the key finding is the filling pressures. That's what actually causes cardiac shortness of breath is the elevation and filling pressures in the heart, which ultimately leads to elevation and competition for space, essentially in the lungs between air and fluid. So Palmer artery pressure is a key component there, in any echo with Tommy systolic pressure greater than 40 even 35 deserves a closer look to see what's going on. And that's true of even in patients that have an echo for for something else. If they have palpitations and they're getting an echocardiogram is part of a routine work up and they're pulling. Pressures are high, even if they're not complaining of shortness of breath. Or that's not part of the indication for the echo. Any elevation pulling pressures by Echo certainly deserves a closer look. So this is a kind of a slide that helps sort of helps us differentiate certain echo parameters when we're looking at Pullman arterial hypertension versus pulmonary venous hypertension. You can see there in the middle. There's a number of different categories or parameters measurements that we look at the RV size. Um, again. Like I mentioned the first case, the RV may be enlarged more so in Pullman arterial hypertension than in pulmonary venous hypertension. Although it may be enlarged venous hypertension, too. The left atrial size really is very helpful, and you can see those examples. They're kind of the middle of the left side of the middle of the right side, showing the kind of shrunken down size of the left atrium in palmar arterial hypertension versus the dilated left atrium that we commonly see in pulmonary venous hypertension. Other things where, how the interracial septum is moving, whether or not there's notching in the outflow signals coming out of the right ventricular outflow tract. That kind of gives us a clue as to whether the pressures are elevated and then the rest of the couple of the other parameters there are related to the diastolic function of the heart. So, of course we're doing an assessment of the diastolic functionalities echoes. If there is an abnormality in the diastolic function, Um, and they have other risk factors for diastolic heart disease, then it's, you know, often there. It's usually related to that, as because of the fact that the heart failure is much more common than true pre capital department hypertension. But the key to making the diagnosis is the Swan Ganz catheter. So if we have somebody where the pulmonary pressures are elevated by echocardiogram, they have shortness of breath. And we're not entirely clear whether it's Pullman, Venus or pulmonary arterial hypertension. Then we go to the the Cath Lab and do a right heart catheterization to ensure and get a better understanding of what their pressures are. We don't always have to do this because if it's clear cut that it's probably Venus hypertension. Then we don't necessarily do right heart catheterizations and all those patients. But if it's not sure if we're not sure, then we certainly do have to do a swan. And the reason for this is we get all this information that sort of laid out here. In this picture, we get an assessment of the R A pressure RV pressure P a pressure, but the key component of what we can get is an estimation of the left atrial pressure. And that's done, of course, by the Parliament Kappler wedge pressure and then, using those parameters we can. We can measure the pulmonary vascular resistance. And that's another clue that helps tell us whether or not this is left sided heart disease or pulmonary venous hypertension, or whether this is more of a pulmonary arterial hypertension situation where there's more intrinsic lung disease. So here are the parameters that we look at specifically what we're doing right. Heart catheterization So mean pulmonary pressure greater than 20 millimeters of mercury defines Palma hypertension, and that's been reduced over the course of the last several years. Before, we had a definition of greater than 25 millimeters of mercury. But now we're realizing that that group between 20 and one and 25 they may have a higher risk, uh, as well. And so we've sort of lowered that threshold to make the diagnosis of pulmonary hypertension again. The key component is knowing what the wedge pressure is. If it's greater than 15, that typically is more consistent with pulmonary venous hypertension. If it's equal or less than 15, that is more consistent with arterial hypertension and Then again, that's just the first step in making the diagnosis. We then have to go further and define whether which you know what's caused apartment hypertension. So if it's arterial hypertension, then there's subsequent work up that needs to be done to assess for whether it's Group 13 or four. Um, And then if it's group to, uh, there's other assessments, of course, that most likely have already been done by echocardiogram to tell us whether it's related to reduce your heart failure. Preservative heart failure, valvular disease potential restrictive cardiomyopathy is infiltrated. Cardiomyopathy is that kind of thing. One of the key measurements that we make is the pulmonary vascular resistance, and this is defined as the mean pulmonary pressure minus the Pullman capital wedge pressure, something we call the transformative gradient. We divide that by the cardiac output, so that gives us the resistance within the pulmonary circuit. Um, and typically, uh, in patients with an elevated mean pressure and normal wedge pressure, you can get a sense that that transparent gradient is going to be quite high. And so the woods. So the result of the PBR is on the high side. We use woods units to help define what the PVR is so greater than six is typically, uh, more clear cut for pulmonary arterial hypertension, whereas less than three is more clear cut for pulmonary venous hypertension. But then there are those patients between three and six, even beyond six. Sometimes that can have a mixed picture where they're mean. Pressures are very high, but they also have an elevated Pullman capital wedge pressure. These are more complicated cases, like the 11 of the ones that Dr Heywood mentioned before. So we're going to focus again on on kind of treating, um, the arterial side, and we'll leave out. The pulmonary venous side is believed Dr Srivastav is going to be covering that coming up. So who to treat for groups 13 and four Again, it's key to make the ones we made the diagnosis of pre capillary pulmonary arterial hypertension. We then need to go further to figure out which group this patient, what's causing the pulmonary arterial hypertension? Um, and again, it's because the treatment strategies are vastly different, So part of it is taking a very thorough history. Certainly if they've had a history of connective tissue diseases congenital heart disease. And if there's anything that comes up on the echocardiogram that's suspicious for that liver disease, toxic exposure, these are all things that will help us kind of categorize them between 13 and four. Of course, if they have severe sleep apnea or severe COPD or pulmonary fibrosis, then that is also helpful in making a distinction between which group they may be. They may fall in other diagnostic testing that is often done and that we do to help differentiate our things like pft s sleep apnea studies Hi rez CTS to look for fibrosis and then in a C T angiogram or VQ scan to look for, uh, pulmonary embolism or evidence of chronic thrombosis. Bolic disease. So what's the path of physiology of pH? It's really a vascular apathy of small vessels in the pulmonary circulation, and it comes down to an imbalance of signals. There's certain signals that are beneficial vaso dilator zor growth inhibitors, and it's generally an anti thrombin attic state versus on the other side and visa constrictors type signals. Proliferation signals an approach from Biotic State, and it really comes down to an imbalance of these signals and What we can see as this develops over time is a worsening of those things, including internal hyperplasia, hypertrophy of the medial tissue as well as the advent Tisha and then eventually thrum biotic lesions within within the vasculature itself. So you can see here on the bottom, you can see kind of the progression of what can happen starting with phase of construction, then remodeling and inflammation of the vasculature ultimately forming these plexus form lesions and then thrown Bostic lesions. Yeah. So when is the right time to treat these patients? The goal is to, you know, as cardiologist, we you know, we have a tendency to focus on the left ventricle. We have all these medicines, devices and coronary stents. Everything that we do, a lot of what we do is to preserve the left ventricle, but palma, hypertension, and it's a lot different. Of course, you know, it's the goal is to save the right ventricle, and we don't really have a lot of treatment options that are directed towards the right ventricle in terms of cardiac specific, even mechanical circulatory support on the right side is somewhat limited. And so what we need to do is treat the Pullman hypertension earlier and earlier. And that's why I kind of said before that it's important to do an evaluation in anybody who has elevated Pullman pressures by echo, mostly because that that may progress unchecked. And the patients may develop RV issues, RV dysfunction and that once that happens, that starts the spiral of multi organ involvement, including congestion of the liver, congestion of the kidneys. Um, and then those patients are much, much harder to treat, and their mortality goes up significantly. So you can see here the dotted line is the peripheral vascular resistance you can see as things progress that just continues to get worse. The pulmonary pressure goes up to a certain point and then starts to come back down, mostly because the right ventricle isn't capable of generating pressure is that high anymore? But as that happens, the RV starts to fail and the right atrial pressure you can see on the bottom line that starts to increase. So once the right atrial pressure starts to increase and stay increased with the drop in Pullman pressures, that's a key sign that those patients are really far along into RV dysfunction and so the key there is in our minds to help treat this before it gets to that point. We use the W h O R N Y classification for patient functional status, and they're pretty parallel in terms of their descriptions. Class one. No limitations class to mild limitations with usual activities, Class three, market limitations. And in class four sort of limitations at rest. Okay, um, so how do we How do we treat when do we start treatment? So if we've confirmed pH by the by our right heart catheterization, we typically do a visa reactivity testing in the catalog at the same time we use inhaled nitric oxide. And, um, this is to see if there's a There's a small subgroup of patients with pH that will respond to calcium channel blockers. And if they respond to inhaled nitric oxide testing in the cath lab, then they maybe responders to calcium channel blockers. So you know, it's rare that patients are true responders, but we do this testing in the event that we find somebody that may fall into this small cohort of people non reactive, which most people are. Then we kind of categorize them into low or moderate risk and high risk, so low or moderate risk our patients in better functional class status without some of these high risk features, which are listed over onto the right. So what are the high risk features that we get very worried about? So patients have had a history of sync api that we think may be related to Pullman hypertension. That's a red flag sign right off the bat. Um, we had a case, actually, of a patient who was being evaluated for sync API by one of our partners. And, you know, they went down the arrhythmia route. They had to monitor that did not show any arrhythmia. They had a implantable loop recorder. Placed, which did not show any arrhythmia, eventually had an echocardiogram. They live far away. And so there was some issues with coming back and forth eventually had a echocardiogram that showed Palmer pressures that were measured in the nineties. And so my partner came downstairs and said, Hey, can you take a look at this eco? This patient has Pullman hypertension and, you know, in talking with my partner, she explained that the patient had episodes of syncope E and I said, You know, that's right. There is a concerning sign. And so we just admitted him directly from clinic and did the right heart. Cath got him started on combination therapy, which is listed there, and he's actually doing much better. Uh, he's basically an entirely new men, which is great. He's also abstained from using methamphetamine, which which is great. So if we have patients that have this high these high risk features, then those are patients that we start off with combination therapy right off the bat. And often we use I V therapy in those patients. So going back to our case from before our woman with Hep C and cirrhosis, who is referred and then diagnosed with Paul Material hypertension. She was started off initial initially on combination therapy with Pio treatment, as she was more functional. Class three, not so much class four, and she didn't really have yet a lot of signs, high risk features. Um, so how do we treat patients? What are the agents that we use when we're talking about combination therapy? I v therapy that kind of thing. So there's really three pathways that we target when we're when we're treating pulmonary pretension. That's the end of feeling pathway, nitric oxide pathway and then the process cycling pathway. Thankfully, for something like Palme hypertension, we have these multiple pathways that we can treat. We can start patients off on single or combo therapy and eventually, often patients who are kind of refractory. You end up on some sort of treatment for all three. End of feeling and pathway. The target of therapy is an antagonist for this end of feeling receptor. Again, it's going back to that seesaw slide that has pro is a dilator factors and anti proliferation factors versus the factors that are pro vessel constriction. So these therapies are targeted, reducing vessel constriction and proliferation, or promoting those agents that increase visibility, ation and anti proliferation. So in the first category, the End of feeling pathway, these are antagonists for the end of feeling receptor because they're in the feeling receptor, when activated, promotes basal constriction for the nitric oxide pathway. There's sort of 22 options that we can target. Inhaled nitric oxide, of course, is the direct agonist and increases basic salutation. Or we can use the fossil diasporas pathway and it inhibits fossil diaries. Type five, which then helps promote base of dilatation and then the last pathway, the process. Cycling pathways and agonist pathway. So these are derivatives of process cyclones, ivy, oral subcutaneous that we can inhale that we can use to promote facilitation. So there's a variety of different medicines, um, in each of these different pathways that have similar mechanisms of action. Um, examples here are listed Bo's Centene and Percent and Massive 10 10. And then the Feeling Pathway Doctor would already mentioned sildenafil to Dallas fill in the nitric oxide pathway as well as real gigawatt, which works in the nitric oxide pathway and then, in the process, cycling pathway again. Like I mentioned, we have lots of different avenues for treatment. I v p o as well as subcutaneous. So there's some. We have a variety of different options available. Sometimes we start patients off on all P o therapy. If they progress and aren't doing as well, then sometimes we may need to transition to I V therapy, and the goal is to improve their functional status. We measure that with six minute walk testing and again to prevent RV failure and preserve already function for as long as we can. So we do serial assessments of their functional status. Using six minute walk test in the hallway, screening blood work with certain medicines. We do need to look at LFTs periodically. We do do echocardiograms periodically to assess RV function as well as an estimate of pressure that way. And we do also do right. Heart cats are listed here every 3 to 6 months. It's not that frequent. It's probably more every year. If patients are stable, we'll do a right hard cap to ensure that we're treating those pressures adequately. We have a low threshold to add the second or third Asian agent and start combination therapy predominant, particularly if they're not symptomatically improved, or if they start to develop some of those high risk signs like we reviewed before, um, and early referral for consideration for long transplantation before the development of significant Army failure is key. Um, and you know, other end organ damage, which can ultimately happen again. Liver failure, renal failure, those kinds of things. In rare cases of severe elevation, MP a pressure could consider a natural step tosta me. This is more of a palliative measure And that's just to reduce our A and R V uh, pressure. And then, in those instances where UM, what if there's obstructive shock? But due to a P E, for example, um, patients can be supported on temporary mechanical support to help the R B as it recovers from from the insult so we can use ECMO. There are other trans catheter right side of ventricular support devices available as well. In those instances, um, so that was all the review of Group one Palma hypertension. Because those medicines are geared and studied towards predominantly, the data is in the field or in a group of Group one Pullman Hypertension Group three, which again Dr Fan Review, predominantly a Perenco process. Bottom line from From, uh, is to really treat the underlying lung disease, whether it's aggressive treatment of the COPD, pulmonary fibrosis, that kind of thing. Rarely we do use Palmer. Antihypertensive is on occasion in this group of patients. It depends on certain instances if they have some evidence of severe right ventricular dysfunction, and we're trying to reduce the pressures as best as we can, and they've maxed out on other therapies. Occasionally we will consider them. Same thing with group for anti coagulation. Of course we can use or a single watt in combination with an end of feeling receptor antagonist. Um, And then surgical evaluation and experience center is key. Thankfully, we have our partners at UCSD for this, and we have sent several patients over there to be considered for pulmonary Mm. Vasectomy. Essentially. So going back to our case, 56 year old woman with a history of Pepsi and cirrhosis referred for her pH. She was started on combo therapy with paddle, a filling mass, attentive and seen in clinic initially monthly. And she had a pretty dramatic improvement in her symptoms. Functional class went from four down to two over the course of several months. And we had a plan initially for surveillance. Right? Heart catheterization. What you can see here is the echo from several months later. So the first echo on the left that long Preston along axis shows, um, our RV dysfunction in our small l b. And now you can see on the right after treatment. Harvey function has improved pretty significantly. Um, and the size of the army has improved as well. And this is just the same thing in the four chamber views. So pretty dramatic improvement once we were able to treat her Palmer hypertension and she was stable like this for some period of time over the course of a year. 18 months, actually. But over time started to develop worsening of her liver disease, ended up developing some evidence of portal, hypertension, portal, hypertension or abdomen, developed viruses and underwent a tips procedure. And after the tips procedure, something changed her. Whether it was the flow coming back into the venous system, her polling pressures went back up significantly. She became much more symptomatic. Uh, and we did do another writer cat at that time and showed that her pulling pressures were back up. Unfortunately, so she was started on an I V. Therapy is a third agent and then, um, started the evaluation for liver transplantation. So, um, key points here. We have to establish wh group prior to treatment again differentiating number one between pre and post capillary hypertension, which we can do with the right heart calf and then within pre capillary hypertension. The lung group defining whether the Group one, Group three, Group four. That's key because treatment is different, depending on what group they're in. We typically avoid using medicines in Group two patients in the heart failure patients as that can sometimes lead to worsen. Palmeri Dema Um, we also try to avoid using them as much as we can in the Group three patients as well, although there are some instances where we do sometimes trial these drugs on them. But again, the key is early and aggressive treatment, but early identification and evaluation of patients with elevated Pullman pressures by eco, um, to avoid RV failure. So with that, I'll conclude, and I think there may be a couple of questions a couple minutes for that at the end Here, Um, let's see, where does inhalation therapy for Ph fit in? How about the oral process? Cycling. So, um, you know, part of it comes down to patient preference, um, you know, for for on combination therapy and we want to add something in the process. Cycling agonist pathway. Um, it depends number one on how sick they are and what their functional class is. If they're. If they're pretty far along and they need more aggressive therapy, sometimes we will go straight to I v. Therapy. On the other hand, if if they're functional class two or three, but their pressures are still high. Um, but and we want to get more aggressive than we may consider either oral or inhaled process. Cycling. It depends on, you know. Part of it is patient preference. The inhaled treatment is frequent, um, several times a day. Sometimes patients have are still working, and they have other obligations that they get harder to do. That kind of treatment. They may prefer the oral therapy. Others are okay with inhaled therapy. So it kind of just depends on how the patients are doing. Question number two. If there's suspicion of Nick's disease, would you treat the hefty F or the I L. D. Before doing the right heart cath? Or will the right heart cath be able to distinguish the ideologies? Um, it's kind of hard. Part of the suspicion for mixed disease like you mentioned, is the patient's history. So if it's clear that they have Hedgpeth by echo, you know if they have evidence of dilated left atrium and you know, say they have a history of atrial fibrillation, hypertension, all the risk factors for, but they also have interstitial lung disease. On top of that, um, then we may, you know, the threshold to do the right heart calf. Maybe just partially related to how symptomatic they are, Um, and whether or not we can get a good assessment of their pay pressure by echo, sometimes in patients with, particularly with lung diseases, they're eco windows aren't the best, and sometimes it's hard to estimate their plumbing pressures that way. So sometimes we're forced to do right heart catheterization just to know what the plumbing pressures are. But really the mixed disease right heart Cath is useful in that sense, to understand how mixed the disease truly is, because we can get a sense of what the PVR is. Um, so if it's you know, if it's less than two and this is clearly left sided heart disease, then the interstitial lung disease may not really be playing a role than we would be more aggressive in treating the Palme venous hypertension. On the other hand, if the wedge pressure is not so bad, even if they have risk factors for half PF. But the PVR is really high. Uh, then we would kind of blame that more on the interstitial lung disease and work with the pulmonologist on treating that. Okay, great. Thanks so much, Raj. That was very complete. Uh, presentation. Thank you so much.