Aloha, everyone. And welcome. Thanks for coming, too. My spidey senses are tingling. Is it really pulmonary arterial hypertension? We're excited to have you for the next hour to talk about three challenging pulmonary hypertension cases. My name's Elena Velakis. I'm one of the pulmonary critical care fellows at the Medical University of South Carolina, and I'm honored to be introducing our cases and our speakers today. Please download our QR code. It should be useful for each of the three cases. You won't have to re-download the QR each time, but it will be up there. And that'll allow you to participate in our interactive questions. And then we will have time, a couple minutes in between each individual case for questions that will open up the floor, OK? For our first case, interpreting the right heart catheterization, with great power comes great responsibility. For this, I'd like to introduce our speaker, Dr. Francisco Soto of the University of Tennessee. Good morning. Thank you for being here. We put a great show for you. So we're going to be talking about a 55-year-old patient suspected of having pulmonary hypertension and the echocardiogram who underwent right heart catheterization testing. The cath showed, or at least reported, a mean pulmonary pressure of 52, a wedge of 12, a PVR of 9.8, no LVDP was available, so we don't know if those numbers were reliable or not. So I'm Francisco Soto. I have nothing to disclose. So this is the presentation. Yes. Yes. Arun told me that I had to stay in character for the entire thing. I was, I don't know if he was pulling a prank, I was stopped, held two hours at TSA explaining to them why I was missing. So the objectives essentially are going to be for this particular talk to try to help you identify some of the major pitfalls. For the case overview, we're going to be concentrated on three things. Quality control, second, the respiratory cycle, the waveforms, where do you measure them, and three, our case. The top items for quality control, it's hard to cover everything but at least three things. We'll talk about zeroing, leveling, and damping. This is your typical transducer. It has the transducer portion, the top connection goes to the patient, that little black dot, that's your transducer. And the bottom part is going to be going to the monitor connection. So when we do the zeroing, essentially what we're trying to do is remove any extra pressure that the system is detecting. So we're going to lock the connection to the patient on top. And how do I get the video? Okay, there you go. So you lock the stop clocks to the top, you flush this, and then you go to the screen, and if your patient already has a CVP, an arterial line, you zero everything. That way you standardize. And ideally you should be doing this every time you're getting active measurements. Next one is going to be the leveling. Now this is identifying your zero reference point. Because you're doing a PI catheter and we're relying on the wedge, we're relying on the left atrium. When you're doing a CVP, an arterial line, you're pretty much at the level of the right atrium. So to compromise, you're going to look at your mid-axillary line and the fourth intercostal space. That's going to be the best of both worlds, giving you the right atrium and the left atrium. So you get that line. And remember, you have to level that with your black dot of your transducer. There is a very nice video on New England Journal of Medicine on how to do this properly if you want that extra instruction. So in this case, this is your right atrium. That's your left atrium. And imagine that this is your phlebostatic axis. This is going to be one of the most important points of my talk. You have to memorize this. For every 10 centimeters that your transducer is above or below the phlebostatic axis, your pressure is going to change by about 7.5 millimeters of mercury. If they are the same level, then there is no problem. If for some reason somebody came to examine the patient, raised the bed, and the transducer is staying low, you just added 7.5 millimeters of mercury. So your wedge went from 12 to 20, and now you're pushing diuresis in a patient who might not need it. Likewise, if they lowered the bed and the transducer stayed up, now your numbers are significantly lower. You would say this doesn't matter that much for pulmonary hypertension, where you use such specific cutoffs of wedge of 15, mean of 20. This is dramatic. So it's a see-saw effect, if you can remember that. Does leveling really matter? You would say not that much. Anytime I'm in the cath lab, and I see that those are the pressure traces that I'm seeing, a lot of negative numbers. We don't see too many normal patients to give me that. That makes me think that this wasn't properly leveled. And now you level this, and they gave you about 5 millimeters of mercury. As I said in the previous talk, this should not affect your pulmonary pressures of 80 over 40. But if you're dealing with somebody of 20, 23, 19, it can make a dramatic difference in who gets treated and who doesn't. Pressure damping. It can lead to under or overestimation of pressures. In this case, look at that waveform. Not too bad. That's a PA waveform. Let's say we take that particular one. Systolic is 32, diastolic 15, a mean of 21. Imagine this was the old days where we were using a mean of more than 25. So with this number, you would say no pulmonary hypertension. But if you look, pay attention. It might be hard to see from the back. You don't see a dichroic notch there. Now the moment I see that, you flush the catheter, and now you get these things. The numbers are not dramatically different, but enough to give you a cutoff that is going to make a difference. So now your pulmonary pressure is 49 over 14 with a mean of 26. Again, scary. Look at the waveforms. If you didn't perform the procedure, making sure that you review the traces. Line flushing and pressure damping. You perform your square wave flush. This would be optimal. What has been defined is having at least after the square wave, 1.5 to 2 little oscillations. If you get more than 2, that's going to be underdamping, and you can see how the waveforms are stretched out. If you don't get any oscillations, that's underdamping, and the waveforms are going to get all squished. Here, typically your dichroic notch is going to disappear. For the second part, how and where do we measure the pressures? We're going to start with the respiratory cycle. Where do we measure this? At the end of exhalation. In this particular case, where you have an esophageal balloon, you can see in exhalation, that's when the esophageal pressure gets back to zero. What if the patient is intubated? Intubated. That's a board question if we have any fellows. You always measure it at the end of exhalation. Where exhalation is going to be on your waveforms, whether you're intubated or not, that's going to be different, but always at the end of exhalation. In this case, those are wedge waveforms here. You're going to have exhalation. It becomes more negative with inhalation. Exhalation. This is for a spontaneously breathing patient. Inhalation, exhalation. That means when we decide which waveforms we're going to take, we are going to take any of the waveforms that are at the end of exhalation before the pressures start going down. Again, this is a spontaneously breathing patient. Going back, we said it's going to be at the end with the esophageal pressure. The pain in the neck is going to be in the future. This great paper from the Cleveland Clinic, where they essentially looked at, they put on an esophageal balloon, and now look at this patient who has a wedge pressure of 25. But the mean esophageal balloon pressure, it's about 20. That means you have to subtract 20 from your 25, and now this pressure, the wedge pressure of this patient is going to be around 5. So how are we going to standardize this in every, are we going to have to revisit all of the patients that we've done in the past? I don't know, but this might be the correct way to do this. How about the waveforms, type of waveforms and the waveform components? When I step out, aside from the microphone, can you still hear me in the back? Okay. Very good. Thank you. So for the fellows in the room, there are only three waveforms that you're going to see when you're placed in a PA catheter, if you're floating these bedside, blind. You're going to get atrial waveforms, you're going to get ventricular waveforms, and you're going to get arterial waveforms. And that applies to the systemic system. You would say, but what about the wedge? Remember, the wedge is trying to represent what's happening in the left atrium, so that's still an atrial waveform. So if you're lost as you're floating your PA catheter, ask yourself, is this an atrial, a ventricular, or an arterial waveform? And that might give you some orientation instead of just continuing to push that catheter not knowing where you are. Where to measure the pressures? This slide applies for your right atrial pressure and your wedge pressure. You have your EKG, you have your P waveform. The two dotted lines correspond to the systole. For right atrial pressure, you're going to measure these in your A wave. That's going to follow your P wave. How about wedge? Remember, you inflate the balloon and you're waiting for the left atrium to send those pressures back into the catheter, so there's going to be a little delay. So typically, your A waveform coming from the left atrium is going to follow the end of your QRS here. So where do we measure the wedge? Identify the A waveform. In this case, it would be whatever waveform follows the end of your QRS. If there is no A waveform, measure about 130 to 160 milliseconds after the start of the QRS, like somebody who has atrial fibrillation, for example. Now look at this one. What is the mean wedge pressure? Let's see if you can see from the back, and we'll do it together. If this patient is spontaneously breathing, exhalation, inhalation, exhalation, so we are going to look at waveforms that are at the top here. Now this is your QRS, so the A waveform is the waveform, the wave that follows the QRS. That's going to be your A waveform. Now we're going to take the top of that. That's 22. The bottom of that, that's going to be 15. 22 plus 15, that's 37, divided by 2, that's 18.5. The mean wedge pressure of this patient is 19 measured at the end of exhalation. Which cardiac output to use? Direct FIC is the gold standard. I don't do it. It requires a lot of extra coordination and efforts, but if you have it, by all means, that's what you should be doing. The next one is going to be your thermodilution. That's your next best option. That's another big take-home message today. In this study of 12,232 patients, they had 40% of patients that had both thermodilution and indirect FIC. In those, there was a 20% difference in value. Remember, cardiac output is the denominator for your PVR calculation. It can be dramatically different depending on which one you use. In addition to this, for that study, for another study down here, they found that cardiac index was a better predictor of mortality when it was measured by thermodilution compared to indirect FIC. So use direct FIC if you have it. If you don't, then use your thermodilution cardiac output. If somebody in the audience has a better answer for that, I welcome that during the question. Now look at this patient. That's thermodilution. You want those three injections, by the way, to be within 10% of each other to be reliable. Heart rate is 70. Cardiac output is 4.1. And this is the indirect FIC of the same patient. Heart rate is 70, but now it is 3.04. More than 20% difference between those two, which is going to affect your PVR calculation. Which cardiac output to use based on the 2022 European guidelines? Thermodilution if you don't have direct FIC. Indirect FIC or the FIC calculation only if there is a shunt is what they recommend. Finally, for our case, we're going to measure, determine those pressures ourselves. Imagine that you got those tracings and you're trying to decide, my spidey sense is tingling. Can I trust those tracings that I got from somewhere else? So look at this. This is a PA waveform for the record. Don't judge me. This one doesn't have a very nice dichrotic notch. So that was the best I could find for this. So that's exhalation. This is inhalation, exhalation. That means we're going to use one of the taller waveforms before it starts going down. We're going to choose this one. And then for those in the back, the top, the systolic is 87, diastolic is 35. I use this formula for my mean, which is diastolic plus systolic minus diastolic divided by three. So that's going to give you a mean of 52. How about the wedge? Remember, exhalation, inhalation, exhalation for a spontaneously breathing patient. You find your QRS, and we're going to look for the waveform that follows the end of that QRS. That's your A waveform. The V waveform typically follows your T wave. Now we're going to take the top of that waveform, the bottom of that, so that's going to be 14 plus 10. That's 24 divided by two, 12, a mean wedge of 12. That's what I'll be using for a spontaneously breathing patient who doesn't have dramatic respiratory swings. And then the cardiac output, we said we're going to use the thermal dilution. For the final calculations, if the mean is 52, wedge we said was 12, thermal dilution cardiac output was 4.1. Let's calculate the PVR. That's going to be mean pulmonary pressure minus wedge divided by cardiac output. 52 minus 12, that's 40, divided 4.1, 9.8 wood units. Summary, before you start measuring, and I would humbly encourage you every time you're in the ICU, do this routinely. And if you don't know it, ask your nurses. They will love to show you how to do this. Zero, level, flush. When to measure the pressures? Always on exhalation. It doesn't matter if the patient is intubated. Wedge, calculate the mean of the A waveform. PA pressure, look for a well-defined dichrotic notch. Which cardiac output? Direct fake if available. If not, thermal dilution. So for those who had your spidey sense tingling, imagine that we excluded all of the secondary causes in this patient. Now that you see these numbers and we confirmed the traces, is this PAH? Yes, no, maybe. I apologize, I think. Yeah, this is good. Is that okay there? Yeah. We'll stop when we make it to 300. Thank you. Chess is doing this different this year. In the next slide, the names of everybody is going to... Okay, PAH, very good. Now, for the next one, if you believe that this is PAH and you excluded every secondary cause, is treatment warranted now? Yes, no, maybe. Very good. Excellent. Thank you. Don't forget to evaluate this session. For our next case, pulmonary arterial hypertension or pulmonary hypertension associated interstitial lung disease, the tangled web we weave. This is the same QR code for everyone still logged in. For this case, we have a 55-year-old male with a history of inflammatory arthritis and possible mixed connective tissue disease who underwent an echocardiogram with concern for pulmonary hypertension. Additional testing included PFTs showing an impaired DLCO of 48% of predicted and an FEV1 over FEC ratio of 70% and a TLC of 66% of predicted. CT of the chest showed mild subplural bivaselar fibrosis without honeycombing. The right heart cath was done with a mean PAP pressure of 30 millimeters of mercury, pulmonary capillary wedge pressure of 13 millimeters of mercury, and a PVR of 5.2 Woods units. To walk us through this case, I'd like to present Dr. Arun Hosea from the University of Cincinnati. Thanks so much, Alina. That's going to be hard to follow. I don't have a mask or anything. It's rough. But I'm Arun Hosea. I'm from the University of Cincinnati. I'm also Director of Pulmonary Hypertension at Cincinnati VA. You can see my disclosures here, although they're not germane to this talk directly. So for this talk, we're going to talk about pH in interstitial lung disease, and we're going to discuss interstitial abnormalities in pH. We're going to talk about how you distinguish one from the other and what that implies for treatment. So I'm Arun Hosea. I'm from the University of Cincinnati. I'm also Director of Pulmonary Hypertension at Cincinnati VA. You can see my disclosures here, although they're not germane to this talk directly. So for this talk, we're going to talk about pH in interstitial lung disease, and we're going to discuss interstitial abnormalities in pH. So to bring us back to the case, we have a 50-odd-year-old male. There's some mixed connective tissue disease. There's fairly intact spirometry. There is an impairment in diffusion capacity. There's some limitation in TLC. There is some interstitial fibrosis on CAT scan, but it's mild, and you see the human name is listed there. So the first question is, is this pH or is this pH ILD? So if we look to the most recent set of guidelines from the 2022 ESC ERS, they define pH as an elevated mean pH pressure greater than 20 millimeters of mercury with the addition of precapillary pH as an elevated PVR, in this case, greater than two Woods units, which is a little bit different than the Sixth World Symposium, which had the three Woods units cut off in the presence of an intact wedge pressure. These same guidelines go on to describe pH ILD. They note that it can occur in different types of lung disease, including COPD, emphysema, and interstitial lung disease, and they distinguish two distinct sort of phenotypes of pH ILD. You have more of a pulmonary phenotype, where there is an impairment in pulmonary physiology, but not really a whole lot of pulmonary vascular disease, and more of a pulmonary vascular disease predominant phenotype, where you have relatively intact spirometry, but a severe elevation in PVR, in this case, greater than five Woods units, and that's how they sort of distinguish the two as a spectrum. So what does it mean if you have pH ILD? Well, as you might expect, having two different pulmonary diseases is not a good thing. This is data from a German scleroderma network. A little over 3,200 patients with scleroderma grouped into their different types of clinical phenotypes. And you can see that the pH ILD subjects, in this case, the blue line, had the worst survival from all the other phenotypes, including those with pH or those with ILD who don't have pH. Interestingly enough, the pH ILD also had the lowest DLCO of the entire cohort. Not surprising if you consider they have both ILD and pH. Approaching this question again from a different perspective, this is data from a combined French and U.S. scleroderma study looking at patients with precapillary pH. So they had hemodynamics that met the definition of precapillary pH. In this case, they used an agnostic clustering algorithm to group the patients based on some clinical characteristics. You can see FEC was involved, as well as DLCO and PBR. And I want to draw your attention to the second cluster, which they termed pH ILD. And these patients, again, had the worst survival of all clusters. These were distinguished from the other clusters by a greater preponderance of ILD on their CAT scan imaging, in this case, greater than 20%. There were more males in this cluster versus the others. They had, again, a low DLCO, and they had the lowest TLC of all the other groups. So again, pH ILD, not good, but how do you distinguish it from pH? So the challenge here is that you have pH ILD, but the severity of pH is not necessarily related to the severity of underlying lung disease. So you can have fairly severe pH in both mild and advanced lung disease. There's not really a great relationship between right heart cath hemodynamics and the amount of interstitial disease you have on CT scan, and you see that best in the IPF group. And there's not really a great correlation with PFT impairment and how bad your pulmonary hypertension is. So you can have relatively preserved spirometry or total lung capacity and have horrendous pH. Also, pH occurs not infrequently in ILD. So we have maybe the most amount of evidence from the IPF group, again, because it's the most widely studied. And it occurs from anywhere between 8% and 15% of all patients with ILD will have some amount of pH. It is more common to have pH when you have more severe ILD, but it doesn't mean that the pH is more severe itself. And depending on the type of lung disease, you can also have pH in a majority of other types of lung disease, such as sarcoidosis or Langerhans cell. If you have pH with ILD, what tells you how the patients will do? So the severity of pH, unsurprisingly, is related to how the patients end up doing overall. On the left-hand side, you see a cohort study of 176 patients with unspecified lung disease, which includes ILD, but also COPD and cystic fibrosis, et cetera. And they underwent right heart catheterization and were followed over time. And it turns out that having more pH, in this case, at a threshold of mean pH of 35, was associated with much worse survival in this group. And this sort of finding was replicated in the European Compara analysis of patients with pH and ILD, in this case, based on a threshold of PVR. And what they identified was a PVR threshold of five woods units was significantly associated with worse survival. So that's pH and ILD. What about PAH? Is there ILD in PAH? So as many of you know, unfortunately, the distinction is not as clear. This is data from a UK and Irish study looking at patients with a diagnosis of idiopathic pH. And they had preserved spirometry. So these were basically group one IPH patients. And they looked and saw what CT abnormalities might they have. And it turns out that there was a proportion of patients who had considerable abnormalities on CT, up to 7% with fibrosis in their lungs and 3.5% with both emphysema and fibrosis. Now, as you might expect, these patients were more likely to be exposed to tobacco, either currently or in the past. They were also more likely to be male. They had worse DLCO, not surprising. They had comparable right heart cap hemodynamics to idiopathic pH patients without lung parenchymal abnormalities. And, again, they had increased mortality compared to their IPH colleagues. This finding was also seen in the ASPIRE registry, again, looking at IPH patients with precapillary hemodynamics and preserved spirometry, who were grouped as group one. And, again, you see a not insignificant amount of underlying lung disease in these patients. Up to one-fifth in this cohort had ILD, and 14% had both mixed ILD and emphysema. This finding has also been replicated in that PVD-omics study. Patients with pH have interstitial lung abnormalities present. Again, in this group, they were also older and male predominant. They were more likely to be exposed to tobacco smoke. And they had worse survival. They also had lower DLCO, and the two are correlated. So shifting gears a little bit, let's say you have pH with ILD. How do we treat it? So the best data we have comes from the increased randomized control trial looking at inhaled terprostenal in patients with pH ILD. It was a one-to-one randomization. And then these patients met their primary endpoint, which was an improvement in six-minute walk test on treatment, seen in the red line versus placebo, which is the gray line. And these block analyses also identified that they met a number of important secondary endpoints. In this case, patients on treatment had less ILD exacerbations compared to placebo, seen by the green lines versus the blue lines. And they also had an improved trajectory of their FVC compared to placebo, seen by the blue versus red lines here. What about other targeted therapy for pH ILD? So the RISE-IAP study looked at the use of RioCiguat, a guanylate cyclase agent, versus placebo in patients with pH ILD, again, randomized one-to-one. This was unfortunately terminated early due to an increased risk of adverse events in the treatment group, in this case, worse lung exacerbations. And then when they looked at it, there was no significant difference between treatment or placebo in their primary endpoint, which was a six-minute walk change. So this was a negative study that was terminated early. The ARTEMIS randomized control trial also shed some light on how to treat pH ILD. I would note that this is an IPF study, where patients were randomized one-to-one to an endothelial receptor antagonist, ambrescent, or placebo. And this was, again, terminated early due to an interim analysis showing harm in the treatment group, in this case, more hospitalizations and more mortality. And when they did a subgroup analysis looking at patients with pH and IPF, there was still no signal for improvement and a signal towards harm. So again, another negative study. So then we bring it back to our case. We have a 55-year-old male. There's some connective tissue disease, intact spirometry, impairment DLCO, some impairment TLC, some fibrosis, precapillary hemodynamics with an elevated PBR. And the question, is this pH? People don't want to opine. Did you guys vote? That's pretty good. Let's see what we got. Okay, and I split. So that half said yes and then it was split between predominance or maybe or no. So then the second question is targeted therapy warranted? Your thoughts? But the people are more set on the target therapy, it seems. All right, that's a good number. Let's see what we got. All right, the majority say yes. Fascinating. So then I would walk you through what I would say, and then we can open up for questions. So from my perspective, there are some signs that suggest that this is PAH. There's an impairment in DLCO. There's only mild fibrosis on the CT scan. It's not overwhelming for a lot of ILD. There are some signs that suggest, to me, more of a PH-ILD picture. It's a male patient, and those PH-ILD patients tend to be more male. There is an impairment in total lung capacity. And there's some stuff that could go either way. You know, connective tissue disease can be PH or PH-ILD. Precapillary hemodynamics don't really tell the whole picture to me. And there's not impairment in spirometry leaving one or the other. So I agree that, you know, is this PH? It's not really clear to me. I would say it's probably somewhere in between PH, as it's strictly defined, and PH-ILD. So I would say maybe, because I'm not sure. However, I would note that there are some high-risk features in this case. Namely, the PVR is greater than five, which suggests that, A, both, that this is more of the pulmonary vascular component, if this were PH-ILD. And also, there is an increased risk of mortality in patients with PH-ILD with a PVR greater than five. So I would say that, yes, target therapy is warranted, with the caveat that data currently favors inhaled triprosomal from the increased study. There's some consideration for PD5 inhibitors. And then the Artemis study would lead me to caution the use of endothelial receptor antagonists. And the RISE-IAP study results would, again, lead me to caution the use of guanylate cyclase class agents, in this case. But with that, I will thank you for your attention, and ask if there are questions. Last, but not least, we have pulmonary arterial hypertension, or pulmonary hypertension with left heart disease. Hulk smash. For this case, we have a 55-year-old male, again, with hypertension, hyperlipidemia, biatrial enlargement, left ventricular hypertrophy, and grade two diastolic dysfunction. And technical difficulties during right heart cath and hemodynamics are shown here in this graph. To walk us through this case in discussion, I'd like to introduce Dr. Paresh Giri from the Beaver Medical Group in California. Thank you. Good morning, everybody. Aloha. I can't beat Spidey Francisco's web. But I'm gonna ask you a question. How many of you have seen the movie Madagascar? So in the movie, Alex the lion and Marty the zebra are two friends in New York City Zoo. They end up in Africa, and Marty mingles with a herd of zebras. So Alex has to find his friend in this crowd. How does he do it? So he starts by describing Marty, his features, his uniqueness, his characteristics. In short, he is phenotyping. So what does phenotyping got to do with pulmonary arterial hypertension? So did you know that there are three subphenotypes within who group one PAH that is emerging? Did you know that hemodynamics are insufficient to separate them? And did you know that assessment of comorbidities might help? Let's find out. We've been given this case with a mean PAH pressure of 30, a wedge of 13, and a PVR of 5.2 units. This patient clearly fulfills pre-capillary pulmonary hypertension definitions. And the cutoffs have undergone changes as listed below. Post-capillary patients will have a wedge pressure elevated above 15. And combined pre- and post-capillary patients will have an additionally elevated PVR. What if I told you our patient had a right heart cath two weeks ago? Prior to 10 kilogram diuresis, his mean PAH pressure was 51, wedge was 30, and PVR was 4.2. Now looking back, well, he clearly meets combined pre- and post-capillary definitions, doesn't he? So looking back, could you have predicted this post-capillary component in this patient? Well, one way to do that is to look at your patient closely and phenotype. So we'll focus on phenotyping who group one patients using two registries and one randomized control data. The very first registry that reported primary pulmonary hypertension in the 1980s and a more recent contemporary database called the Compera. And you can see that in the Compera, the patients are older, less females, more comorbidity. And there was a recent cluster analysis performed and there were three different clusters that emerged with three clearly different survival rates in that database. The first cluster was young females, similar to the primary pulmonary hypertension cohort described in the 80s. Cluster two was older females and cluster three was older males. Remember, all these patients had pre-capillary hypertension, PH by definition. The PVR and the mean PA pressure was highest in cluster one, but the survival was highest as well. Cluster one had no comorbidities and cluster two and three had a significant amount of comorbidities listed here. In this landmark randomized control trial, 500 patients helped establish that initial use of the comorbidities in the first cluster established that initial use of dual oral combination therapy was superior to monotherapy. Well, 105 patients were excluded from that analysis. Why? Because there was concern for PH left heart disease in the study population. The protocol was amended, the wedge was decreased. And if the wedge was borderline, like in our patient, the PVR inclusion values were increased. And patients with more than three comorbidities were excluded from the study. The excluded cohort was older, had fewer females, had more comorbidities. And they experienced more clinical failure events than the primary analysis cohort. So we see that even in randomized control data, as well as in registries, patients that fulfill pre-capillary pulmonary hypertension hemodynamic definitions, their survival, their demographics, their comorbidities are not the same. Comorbidities are the elephant, excuse me, the hulk in this room. That's my preference for the hulk. That's all I got. No webs, no punches. And increasing comorbidities is associated with increasing who group two prevalence. But they all fit pre-capillary hemodynamic definitions, don't they? So why not treat them? In Compera, cluster one received typical PAH therapies and combinations. In cluster two and three, mostly PD5 inhibitors were used and less use of ERAs and other combination therapies was noted. In response to treatment, there was increase in six minute walk distance in all clusters, but diminishing magnitude in clusters two and three. The decrease in BNP was diminished in magnitude in clusters two and three. Improvement to low risk shown here as the green bars in the follow-up histograms was also diminished in clusters two and three. In the ambition, the difference between the combined and combination and monotherapy was diminished compared to the primary analysis. And again, change or decrease in BNP levels was diminished in magnitude in the smaller cohort. In addition, there were some safety concerns. There was more side effects, more edema in the excluded cohort, and there was more drug stoppage in the excluded cohort. So a pathophysiological continuum might exist where as we move from left to right, there is declining pre-capillary component. There's declining efficacy of PAH therapies. Whereas on the other hand, there's increasing co-morbidities and increasing side effects of PAH therapies that we administer. Thus three phenotypes within who group PAH have emerged. The so-called classic phenotype, the left heart phenotype, and the cardiopulmonary phenotypes. The left heart phenotypes are predominantly females, the cardiopulmonary predominantly males. They both have pre-capillary PAH by definition. So hemodynamics are insufficient to separate them. They both have high risk factors for left heart disease, but the cardiopulmonary phenotype has more pulmonary manifestations, and the mortality is higher. So now is your chance to answer, use your audience response and answer, is this PAH? 55, should we move? Yeah, I like it. Lovely. What about treatment? Come on, maybe? So I answered maybe to both, all right? I may be hedging, but here's why. I need more information, right? So does the patient meet pre-capillary pH? Yes. Does the patient have the classic phenotype? No. So with a high TPG and a low cardiac output, if you back-calculate from the given data, I'm concerned about this patient, especially if you tell me this patient has right heart failure. But these other differentials still need to be sorted out. So what do I do? I roll up my sleeves and dig some dirt, if you will. So I assess risk factors for pre-capillary pH, family history, drug and toxin use, presence of connective tissue disease, thromboembolic disease. Then I would dig some more dirt and obtain risk factors for post-capillary pH. Other comorbidities listed here, EKG and echo findings, CPET and MRI findings. Our patient with hypertension dyslipidemia has at least an intermediate probability of pH left heart disease. And during right heart cath, even after we did all that Francisco taught us to do, if the wedge is borderline and there is an intermediate risk, we cannot rule out pH left heart disease. So additional maneuvers are warranted. For example, fluid challenge, exercise challenge, LVDP measurements. There are validated risk scores now available to assess presence, a rule in or a rule out, presence of heart failure, preserved ejection fraction in our patients, which we could utilize. Our patient probably scores around three and therefore warrants further stress testing. For treatment, recent guidelines have separated recommendations for patients with and without comorbidities. They recommend monotherapy initially for patients with comorbidities with close assessment and follow-up. For post-capillary pH patients, pH therapy is not recommended. And for combined pre and post-capillary patients, no, the insufficient data to actually make a recommendation. So in summary today, we learned there are three sub-phenotypes that are emerging within who group one pH. We learned that hemodynamics are insufficient to separate them because they all have pre-capillary pH. And without established guidelines to distinguish these sub-phenotypes, we have to assess their comorbidities, assess risk factors for pre and post-capillary pH, and then maybe, just maybe, we will become as good as Alex in finding our Marty. Thank you.

pulmonary hypertension

right heart catheterization

quality control

pressure measurements

pulmonary hypertension associated with interstitial lung disease

differentiating PH and PH-ILD

phenotypic variability in WHO Group 1 pulmonary arterial hypertension

personalized approaches in PH management

PH