Thank you, Chess, so much for organizing the meeting, for allowing us to present on actually one of the most challenging types of pulmonary hypertension that's out there, and also one of the most common. Thank you, my co-chair, for mentorship. Dr. Suit has been mentoring me since I was a fellow. That kind of dates both of us. And I'm very honored to introduce her for the first talk. That is the clinical presentation on pulmonary hypertension and left-side disease, the scope of disease. Thank you, Dr. Sulekha, and thanks for inviting me to participate in this session. So I'm going to start with the case, because that's what we see in our clinics pretty much every day. So a 75-year-old lady, and if you have your apps, you can vote, diagnosed with lupus about 10 years ago, at which time she presented with pneumonitis. She has a history of systemic hypertension. She's treated for obstructive sleep apnea. She developed progressive dyspnea over the last couple of years and now is dyspneic with minimal exertion, reports lower extremity edema, had a recent fall, but it was unclear if it was mechanical or a syncopal episode. On examination, her blood pressure is reasonably well controlled, mildly tachycardic. JVD is mildly distended, otherwise unremarkable, but has 2 plus lower extremity edema. Her pulmonary function tests are essentially normal, and you can see the CT is not completely normal. She's got some evidence of restial kind of interstitial lung disease related to the lupus. Her cardiac echo that was submitted to us from the outside physician, LA and RA were mildly enlarged. There was moderate TRNMR, mild aortic and pulmonic regurgitation. She had grade 2 diastolic dysfunction. EF was 55%, and the RVSP was, the PAP was estimated at 72. On digging through her records, in 2017, for reasons unclear to me, she had a cardiac cath, at which time her RA pressure was 14, her mean PA pressure was 29, wedge was 10, and the cardiac output was 5.2 with an index of 3, yielding a PVR of 3.6 woods unit. And nothing was done at that time, and just before she was referred to me, a cath was repeated because of her symptoms of dyspnea. At this time, her RA pressure is 14, her mean PA pressure is 45, wedge is 17, her cardiac output is 2.9, and her index is 9 points, her PVR is 9.6 woods unit. So the question I have for you is, what would you do next? Initiate a PDE5 inhibitor, initiate a PDE5 inhibitor and ERA, inhaled prostacyclin, or none of the above? I hope some people are participating. None of the above. So I think we're already off to a good start here. And some 25% of the people wanted to. So this is what we hope to address in the rest of the session here today. So what we did was we chose to get the tracings from her outside physician. And you can see here the RA pressure was quite high. The RV was pretty impressive. The RV ADP was 17. And her mean PA pressure was 43, as reported. But the wedge was 20, right? And we also elected to repeat an echo within our center. And you can see that she does have some left ventricular hypertrophy, but her left atrium is moderately dilated, suggesting that there's sort of a persistent elevation of that left-sided pressures, right? But this kind of a case is not unusual because she had some risk factors for pulmonary arterial hypertension. She has a history of lupus. She had a previous CAD that looked very pre-capillary. And now she's evolved into this patient. So how do you manage this patient? And how do you evaluate this patient? And this is what we hope to address in the next 55 minutes or so. So we made a diagnosis of severe pulmonary hypertension associated with diastolic dysfunction. And most of you got this answer right. And we basically, I guess we could do it again. Mm-hmm. We'll use this forward. Yeah. I'll just let see if anybody changed their mind. All right. We got better. So pulmonary hypertension, as we define it now, is a mean peer pressure greater than 20 millimeters of mercury. And when we insert the term pulmonary arterial, we imply that the process is pre-capillary, right? So mean peer pressure of greater than 20 millimeters mercury. With a mean pulmonary artery occlusion pressure of less than 15. And a PVR greater than 3 woods unit. Now this is all up for debate, but that's a whole other story. And just to give you the equations, we calculate the mean peer pressure with systolic PA plus 2 times diastolic divided by 3. And the PVR is your mean PA minus the wedge divided by cardiac output, because we'll be using these terms a lot. And of course, pulmonary hypertension is a manifestation of several disease states. And that brings us to the classification. But I want to remind people the reason this classification was divided the way it is, is because the different groups share either the hemodynamic profile and they respond to certain drug therapies, right? So patients in the group 1 are the ones we treat with these selective vasodilators that we've been talking about a lot. They have a pre-capillary profile and they have shown to benefit from therapies like ARAs, PDE5 inhibitors, and the prostacyclines. The commonest cause for pulmonary hypertension is group 2. And then pH can complicate underlying lung disease, which again can have a pre-capillary profile or a post-capillary profile. But the management of these conditions and what are the drugs that work for this is completely different. And then CTAF and then a mishmash of conditions that fall into the group 5. So when we evaluate a patient with pulmonary hypertension, we go through this entire workup and we have to put them in one bucket. They can't be in two at the same time because that's what's going to decide what's going to be the therapy. So we start with an echo. And much as we look at the right side, we also look at the left to make sure they don't have underlying left heart disease or valvular disease. We want to look at their PFTs to make sure they don't have underlying lung disease. A full sleep study if they have the habitus of symptoms to suggest that. Everybody gets a VQ scan to screen for chronic thromboembolic disease. They get a screen with an ANA for connective tissue disorder. And more detailed if they have suggestions for underlying disease, HIV testing, and then they need a right heart cath to confirm the diagnosis. When we do the full workup, the commonest reason for pulmonary hypertension is left heart disease. All right. So they're about, I'm missing some things here, so 61.5 million cases of heart failure across Europe and USA. And about 80% of these patients are greater than 65 years of age. And when you look at pH in the left heart disease, 50% of these patients have heart failure with preserved EF. About 70% of patients with mitral valve disease will develop pulmonary hypertension. And 50% of patients with aortic stenosis also have pulmonary hypertension. So a good number of patients have left heart disease and associated pulmonary hypertension. And this is sort of not a benign event, but there are a few things that we have to remember. That it doesn't matter how high the pH pressures get to, the underlying trigger is the elevated left atrial pressures. So the left atrial pressures increase that sort of affect the venous system. And then subsequently, an arteriopathy may develop. So the left atrium is never normal here. And then a small subset of these patients will develop pulmonary arteriopathy. And this has a huge impact on the patient's functional capacity, incidence of hospitalization, and also has implications for further curative therapy, such as heart transplant or mitral valve replacement. So this is not benign. And other comorbidities, such as COPD, sleep apnea, also contribute to the development of this arteriopathy. So just to remind ourselves that these two circulations, the low pressure and the high pressure, are clearly connected. And when the left ventricle is out or there's mitral valve disease, it's the left atrium that sees the high pressures that are then reflected back into the pulmonary vein and then into the pulmonary arterial system. So you can get pulmonary hypertension in many different forms. One is the pre-capillary, where the PA pressures would be high and your wedge would be normal. Or it could be post-capillary, where the pressure is just coming back from the left side into the pulmonary vasculature or a mix of both. So pre-capillary, the profile is that your PA pressures are high, wedge is normal, PVR is increased. Post-capillary, your mean PA pressures are increased, wedge is high, and your PVR is not that high. It's less than three woods unit. And when it is mixed, you have increased mean PA pressure, increased wedge pressure, and a PVR that is greater than three woods unit. So how does that happen? Initially, when the left heart disease develops, there's elevation of PA pressures, mostly because the pressure from the left atrium sort of reflecting back. And as the pulmonary artery starts to stiffen, you start to see the mean PA pressures go up. And there tends to be a differential between the left atrial pressures and the pulmonary artery pressure. And as the arteriopathy and the venopathy develops, you start to see significant increase in the pulmonary artery pressures. So this is kind of a, I'm not going to go through this complicated slide, but clearly both systolic and preserved heart failure lead to a whole slew of metabolic and cellular level changes that lead to the development of this arteriopathy that we see. And this has been shown. So this was a study where they looked at thousands of cats, and they basically categorized them as patients who had IPH, patients who had pulmonary hypertension, but there was no differential between the transformer gradient and those who had an elevated PA pressure out of proportion to what they would expect for that wedge pressure. And 10 of these patients actually underwent, they had biopsies on them. So you can see here that patients with pH left heart disease, with the transformer gradient that is essentially normal, you do not see a lot of arteriopathy. But as that pressure starts to go up, you start to see the vessels sort of develop, there's thickening of the vessel wall and development of that arteriopathy. And this is a patient whose transformer gradient is 13, and this is a patient who has IPH. And you can see a similar vasculopathy kind of develop in both these conditions. But what about the venules? And that has been looked at too. So this is a controlled patient, the veins. This is a patient with reduced EF, and you can see there's some arteriopathy. There's a patient with preserved EF, and you can see the thickening of that veins. And for comparison, this is a patient with PVOD, which we know is a condition of obliteration of the pulmonary venous system. So you can see that both the veins and the arteries are involved in this condition. And not to forget the left atrium, because the compliance of the left atrium also comes into play here. So no matter how you look at it, whether it's heart failure with preserved or reduced ejection fraction, once they develop pulmonary hypertension, their survival is much, much worse. And similarly, that paper that I just showed you, biopsies out of, you can see that those who didn't have pH had a different survival curve. As those who developed the pre-capillary kind of pulmonary hypertension, their curve just went down. So it has huge impact on the patient. So if you were to evaluate a patient with left heart disease, we look at pulmonary hypertension greater than mean PA pressure of 20 millimeters mercury. If the wedge is less than 15, we think about pre-capillary. If it's greater than 15, we think about post-capillary. And then we can do some other calculations. If my PVR is less than 3 Woods unit, the trans-pulmonary gradient, which is mean PA pressure minus the wedge, is less than 12. My diastolic pulmonary gradient is less than 7. Then this is all passive sort of flow from the left side. And just optimizing the left heart, treating with diuretics might be enough in this patient. On the other hand, this patient with PVR greater than 3 Woods unit, a trans-pulmonary gradient greater than 12, a DPG greater than 7, clearly has an arteriopathy and falls in that pre- and post-capillary pulmonary hypertension group. So pulmonary hypertension with left heart disease causes impaired exercise capacity, increased hospitalization. Combined, pre- and post-pulmonary capillary hypertension shares some molecular similarities to pH. And exercise limitations and survival is similar in CPC pH as we see in idiopathic pulmonary hypertension. So this is not benign. So I'm kind of almost out of time, but I'm going to take a couple of minutes and just go over some cases just to sort of learn to phenotype these patients. I'll probably just do two, and then we'll wrap it up. So 65-year-old lady with a history of rheumatic fever, had a mitral valve replaced about 10 years ago, was referred here. She has a severely dilated LA RA. The RV looks moderately dilated. Her mean RA pressure is 12. Mean PA pressure is 43. Wedge is 25. And the cardiac output is 3.2 with an index of 1.8. She gets a nitric oxide challenge, and the wedge comes down to 18. The cardiac output goes up a little bit. So the cardiologist feels that this patient might benefit from selective vasodilator therapy. So we look at that patient. We do the math, and the TPG is 18. The DPA is 5. Clearly, this patient has arteriopathy that is independent of the degree of wedge pressure they're seeing, but still, this patient is still group 2. And how best to manage them will be discussed later in this session. Then I have a 67-year-old lady who had ischemic cardiomyopathy. The EF was 35%. Has a very good cardiologist who's now the EF has improved to 55%. The EF looks good. The RV looks a little bit dilated. Her mean RA pressure is 7. Wedge is 12. Cardiac output index is 2.2. And the cardiologist thinks that because the mean PA pressure is still high, the patient still has some limitations. Would the patient benefit from selective vasodilator therapy? And the answer here again is, yes, the patient does have some degree of arteriopathy, but the treatment still is treating the left heart. This patient still has left heart disease. And the last one here, and I will wrap it up, is a patient with end-stage renal disease, longstanding hypertension. Mean PA pressure is 53. Wedge is 22. And is referred here for management of pH because they want to consider him for transplant. And during the cardiac cath, the patient has the systemic blood pressure of 180. So he's given a nitrite challenge, and the mean PA pressure comes down to 28. And if you do the math, which I don't have time to do with you, this actually is all passive flow. So the point is that the pressures can be pretty high even when there's no arteriopathy. So optimizing those underlying diseases is very, very important. With that, I thank you for your attention. And I will hand it over to Dr. Anjali Vaidya. She is going to take us through the diagnostic workup for these patients. Hi. Thank you so much. Great to be here. Great to see everyone. I'm going to try to build off of that wonderful presentation by Dr. Sood and, in a short bit, do my very best to talk us through diagnostic challenges and novel strategies to differentiate group 2 from group 1, pulmonary hypertension. But I'm hoping that I may be able to convince you that not only are the strategies not novel, hopefully by the end of our chat today they won't be considered challenging either. So let's see what we can do. Of course, what we're talking about here are who group 1 versus who group 2, pulmonary hypertension. On the surface, they may seem to have similarities on initial clinical evaluation. Patients are dysmic. They have pulmonary hypertension according to their echo, usually. They have normal ejection fractions, often, as we just heard about. But the good news is they actually don't look anything alike. So if we get just below that immediate clinical initial assessment and surface, I think we can show how really different they are. So we're going to go through today the clinical assessment of these patients. Just a couple of pearls for each group because there's really so much more we could talk about. We'll talk about, I want to put it in the context of the evolution of PAH guidelines and care. Where does the echo fit into this evaluation? It's going to be a big part of our discussion. Using echo to help predict the hemodynamics. Of course, a discussion on right heart catheterization. And with all of this in mind, a call to action to improve and advance our training in pulmonary hypertension. So I'm not going to focus today on mixed physiology or CPC-PH. There's a lot to talk about in that category alone. We heard some of it already and more to come. This is a really nice paper that was published in the European Heart Journal about six years ago. And they really nicely went through, really, from exam, ECG, echo, all of these non-invasive parameters in our workup of distinct patients. How can you identify clues that their pulmonary hypertension might be PAH, what I call right heart PH, or left heart PH for group two? So just to highlight a couple of things, we'll talk about the ECG in a moment, how there are often classic changes. The echo, we'll dive into deeper detail. They talk about changes on X-ray and PFTs. I want to just highlight for a moment cardiopulmonary exercise testing, which can be very helpful to elucidate the differences in physiology. We're looking for things like reduction in end-tidal CO2 and ventilatory inefficiency in our PAH patients. You're not going to see those changes nearly as much in our group two pulmonary hypertension patients. So getting into some specific details, the electrocardiogram, this is often going to be done no matter where you are clinically practicing in terms of a patient with functional limitation. Often our patients with BHF chest pain, dyspnea on exertion. In our WHO group one patients on the top of the screen, you'll see these classic changes of right heart abnormalities. You don't have to be a cardiologist to kind of recognize the notable changes. You can see the big R waves in V1, V2 representing right ventricular hypertrophy, those T wave inversions, and the right-sided pericardial and inferior leads that tell us that there's evidence of right heart strain. Often you'll see a right axis deviation. These are the kinds of findings on the ECG that should point us not towards coronary ischemia, but to right-sided disease, pulmonary hypertension from the arterial side. On the flip side, if you have a patient with WHO group two pulmonary hypertension and you're trying to sort it out and you see their electrocardiogram, you're going to see a relative absence of those right-sided features. You won't typically see the right ventricular hypertrophy, right axis, or those right-sided T wave inversions in the pericardial leads. So really different phenotype just from a surface ECG. There's a bedside physical exam maneuver that takes about a minute to do that can be extremely helpful to distinguish between pulmonary arterial hypertension versus pulmonary venous hypertension. This is the systolic blood pressure response to a sustained valsalva maneuver. So really simply at the top of the screen is what is normal. So you have a patient with the blood pressure cuff on, you measure their systolic pressure, you inflate the cuff to about 10 millimeters of mercury higher than what their systolic pressure is, so you are obliterating those choric cough sounds. You ask them to do a valsalva maneuver, which they will then sustain. So of course, what does that do? That increases their intrathoracic pressure, reduces preload, reduces initially that number one is an increase in systolic blood pressure at the beginning of this maneuver. That's just an SVR increase, that's normal. But because you've reduced your preload and venous return to the heart, in a normal patient, their systolic blood pressure will then quickly start to fall within a couple of heartbeats, that's normal. If you have left heart congestion, this tool can be very helpful in all forms of left heart failure, because what you have in that scenario is a patient who has a really large pulmonary venous capacitance, really elevated left heart filling pressures, and so when you perform a sustained valsalva maneuver in these patients, their blood pressure will go up initially as you expect it to, but even with the reduction in preload, despite elevated intrathoracic pressures, you have enough of a pulmonary venous capacitance to maintain that stroke volume coming out of your left side of your heart. And so in patients that have left heart failure, we can use this maneuver, regardless of if there's pH, to identify the presence of left heart congestion simply on physical exam. This has also been shown specifically in the pulmonary hypertension population really nicely. This was published in Jack about 12 years ago, just doing this very simple clinical bedside maneuver in patients that had pulmonary hypertension to identify those who had an elevated pulmonary arterial wedge pressure. And you can see a really vast difference in the response to the sustained blood pressure response to valsalva in patients who had an elevated wedge pressure. Now in our field of pulmonary arterial hypertension, I just showed this as a really on the surface quick glance of just a few examples of how many clinical changes in our therapies have come. This is PAH specifically, and this is just a sampling from the New England Journal over the last nine years. We have novel therapies, novel indications, novel uses of combination therapies we've had for a long time, novel classes of drugs, a lot has changed and evolved. With that in mind, all of our professional societies have tried really hard to various extents to keep up with the guidelines on how to manage all of this. So you can see AHA, ACC guidelines from 2009, the 2015 European guidelines, which we've been using a lot up until about a month ago, we may continue to. There's ISHLT guidelines, even the CHESS Society came up with a document, and then many of you know just in the last month or so we have a new big document coming out of Europe. So I share that also just to sort of share what a force there is behind trying to understand how to integrate the growing areas of this field, the therapeutic options and the diagnostic evaluation. So there's so much that can be done in the diagnostic evaluation of these patients. So looking at just a couple of these examples of the guideline statements from over the years, here's the AHA, ACC, for example, from years ago. Once you get past that initial clinical history exam, the very first test here that you'll see is that echocardiogram. It's often really one of the first things in the evaluation of pulmonary hypertension. Here's a similar version of that diagnostic flow sheet from the European Society guidelines in 2015. Again, once you initially have pulmonary hypertension on your mind, the very first step in the diagnostic evaluation, again, is the echocardiogram. This is our most recent document from Europe that came out a month ago. And on the right side of the screen, when they first finally consider pulmonary hypertension, again, the first test is that echocardiogram. So we are all chest physicians. One of the things that I love about this group of colleagues is because we have this dedication to chest medicine, we all review the primary chest data directly. For example, here is a CT scan report with a lot of words describing a lot of abnormalities. I really love all of you in the audience because I know that when you see these patients, you're not going to spend as much time on that report as you are in looking at the direct image yourself. And you're gonna use direct review of the imaging to get better clinical nuanced assessments of what's actually going on with the patient in front of you. This same is true, of course, for the echocardiogram. So we really can use this. It's at the very top of the algorithm for all of our diagnostic evaluations in pH. It is kind of at the forefront of our assessment. So how can we use it to identify who group one versus who group two pulmonary hypertension? We're really trying to make that distinction, as you heard about the pulmonary vascular resistance, the pulmonary arterial side versus the left atrial pressure. These are just a couple of example images of what the echo classically looks like when you have right heart pH or PAH who group one. You have the interventricular systolic septal flattening. This is what's classically described as interventricular systolic flattening in the context of pressure overload. We've all probably seen this in echo reports. Please interpret that in your mind, actually, as a marker of afterload or resistance or an impedance. It's not specific to all forms of pressure, right, because pressure can be flow. It can be left-sided pressures. When you see that septal flattening in systole and it's red as septal flattening consistent with pressure overload, think of that as being a high resistance. The apical four chamber in the middle of the heart shows classically how abnormal the right heart is in PAH. The RV is forming the apex of the heart. The apical angle is wide open. There's hypertrophy. The RV is bigger than the LV. Your RA is huge. You have interatrial septal bowing from right to left. This is not the phenotype of an echo when you look at the pictures that will represent left-sided pulmonary hypertension. And of course, here is that RVOT Doppler profile that has been in the literature now for over a decade showing that abnormal shape, the reflected wave from an elevated pulmonary vascular resistance that really gives that abnormal notching profile. So some data to support how we can use this. Years ago, there was a paper published showing specifically, just looking at that notching profile in the RV outflow tract, normal is just a parabolic symmetric round-shaped profile. That indentation, that notched profile that represents an early reflected wave specifically from a high resistance in the pulmonary vasculature, you can see was highly associated with a dramatic increase in pulmonary vascular resistance compared to those that had normal. We wanted to build off of this and come up with a score that would create an ability to predict not just the pulmonary vascular resistance, but really take into account that versus left heart filling pressures on an echo and can we do that to make the distinction. And so we came up with a simple model containing just a few variables out of, after a lot of echo quant and analysis of many features representing the right and left side of the heart, this is ultimately the echo score that we came forth with. This was published 10 years ago in Circulation Cardiac Imaging. Very simple concept here. If you have features that represent left heart, pulmonary hypertension, pulmonary venous hypertension, you would get a negative point. And on the echo, that simply refers to what we call the E to E prime ratio. This is sort of part of diastology and representing the relationship between high left heart filling pressures and the relaxation abnormalities on the left side of the heart. Not gonna get into it in more detail to torture you today, just to say recognize that ratio E to E prime, that term represents left heart filling pressures if it is high. The other thing, very simply stated, is you're not gonna have pulmonary venous hypertension or WHO group two pulmonary hypertension, also known as left atrial hypertension in the context of dyspnea and pulmonary hypertension without having left atrial enlargement. So however you want to quantify it, if you have an elevated LA and a high E to E prime on your echo images, you get negative points. That goes along with having left heart pulmonary hypertension. The flip side is if you have a patient with an echo who has elevated RVSP and they have a normal left atrial size, no matter how you want to quantify it, and they have that RVOT pulse wave Doppler profile that I showed you before and it has that notch profile or a steep acceleration time, those would be positive points. Those are features that represent pulmonary arterial hypertension or a high pulmonary vascular resistance. Here are some of the data from that work. You can see as the scores went from negative to positive, the wedge pressures fell, the trans-pulmonary gradients went up. The mean pulmonary pressure didn't really change and you see that pulmonary vascular resistance also rise. This is simply just from looking at echo images to predict the hemodynamics. Couple side-by-side echoes to sort of show you examples of this on the left. We have a patient with pulmonary hypertension according to their echo. Their left atrium is enlarged. Their E to E prime is elevated. You can see that ratio here. The RVOT pulse wave Doppler is normal. There's no mid-systolic or late-systolic notch. The acceleration time is within normal. As a result, that predicts a patient that would have pulmonary hypertension on the basis of left heart disease. They have negative points on their score. They still had significant pH, but their wedge pressure was markedly elevated. Their pulmonary vascular resistance normal when we count them. On the flip side, patient on the right also has significant pH based on their echo. Their LA is small, normal in size. Their E to E prime is low, representing normal left heart filling pressures. They have a dramatic notch in their RV outflow tract with this deep acceleration time representing an elevated pulmonary vascular resistance. This patient has a score of positive two. When we count them, they have normal left heart filling pressures, severe pulmonary vascular resistance elevation, but really note that the mean pulmonary pressure, by the way, or the PA systolic pressure on echo is not what predicts whether the pH is coming from the left side of the heart or the pulmonary arterial side. That's really important. It's really the underlying profile of these patients. Now, I know I made a big deal about how we're all looking at the echo images directly ourselves, but sometimes we might not have access to those images and we have a sick patient in front of us and we have to sort out what's going on with them. So we wrote this paper a couple of years ago. This is work building off of that concept, but just simply looking at echo reports. So you don't have to look at the pictures, but using similar concepts based on routinely reported echo Doppler parameters on just run-of-the-mill standard of care echo reports. The score is similar in concept. You'll see positive points if it were features that went along with the high pulmonary vascular resistance or PAH negative points if it fit having pulmonary venous hypertension. Again, you'll see that E to E prime, which is routinely reported. It may not be discussed by the echocardiographer, but the sonographer has obtained it and it auto-populates the report. You just have to look for those numbers. Left atrial size will always be described. The presence or absence of that systolic interventricular septal flattening is always, it's always there if it's present on the report. If it's not noted on the report, that's a really important sort of pertinent negative on your echo report in the context of interpreting pulmonary hypertension. So a couple example echo reports. This is a report that showed a normal sized LA, an E to E prime that was low, the presence of septal flattening, and on cath this patient had PAH hemodynamics. Here was their score, positive three based on their virtual echo screening tool. Another patient with an enlarged left atrium by qualitative or quantitative description, whether you do LAVI or AP diameter or qualitative description, any of that is fine. E to E prime noted markedly high and you note an absence of the description of septal flattening consistent with RV pressure overload. So when this patient's cath, they have markedly elevated left heart filling pressures, normal pulmonary vascular resistance. Their virtual echo screening tool predicted that with three negative points. Here is a similar graph of the same concepts as the score from just looking at the echo reports goes from negative three to positive three. Then the wedge falls, PVR goes up. Here's the prediction ROC curves to predict the presence of a high PVR, who group one versus who group two hemodynamics. You can see markedly improved compared to PASP alone and similarly able to distinguish between who groups one and who groups two directly. So in summary, negative scores, positive scores can really give you the difference between pre-capillary versus post-capillary pulmonary hypertension based on all of those features. When you see patients that have positive scores on echo, you're really going quickly towards your ANA, VQ scan, right heart cath, and workup. On echo, you can look at the RV apex to also predict hemodynamics. This paper shows when the RV apex is really wide open, that's highly predictive of an elevated pulmonary vascular resistance relative to normal when that RV apex is narrow. So another study just looking at structure and morphology of the right heart to predict hemodynamics in pulmonary hypertension. This is just another image sort of putting all of those features together. So the last thing I just want to mention quickly is the right heart cath, which is a really important part of this assessment, of course. This is a publication that came in Jack, written by a handful of hemodynamics pH folks from around the country. They emphasize the importance of early right heart cath with proper technique. So just a few quick points from that. Make sure that our patients are zeroed. Make sure you're leveled with the transducer. Oftentimes there's over-damping or under-damping from artifact that can happen in the line. This is really important in our pH evaluation to make sure that we are getting accurate hemodynamics because that wedge pressure cutoff, if we're off by a couple millimeters of mercury, can make a big difference in our ultimate diagnosis. This is just an example of what over-damped or ringing artifact can look like and how you can kind of troubleshoot that when we're in the cath lab. And the last part is just an example, a really practical thing when you're obtaining right heart cath in the cath lab and you're trying to get that wedge catheter, that wedge pressure, remember in PAH, the arteries are enlarged, their caliber is enlarged, they're stiff, they're not compliant. It's much harder to fully occlude and get an accurate wedge pressure when you're attempting that in the cath lab. What often happens is an under-occlusion or a partial occlusion and you get a mixed wedge pressure tracing between PA and true wedge and it can falsely overestimate the wedge pressure and give a false diagnosis of WHO Group 2 PH. So how do you know? You look at the echo, the echo doesn't lie. So finally, the last thing is we do need more training for pulmonary hypertension, so we do have a fellowship for that at Temple. Please spread the word if anyone is interested. And in summary, WHO Group 1 versus WHO Group 2 pulmonary hypertension, we really have a rapid and complex evolution of the field. The blood pressure response to Valsalva, ECG, CPET can be really helpful in non-invasive ways. The echo's at the top of the diagnostic algorithm. All of us chest physicians are responsible for primarily reviewing that data, using the echo scores to predict WHO Group 1, careful technique in our cardiac catheterization, and we are all in this together to improve the education and training. Thank you so much, Anjali, great, great talk. We have Dr. Ron Budiz. We have Dr. Ron Budiz from UCLA, chief of cardiology, by the way, that is going to, and he's one of the people that have been around, you know, inventing this pulmonary hypertension field. He's going to talk about current and future directions in the management of pH. I first described pH in 1948, so I was. There you go. I've been around. Thank you for coming, welcome everybody. Let me just ask you, these are my disclosures, let me just ask you, I don't have ARS response questions. Let me ask you this question. What is the treatment indicated? I've answered it for you with the sound of silence or crickets. Let's talk then about where we've already been with respect to what we mean by pH-left heart disease, and I think Yamada said very early on that part of this is pathophysiology, but also part of it is whether there are treatments that are specifically indicated. From the more recent guidelines from 2022, we see a nice clinical classification in a nice color form, and we're focusing today on either the isolated post-capillary or the CPC pH patients. That's all pH-left heart disease. So when we first looked at the misdiagnosis of the community out there, there was a study called the referral study, and the idea here was to pick up patients that had PAH that actually were misdiagnosed and maybe underdiagnosed or were called PAH and didn't have it. But if you read across the horizontal, you'll actually see that there were some patients in this trial where they were actually classified as group two, and they were something else. So the first reminder, if you are dealing with pH-left heart disease, is make sure you actually have the right diagnosis. Like Anjali said, there are ways to look at the echo, there are ways to look at the transformative gradient itself. The second part is that we've now seen a little bit of a difference in the definition from the European standpoint, and I think it's pretty controversial. But what they're talking about with combined pre-post-capillary pulmonary hypertension I think is most important, because this represents an area, a subdivision of pH-left heart disease that has more features, if you will, we think has more features, with isolated pre-capillary pH or PAH. However, I would argue that when you have patients who have persistently elevated wedge pressures, left atrial pulmonary venous pressures, that you have what I call is a broken pulmonary circulation. These are electron micrographs showing that the capillary endothelium is disrupted, and the alveolar epithelial basement membranes are continuous, and here you see an alveolar epithelial layer and a capillary endothelial layer that's disrupted. You see disruption of all layers of the capillary wall. Here's one with a red cell passing through. And then a scanning electron micrograph showing breaks in the alveolar epithelium. So that interface between the alveolar capillary membrane is broken, and it is pathophysiologically different than the proliferative phase of smooth muscle and lack of apoptosis and all the other things in this hotbed of a cauldron, if you will, of pre-capillary pulmonary hypertension. So what do these new guidelines say? Because the old guidelines basically gave us a little bit of a treatment algorithm that said maybe there's a little bit more we need to do going forward to sort of isolate. So it's already been mentioned, the right heart catheterization when you are suspecting pH in patients. For patients left heart disease and suspected with features of pre-capillary, then you referral to a pH center. So that, I think, is really the theme, I think, probably for the next three days when we're talking about PAH or questionable pH and what to do with it is refer to the specialty center. There's another thing here that they talk about in patients with left heart disease and CPCPH and a severe pre-capillary component, that is, by their definition, a PVR of greater than five, not greater than two, to individualize your approach to treatment. And I hope that that would be true for every patient you see anyway. When you have a normal weight pressure at rest but abnormal response to exercise or fluid challenge and are treating with PAH drugs, close monitoring is recommended. Wink, wink, we'll come back to that in a second. With exercise or fluid challenge may be considered to uncover pulmonary capillary pH. Again, a lot of controversy here, but this is what they now put in writing just a few weeks ago. So there've been a couple of papers that have summarized what has been seen in patients with left heart failure and PAH drugs. There's been that one, there's been this one as well, both from 2018. This one I like because it actually showed that while you have a benefit, a hemodynamic benefit, which is I think a core marker for what we look at in PAH, certainly to defend the concept of pathophysiologically what we're doing with our treatments, you then look at the diamond here, which everything is to the left and doesn't cross over the one line, and that diamond suggests in a meta-analysis that there actually is a favoring of treatment. However, if you look at mortality, there's no benefit and all cause mortality. And so this really has to take us a step back and say, well, what are we looking for as endpoints when we're going to attack this disease that may be affecting millions, not just a few thousand with pre-capillary, but much more common, and as you see, it favors placebo, that mortality is increased. So there's a nice advisory here. It's called elucidating the clinical implications in pathophysiology of PAH and heart failure with preserved rejection fraction, a call to action. And I just took a couple quotes from this. The first one is the prevalence of pre- and post-combined PAH among retrospective heart failure referral populations ranges from 12 to 40%, so quite high. But the pathophysiology of the underlying subgroup is poorly understood. Even with those electron micrographs that were from 60, 70 years ago, we understand some basics, but we still don't understand exactly the dynamics. We do know, however, that the prognostic implication, in this case, right ventricular dysfunction in patients with HFPAP is very prognostic, and everything falls to the hazard ratio greater than one to the right side in this forest plot, suggesting that there is a direct link to RV dysfunction, irrespective of whether you actually have PAH, it's RV dysfunction. So I would argue that, really, the big question today for many of us in the trenches who are treating PAH and get patients referred to us, ideally in the minds of the referrers, I think, to get treated, to make the patient feel better, because we have a lot of bag of tricks up our sleeve, and we have therapies that are proven in group 1 PAH. So here is a summary that I came up with a few years ago, and it's updated now from the clinicaltrial.gov website. This particular one was oral triprosaniline HFPAP but terminated by the sponsor. This one was an ERA that was completed, and the primary endpoint was fluid retention, which actually had numerically more fluid retention than placebo, and then BNP and functional class and those sorts of things were not significant. So that's just a summary of the paper. There was a paper and a really nice series from Marco Guazi and his group in Italy that really were putting forward the idea of sildenafil, and they had a pretty good number of patients and really kind of compelling data to look at sildenafil in patients who had heart failure. And what we found when they finally did the trial was the RELAX trial, a billion dollar trial, that failed in primary and every other secondary endpoint. However they tried to carve it up, it showed that it didn't work. Maybe a one-off on that was Rio Ciguat, where you had an even more potent nitric oxide-based therapy and it provided a balanced drop in SVR and PBR, which didn't really get anywhere for pre-capillary pulmonary hypertension. Denervation, there was a trial, it was 100 individuals recruited in China, but it was last updated on the website in 2019. And then levosimendan, it was planned when we looked at this, but actually now has results. And I call these out because it is a distilled down version of patients that made the cutoff for what they considered treatable patients with left heart failure and pulmonary hypertension. They got 24 hours of open-label 0.1 milligrams per kilogram per minute of levosimendan, and then they had a lead-in period from the office to week two, all the way out to week five back in the office, titrating it off, and they had 17 completers in each arm. And this is what they showed with respect to six-minute walk distance. On the right side, you can just see, if you want to look at the individual responses, the number of reds that actually were on drug is far to the left, and they had positive responses, and there were a few that went negative, but by and large, more blue on the downside below zero. And a quote from this paper was, the HELP study is the first to show significant beneficial effects on hemodynamics and exercise tolerance in PHF-PEP in a double-blind, multicenter study. So that was just last year. It's up and coming. We have also the Tocetatracept, one of the studies of Tocetatracept that is underway and recruiting is called the Cadence Trial. And another one, which I think is more promising, but perhaps not just specific to PH, left heart disease, it's more specific to left heart disease, is the SGLT2 inhibitors. This particular study shows that EMPA reduced mortality and prevented progression in experimental pulmonary hypertension in a monocrotaline rat, and just highlights from the study that was finally published a couple years ago, there are few treatment options. They use the monocrotaline rat model as a rationale to determine if EMPA alters PH-related outcomes. It lowered mortality in the monocrotaline. It reduced right ventricular systolic pressure in that model and attenuated maladaptive remodeling. And that's the figure for that. I'm just gonna skip. But then, just last year, they published this actual human trial based on that monocrotaline, and they had about 30 patients in each side, and they monitored with the CardioMEMS device that is about the size of a penny and inserted into the pulmonary, proximal pulmonary circulation, and they showed the effects here with a P-value of 0.7, so maybe you wanna call it a trend or you just wanna be conservative and say not statistically significant, but a difference in mean pulmonary artery pressure, and it was sort of continuously dropping over time as it went out to week 13. There were quality of life scores that didn't make it, but one thing that did make it with a P-value of 0.01 was a decrease of antebromian P by at least 20%. Another study of sacubitril and valsartan, otherwise known as Entresto, and N of 14. The last I saw was completed, but still not reported since a year ago, and therefore, no results reported from that. So this is back from the 2015 guidelines, and I kinda like this better for a general approach. You get down through this echo probability, and you have left heart disease, no signs of severe pH and RV dysfunction, you treat the underlying disease. So by and large, the bulk of the patients that I get in my clinic that are referred, and those 75-year-old patients who have left heart failure, we treat the underlying disease. So what does that mean? It means that you have drugs already that are not indicated for lowering PA pressure, but they happen to lower PA pressure because they treat the underlying disease, diuretics, ACE inhibitors, ARBs, all the things that we're used to in our armamentarium of treating heart failure. So with that, I just wanna say we know already that pH left heart disease is common, way more common, and way more likely on an echo. If you read an echo, it has pulmonary hypertension, and you read a lot of echoes like I do every day, 15, 20 echoes, you're gonna see three or four echoes that have pH regularly. But you're not gonna be calling your coordinator for enrollment in the trial, or for a clinic visit, because you pretty much know if the indication for that echo said 75-year-old man with diabetes, AFib, and hypertension, and there's left atrial enlargement on the echo, and other signs of left heart disease, it's probably not something that you're going to jump at. The underlying pathologies and pathophysiologies between pH left heart disease, even CPC-PH and PAH, are just different, and that's acknowledged even in the most recent guidelines. And there are no approved treatments for pH related to any kind of left heart disease to treat the underlying disease. If the guidelines are telling us now that with severe CPC-PH and a PVR greater than five are treatable with a quote, individualized approach, close monitoring is needed, I think that is an understatement. And maybe a gross dereliction of duty in our communication to the rest of the world as to what to do with pH therapies. If you're going to do this at all, it has to be done at a center that knows PAH, that knows the drugs, and that knows diastolic pressure gradients and echo markers and how to follow these patients. There are pharmacologic agents, though, that are promising. More work needs to be done. I think mortality has to be the key endpoint in the end before approval. No surrogates allowed. Thank you. Thank you. Thank you so very much. It's been a marathon. How do I get out of here? Okay. So I'm just going to wrap up with a shorter talk only to discuss a couple of practical ideas in terms of management of pulmonary hypertension in left heart failure, and I'm going to focus, if that one ever loads up, on left heart disease, namely HFPAF, because I think that is the most challenging. It's easily missed or easily confused with PAH. When you see a patient with left heart disease, you have actually three goals in their evaluation. You have to kind of figure out the clinical phenotype, and we discussed about. You have to figure out the pretest probability of group one versus group two, and Anjali discussed about it, gave a couple of tools. And then we need to talk about the hemodynamic evaluation. So important here, we know that, as prior speakers said, actually all of them, not all left side pH is the same. You can have various pathophysiology that leads to a pulmonary hypertension group two, but also you can have various degrees of remodeling in the pulmonary vessels and your right ventricle, and I like to remind you there is this RV ventricular phenotype, and also associated most of the times with combined pre-capillary, post-capillary pulmonary hypertension, and to remind you about this magic number of five wood units that actually, across the board of the types of pulmonary hypertension increases significantly morbidity and mortality. So good point there. Whenever you have something like that, please refer to a center. We may have a couple of tricks, we may have trials available and so forth. Now in terms of the likelihood of pulmonary hypertension, this is what the newest guidelines are saying. This table was present in the older guidelines from 2015, and then the proceedings from the WHO symposium, the sixth one in NIS 2018. They are a little bit more complete nowadays. They have introduced more CPAT findings, for example, MRI findings. And of course, it requires a little bit of thinking because the patients are not going to come to you in one column versus the other. So you actually need to put down information and to decide where do you wanna place this patient in terms of their probability of having left side disease, pulmonary hypertension. And your main goal there is to do two things. To avoid unnecessary right catheterization, i.e. to identify post-capillary disease. And frankly, I would love to be able to tell you one quick, or not quick, but one foolproof, 100% sure method of identifying that one and saying, well, we don't need to go further. And unfortunately, we don't, but you have a couple of tools like Anjali was already mentioning. The other thing that's very, very important when you face with these patients, and I cannot emphasize that enough, people can have more than one type of pulmonary hypertension. So you do not wanna miss someone with pre-capillary disease that you may be actually able to do something about it, or CTEF that, again, you would be able to treat, even though they look like a group with risk factors for metabolic syndrome and so forth. So this is from the newest guidelines. You don't find it in the document. You find it in the supplementary, your supplementary data there. And they kind of split the patients in two groups if you have high risk or established left heart disease, then you may consider right heart cath in certain circumstances. An example there would be if you evaluate the patient for transplantation. And also on the other side, when you have people that have lower probability for left heart disease, but presence of RV dysfunction, then it's a one indication to actually proceed with right heart catheterization. And then you figure out if you're talking pre-capillary or you're talking post-capillary disease. In between these categories, you can add by a couple of scores, like pre-test probability scores that we'll discuss about that and can kind of help you know to find where you are. But I wanna raise a couple of issues here. I think each time you have risk factors for group one and group four particularly, and I would include group three and five as well because we have some ways of managing those patients as well in terms of therapy. I'm not going to open this can of worms, but there are some ways. Please think and refer for a right heart catheterization at the center. The other thing is going to be the timing of the evaluation, the use of the prediction scores and how to apply them. And then when you end up doing right heart catheterization, who needs provocative maneuvers? Because provocative maneuvers are sometimes going in cases when you have uncertainties are going to unmask left side issues. First of all, very, very important, you have someone that's coming in acute pulmonary edema from systolic hypertension and they have fluid overloaded, they are hypoxic, that's not the best time to put a swan catheter in those people. You gotta get them to their best possible fluid status and oxygenation because all those things are going to give you false information. Then you would think maybe to correct the underlying comorbidities and I wanna discuss here a couple of points. Again, I'm not talking about the patient that has obesity, hypertension, diabetes, so risk factors for metabolic syndrome and they have the right ventricle that's completely dysfunctional or they have scleroderma. I'm talking about people that don't have these red flags. Should I correct first the comorbidities and for how long before I go ahead and I do a full workup? And I just wanna give you two examples here. So these are meta-analyses that are done. You lose weight, it's true, it's a ton of weight that those patients lost, 45 kilograms over up to nine months, but the mean PA pressure went down by, again, five millimeters mercury. CPAP using OSA, you will say, well, maybe why are you bringing group three? Well, I'm not bringing group three. OSA goes with high BMI and high BMI virtually goes in every single risk predictor, prediction risk score in left heart disease, pulmonary hypertension. So you actually treat people with CPAP and their mean PA pressure, as you see there in the fixed effects model in the meta-analysis, the PA pressure goes down by 13 millimeters mercury. I should not say mean PA pressure. This is mostly echo data except for the first study, but that's also important because if I can show some improvement in that inaccurately estimated RVSP of 10 millimeters and then you lose some weight and you go 10 millimeters and you control your systemic blood pressure and you go another number of millimeters, maybe I end up with a normal right ventricle and I can avoid a right heart cath. Anjali already discussed about the Opotovsky score. We also have, from Italy, the Alto score. Pretty much they say the same thing. They are very good at extremes. In the middle, the prediction goes a little bit in the lower range. And the same thing with the Alto score. For example, they show that if you have score less than five, it's very unlikely to have precapillary disease. The other thing, we have scores that predict HEF-PEF. So this one, H2-BFEF score, it's designed not for pulmonary hypertension and HEF-PEF is designed for HEF-PEF. It's published, it's well-known. We have also scores that are trying to predict PH-HEF-PEF and this is a retrospectively designed score in France and again, at extremes, you have more certainty that you're dealing with precapillary versus postcapillary disease. In the middle, you have less certainty. Also, we have these optics scores. So this is also a clinical score that's developed in the Netherlands. They actually developed it in two centers and they validated it in the community. There are a couple of criticisms to this score. Dr. Simon here actually wrote a beautiful editorial to that. They have some lack of generalizability. That's number one. Number two, you do need certain echocardiographic measures and sometimes they didn't have them available. But pretty much it's information as you see that you can actually get in the regular history and to distinguish precapillary versus postcapillary disease optics which is designed for HEF-PEF pulmonary hypertension performs better than the HEF-PEF score, not surprisingly. It does perform better but it's not a full proof. Again, as I said, there's no way I can tell you 100% noninvasively you have HEF-PEF, you have postcapillary disease. And this is a Scottish group that actually compared the two scores in their patients. And on your right side, you actually can see the patients that were misclassified as postcapillary disease when in reality, they were precapillary. And so that is very, very important. We can't afford to miss these people. We do have diagnosis for that. Anjali already spoke about the VEST. That's an echocardiographic screening tool that came up during COVID time when we actually didn't have access to the patient to put the probe on their chest. So you had to rely on reports, excellent predictive capacity. And I have to give a big shout out to my former brilliant fellow, now a pulmonary hypertension doc on his own, Himanshu Deshwal. He actually, during the same time when we were flooded after the gates opened, patients came back, we were flooded with cath requests. So how do you prioritize? Who are you going to cath out of the 50 new patients that you get in a week? So actually, we looked at our data and we developed this score in which if you have a score above seven, you are actually more than 94%, 95% certain that you are dealing with precapillary disease. So we shall prioritize you. Hemodynamic assessment guidelines say intermediate low probability for group two and risk factors for group one to three. I would say even if you have high probability for group two, if you have scleroderma, if you have risk factors for CTEF, you should end up on a table. Very important when you suspect the RV phenotype and you can use your corroborative information from PFTs and CPET as Anjali has shown. So in that editorial that I mentioned, wrote by Dr. Simon, that was one of the ideas. Even though I cannot actually use a predictive score at the beginning, I can maybe use that score to decide what am I going to do in the cath lab. So this is actually from the WHO symposium from 2017. I think was more user-friendly in terms of telling you exactly what to do. But once you end up having someone going to the right heart cath, you have a couple of choices there. When do you need to do a right and a left heart cath authorization? How are those prediction scores of some help to decide what to do and how to do challenges to unmask as needed diastolic feeling pressures, abnormalities, and left side disease? So this is a classical, the Daryl Tashman Chest article shows that more than 50% of the people that you classify, these are 4,000 cases, a right and left heart cath simultaneous, more than 50% of the times what you classify is pre-capillary disease by wedge. When you put an LVDP catheter, it becomes actually post-capillary disease. So the way you actually may unmask in areas when it's uncertainty, your borderline 13 to 15 wedge pressure, for example, or when you have predictive scores that tell you that it may be a lot of post-capillary disease, it's recommended to either do exercise and fluid loading. To compare them, exercise it's more effective in increasing the wedge pressure and then masking the left-sided feeling problems, but fluid it's obviously easier to interpret. So in summary, patients can have more than one type of pH. So if you have suspicion of anything pre-capillary, risk factors for group one, group four, and mainly please let's consider a cath no matter how old and how much diabetes you have. Predictive scores may not help you at the very beginning because they still can misclassify pre-capillary disease, which is poor form in terms of addressing that respective patient if you don't treat, but they can add to clinical decision-making later or in particular tell you what to do with the cath. The timing of assessment is important and perhaps we should give a couple of months to correct the risk factors for left-side disease. And particularly when you have people with at least intermediate risk factor for intermediate level probability for left heart disease, I would say let's measure the LVDP to start with. This is what we do in our practice. We do right and left when we have suspicion or very many risk factors for left-side issues. And a right heart cath with probative maneuvers are useful in borderline and intermediate risk left heart patients. Thank you. We are way.

pulmonary hypertension

left heart disease

diagnosis

pre-capillary PH

post-capillary PH

combined pre- and post-capillary PH

specialized care

comorbidities

treatment approaches

ongoing research

PH