Charles D. Burger, M.D., a clinical expert in the diagnosis and management of all forms of pulmonary vascular disease, presents on the approach to pulmonary arterial hypertension in the Advanced Heart Failure Grand Rounds series.
So in terms of disclosures, we've participated over the years and multiple industry sponsored multi center interventional trials for drugs primarily propofol Maneri, child hypertension and as such, the various pharmaceutical companies that make the agents have sponsored the trials. I haven't received any direct monies from these folks for that research. Uh, and I won't be discussing anything off label. The objectives this morning are to get a better sense for the various diagnostic groups. It's always a little computing with ph because there's functional class, which is a symptom categorization of severity of the symptoms. And then there's a functional diagnostic classification that originally was designed by the World Health Organization and has been taken over by the pulmonary hypertension community to be used to help pigeonhole patients into a proper designation so that treatment decisions can be made. And that's really their diagnostic group, even though it's entitled classification. So sometimes that gets confusing for folks, we'll talk a bit about that. The world symposium on former hypertension generally meets every uh, 3-5 years last met in 2018 February. And so there were some updates out of that that will bring to your attention. I'd like you to focus on the guideline based recommendations, understanding that individual decisions have to be made for each patient, but uh, to get you to be as accurate and as timely and your diagnosis as possible, a little bit of a sense of how to choose the best initial therapy and then talk a little bit about diagnostic group for which is chronic crumble, invalid disease, pulmonary hypertension. So, when you talk about pulmonary hypertension is really a condition where the pressures and the primary circulation are high, multiple causes fully hypertension. Uh, per se, isn't a diagnosis anymore than tachycardia as a diagnosis. You want to know the underlying reasons for the pulmonary hypertension in order to understand and develop a true diagnostic classification so that you can make the right decision for treatment recommendations for the patients. So on the front end, we always think about those things that tighten up the blood vessels uh and increased resistance to flow. Therefore, upstream right heart has to generate higher pressure. So, you know, reversible basal constriction can occur obstruction with C. T. E. For example, the vessels can be obliterated with scarring. Uh So there are a variety of ways that the special caliber can decrease and that's really where group one potential hypertension balls on the downstream side of the equation with which you're most familiar. Anything that would elevate pulmonary venous pressure from Hungary vino inclusive disease all the way to issues with the left heart uh can of course, ultimately increase the pressure that the right heart has to generate to overcome that downstream pressure. And one that many people forget about is that if you distended pulmonary circulation with more cardiac output, The pressures will increase. So with exercise, if you take your pick up from 5-15, you distended the pulmonary circulation. And although it has an amazing capacity to accept that the overall mean pulling out internal pressure will increase. So high flow states that are pathologic, large arterial venus, uh connections, fistulas, malformations particularly are chronic renal disease, patients liver disease that has high cardiac output state, can all increase the main political pressures with the fuel recirculation. Think absolutely normal. So that's important to bear in mind what's going on behind the scenes? Well, we know that there can be some genetic predisposition. Uh the one uh that I will allude to momentarily. That's uh why this known is foam mortal genetic protein receptor too, which is a disruption and transforming growth factor pathway. Many of the pulmonary vascular changes that occur really mimic what you would see with benign nia pleasure. That cells grow out of control. They don't respond to normal cellular signaling mechanisms. They have abnormal life cycles and they produce total disarray in the micro circulation of the pulmonary vasculature. Metabolic arrangements can contribute to this. There's a lot of interest in that the uh into type and find a type of metabolic syndrome and its impact on the coronary circulation and then some wealth or inflammatory injury. So this is just one of the many a pathologic path, a biologic pathways that you can pull from the literature or a lot of these slides look overwhelming uh and really a lot of overlap with a lot of other conditions. But I would just call your attention to a couple of things. So that bomb work. Oh, uh, genetic protein receptor two mutation as I said, is the one that really fits with heritable pulmonary arterial hypertension for the most part. And when you get disruption there, ultimately you end up with hyper proliferation of the pulmonary artery and the thallium, vascular smooth muscle hypertrophy and the vascular wall, all of which narrow the pulmonary vascular lumen and increased pulmonary vascular resistance. We know that there can be various things externally that can trigger this disruption from high flow states for cardiac shunts to drug and toxins bent then thing at the top of the list and these can increase a lot of abnormalities and signaling this uh promo domain uh extra terminal motif has been one that's received a lot of attention to BRD four which is seen other cardiovascular diseases. You may have some familiarity with it, but certainly can lead to all three of these things at the bottom of the slide, which can ultimately, to vascular occlusion and fibrosis. And then a big one on our list, which we'll talk about is systemic sclerosis, which has about a 12% chance of Ultimately evolving into group one for arterial hypertension. Yeah, at a physiologic level, as the pulmonary vessels began to move from normal state into this vascular smooth muscle hypertrophy and pulmonary epithelial disruption that PVR obviously continues to rise as the vascular lumen narrows upstream pressure has to increase to parallel that and overcome this higher resistance. Carrick outputs able to keep up with this initially with right ventricular hypertrophy. But over time you get dilatation of course of the right heart and you begin to get systolic hippo kinesis as the primary vascular apathy gets more and more severe and ultimately, if you die puller arterial hypertension, you die because the right heart fails. And I would just ah show you that at the end stage these pulmonary pressures may fall off. So you could be reading an echo where the pulmonary pressure uh appear to improve. Yet the condition has worsened because contract ability has really dropped off of the Starling curve and PB are still sky high, right ventricle apolo still sky high and you're basically at right heart failure. Cardiac output goes down to a critical level. What are the symptoms presentations? If you look at? About 3000 patients in the reveal registry, which is 50 for us? Base flooring hypertension centers fairly non specific. Most have dismissed, particularly with exertion. I bet you certainly couldn't have fatigue and chest pain. And about a quarter of patients, the one that probably signals uh pulmonary hypertension is a potential cause of the distance, particularly in a young woman. As up to 4/5 of these patients are female is exertion all sync api order snow. Near sync api asthma tends to be a misdiagnosis in this group of patients, but if this is occurring it's not asthma. And certainly this would indicate significant right ventricular after load. Uh so that with exercise, right heart pressures increase, they displaced to set them into the left side of the heart, decreasing left heart filling and therefore decreasing profusion to the cortex and therefore near sync api or sync api. So this really equate stuff functional class for symptom ontology. So, the functional class, which is again different than the diagnostic grouping, is very similar to what use every day with new york heart association focused class. The only thing that's really uh somewhat a modification is the addition of exertion of sympathy to functional class for telling you that the right heart is insignificant dress and that Aggressive treatments are warranted. Most patients fall within group three, uh which tends to be a rather broad category. And we even subdivided into group three A. And three B. Just sort of help us in the clinic three A. Being taken uh handle most activities of daily limiting. But with heavy exertion, they certainly had the symptoms, rest three B. They can't do much of anything including a DLS but they're not symptomatic at risk. So this is the breakdown in the reveal registry. As I said, most patients fall into group three followed by functional class too. Uh and folks who present with right heart failure fortunately is uh the least common presentation subgroups of uh Group one monitor hypertension as Modified recently by the six worlds. And posting on primary hypertension R as in this slide group 1.1 which is idiopathic of snow. Secondary cause charitable would primarily be be NPR too certainly dragon toxin And the one that's on the rise in the U. S. Is exposure to methamphetamine. Yeah. Group 1.4 has various sort of subgroups, connective tissue disease, HIV portal hypertension etcetera. But those are the three that we see the most of with an increasing population of congenital heart disease due to growing practice dr phillips changes that have been made as there was an addition to separate out home arterial hypertension. That has both been acute in a long term response to calcium channel blockers. This is a small percentage of patients but it is important to call them out because they have an excellent prognosis and don't need The newer, more expensive agents that have been developed over the last 15 years And then a combination in 1.6 uh former racial hypertension that occurs because the pulmonary being decided. That equation is obstructed either with P. V. O. D. Or pulmonary capillary hemangioma texas. If you look at reveal and the breakdown about 45% or so or idiopathic with another 50% in that associated category and of that associated category half of those or connective tissue disease. And if you took a pie graph of this side, three quarters would be scleroderma. If you compare that to what we see here in Florida, looking at a group of over 400, a pretty similar breakdown with big percentage of idiopathic and of the associated conditions scleroderma and liver disease. Because we're a big transplant center certainly have been historically are too big subgroups associated pulmonary hypertension. And then we see a fair amount of chronic problem Bilek disease. Ph so just a question to kind of wake you up with your coffee, Which of the following have been validated and screening for group one for material, hypertension associated conditions. HIV. Serology A and a overnight X cemetery or H level. Mhm. five seconds to think about it. And we actually looked at it and right with one of our current hospitalists actually doctor Pagan and a positive A and A is the one of all of those that's really been validated. All you'll see many of those listed on the guidelines with a good area under the curve as an excellent screening test for connective tissue disease. If you make the diagnosis of pulmonary hypertension first and then you're looking for secondary causes and anna certainly should be done. We looked at HIV and Over 400 patients, only, one of which was positive. We knew she was positive. She just didn't bring the test with her. So we repeated it. So in certain populations you really just need to quiz for exposures. Uh, if you work in an urban setting that might be a little different. But HIV has not been validated as a screening test, even though it appears on the guidelines, Just as if you were wondering about that choice as a distracter under question. How about the other way patients in a busy rheumatology practice, should they be screened for pulmonary hypertension? Certainly if a patient's dissonant, do you want to work that up is cleared? Every predisposes? Not only the pulmonary hypertension by interstitial One disease, there have been a variety of screening algorithms that have been designed and tested worldwide, actually, one of which is detect which was spearheaded out of ann arbor, looking at a couple of steps. So, patients with scleroderma often had to expectations. But if they tell you that they're increasing or increasing in size, number or size, that's worrisome that there's an accelerated pulmonary vascular process ongoing. Is wearing clinical clue for you to take home from today? Certainly that anti central antibody with uh what appears to be limited scleroderma crest syndrome. And then you see other diagnostics that point this way, right axis deviation on big. If you've done primary function test to screen for LG and the deal ceo is quite low. But when volumes are well preserved, that makes you think a little bit more about primary vascular disease. And then certainly if there's stress on the right heart is indicated by an elevated brain nature out of pet type, then you would move to echocardiography and that that's abnormal right heart catheterization. And if you compare a lot of these various screening algorithms that have been tested worldwide, they're all quite sensitive no matter which one I emphasize detect today and lecture. But there's others. If you're inquisitive in this area that you could look at. So good sensitivity. Obviously not degrade as the specificity, but this is how you want to proceed with screening. Ultimately, if the echocardiography suggests ph then absolutely right heart catheterization is ah paramount and critical to not only confirm the diagnosis but look for other causes that can only be measured by right heart catheterization such as left to right shunting with an oxygen saturation run as an example. So full complement of thermodynamics are required as well as that saturation run and then testing with acute basil violators which is typically inhaled nitric oxide in our practice. If you look at echocardiography and its role. Uh We developed a uh methodology by which you can measure main financial pressure on eco Years ago and published it. It's been incorporated in demeo standard primary hypertension echocardiography report across the enterprise showing good bland Altman correlation With the mean by Echo uh compared to the mean by right heart cath. consecutive patients with this stunt simultaneously. So excellent performance in an outperform right ventricular systolic pressure. It's important for two reasons. One is it's better and to its mean pulmonary pressure that defines for hypertension, not pulmonary artery systolic pressure with an excellent area under the curb using our methodology. So you should just be aware that we developed that on this site. Been more recent work with our cardiology division. Looking at ways to use the echo to determine if you need to move to right heart cath. If all indications are that this is left heart disease and obviously the clinical setting in which this is most comment is heart failure with preserved ejection fraction. So with a lot of work with validation cohort of well over 300 patients looked at a trance pulmonary ratio using our methodology for the main political pressure and then dividing into that a prime ratio from the medial micro valve and flow velocity. Uh to get a ratio that would suggest that this is left heart disease versus pulmonary arterial hypertension with pulmonary vascular obstruction. So a ratio of 2.7 really fit more with just being left heart disease versus a ratio for hire pulmonary vascular disease. And if you look at the performance, just of that ratio, the area under the curve was about .7 if you added on a couple other echocardiogram fix measures such as ejection fraction uh and stroke by him As well as whether or not the patient has systemic hypertension in this area of the curb, gets up to a .8 range and that played out in a validation sample as well. So hopefully this looks like it's well on its right being published in print. And once that happens we can have more widespread use of it. Yeah. As you know, the focus oftentimes on the echo is what is the pressure and that's based on what you see with the tree custard regards to jet velocity. But there's so many more clues. I sort of kid diplomacy fellows look at page 234 or five of that echo report because you really want to look at what's going on with multiple other measures that are available to you, Not the least of which are measures of right ventricular systolic contract ill. Itty such as F A C tap, see uh lateral velocity micro valve, the thai index or the RMP or the right ventricular strain. So all of those are useful but if you're not as familiar with those, certainly looking to see if there are other signs that this might be pulmonary hypertension, such as what's going on with the right ventricle as it dilated is the septum shifted over toward the left, which really tells you there's quite a bit of pressure overload on the right side. And you can look at some of these other uh more technical terms, obviously the cardiology uh and cardiac transplant fellows would be doing that. You might not be doing as much of this as a critical care fellow, but all of you would be looking at right atrial pressure as estimated by white guys on with the emperor vena cava, both in terms of baseline size and its response during negative interest, Jurassic pressure inspiration to help estimate R. A. P. And I'll show you that that is a very powerful prognostic measure parameter. If it's elevated, ultimately you go to right heart catheterization now historically. Uh I mean Former area pressure 25 or higher have been used for the definition. This has changed. I'll show you sort of the reasoning behind that by the world Symposium on pulmonary hypertension, but it's now 21 or higher. So they introduce what we had been calling, borderline elevation and political pressures. But very importantly, for purposes of pulmonary hypertension, you must have elevated pulmonary vascular resistance. So if it's downstream, you're not likely to have that. If it's just a high flow state, this is going to be normal. So you can't just do it off of the main pressure. You have to have the full complement of thermodynamics to get the former a vascular resistance. They see this all the time on outside. Right heart catheterization where no cardiac output is measured. Uh, and we don't have this value. So it becomes worthless and we have to repeat it for the patients, which is a shame for them. So, the old definition from 2013 was mean pay pressure 25 or higher. Again requiring that high pulmonary vascular resistance. The newer definition brings it down to greater than 20, So 21 or higher, but still requiring high PVR. Sure. What are the pros and cons behind this? Perhaps were able to pick up polar to hypertension a little earlier. And of course, particularly in high risk groups such as scleroderma. Uh, but there's also more potential if you lower that threshold for putting folks in a category of having a potentially deadly disease when they don't quite meet the historical definition where we understand the course uh more completely. Uh there's going to be over treatment, I think uh each path patients who will have pressures in this range but just have diastolic left ventricular dysfunction and the increased left heart filling pressures. And then there's no recommendation with lowering that diagnostic threshold pressure between 21 and 24 per treatment recommendations. So they really left it quite open ended. And there was a lot of debate over this and some dissension expressed certainly at the conference to say, well, why would you lower diagnostic threshold and not change the treatment recommendation? It was purely to help follow some of these patients more closely. So it's a debatable move. But it has happened. So what are those changes? I just want to summarize new pressure level to define pre capillary ph to try to simplify the core clinical classification. I called out having a separate designation for those that are acutely and long term responsive to calcium channel blockers. Uh here and also P. B. O. D. And the PCH category. And then most importantly that pressure threshold but still requiring a high pulmonary vascular resistance key diagnostic tools. Once you get to the point where you're honing in on former hypertension is to make sure it's not used to lung disease. Really important to screen for ct ph. I'll talk about that uh and uh heart catherization. We talked about numerous other sort of biomarkers are being studied but the one that we rely the most on at this point is BNP all those a fair amount of evidence with D. Dime er uh and others that they do have predictive uh roles in prognostication. So the diagnostic algorithm from the Six World symposium is if you're headed this way and you screamed and you have a high probability for ph then you really want to get a BQ skin early in the course of a bench. BQ has fallen by the wayside for acute pe that's diagnosed by ct with contrast the protocol, but for chronic C. T. E. Really BQ outperforms more conventional ct angiography. Although advancements are being made and that may not always be the case. Uh You do need to be cute to screen for C. T. E. P. H. And if it's abnormal. The recommendation is that you refer to a ph center because C. T. Ph has a different treatment algorithm. I emphasize this. Speak to Nazi ta for screening. The reason you refer to a sinner is that if the patients are eligible for a pulmonary crumble endarterectomy, its curative. So the acute clot has been replaced by vibe Roddick obstruction that adheres to the pulmonary artery into MMA. And this can be removed surgically. It's a very complex surgery performed at our center by dr kevin land oppo that can result in complete resolution of the pulmonary hypertension. Therefore patients eligible, you want to go that route. We're looking more and more into balloon coronary angioplasty experience worldwide has grown over the last several years. Dr Peter Pollock is heading up our practice with dr Charles Ritchie in radiology. Uh We have two patients that we've done so far but several others that in fact we're going to talk about it. R. C. T. Selection. Meeting this Wednesday along with a couple of patients that might be eligible for pT for those patients that aren't eligible for these interventions or have had them and have persistent ph Real ciguatera which is a soluble violate cyclist stimulator has been approved again for inoperable disease. Not as a primary treatment. Mhm. So you make the diagnosis if they're bezoar reactive? We talked about the potential to treat with calcium channel blockers if they're not basil reactive and they're on the lower side of risk. By functional class B and P. R. B. Performance six minute walk distance. Then you can begin uh with mono therapy will close follow up with low threshold to add a second drug or there's significant evidence of starting to drugs up front. If they present and right heart failure, then you need to proceed with more aggressive therapy, generally infusion if a cross channel or to cross to know. And at that point you might think about odds of them responding and engage uh lung transplant early in the course of events. If you think that that may be problematic or certainly if they don't respond to therapy, whether the pathways I. E. The target for the current FDA approved armamentarium pharmacologic intervention For group one financial hypertension process cycling pathway is the one in which we've had the longest experience. Uh These uh crossed recycling derivatives work through sai click A. And P. And ultimately to uh counteract proliferation that I talked about at the pulmonary micro circulatory level and produce some basil dilatation uh intravenous drugs, oral drugs, inhaled drugs are all available in this pathway. More recently. Uh I. P. Receptor Agnes has been developed also an oral drug and and the feeling pathway. The idea is working on blocking in the field of one which is the most potent endogenous faizo constrictor produced by the human species. And the available drugs are all oral and they block the receptor receptor A. And B. On pulmonary vascular smooth muscle and pulmonary artery and helium again leading uh to counteracting the basal constriction and the proliferation produced by into feelings. So it's blocking these actions in the nitric oxide pathway. Ah Uh huh. You can give inhaled nitric oxide that's problematic to do as an outpatient. Although there are some ways of doing that novel ways that are being studied but historically it's been blocking the breakdown. The nitric oxide with possible demonstrates five inhibitors. So if you block this enzyme then whatever nitric oxide is in the system becomes more available to produce faisel dilation and anti proliferation. More recently, the drug that I referred to earlier, real ciguatera. The side will go. Only cycling stimulator works recycling GMP to generate nitric oxide so low, maybe effective when there's endogenous low levels of nitric oxide, not just by blocking its metabolism. So this is just a table sort of breaking it down by route of administration. All of the er is our oral that are listed here. The two possible demonstrates five inhibitors. All of you are very familiar with, I'm sure are both oral, real shigella again. Oral and in the newer process cycling receptor agonist for all the process cycle and analog czar where uh it ranges from either oral option to inhale to confusion, which are possible giving you the option of either continuous intravenous infusion through an indwelling central venous catheter versus subcutaneous lee. So another question you're probably eyes are glazing over by this point that to wake you up again, I can't see all of you with working off of the power point. I'm sure you're all well dressed with your hair combed 32 year old woman with Ray Nagy to land Jacked Asia's GERD and symptoms consistent with your car association, punctual Class three BMPs elevated six minute walk for 32 year old has reduced 350 m And to handle dynamics by right heart catheterization include right atrial pressure 12 P. a pressure 84/28 with a mean of 47 wedge pressure is 12 millimeters of mercury, respectively. Cardiac output five liters per minute Calculated primary gas resistance seven would units. And then in response to inhaled nitric oxide, the mean pressure Dropls slightly to 40 with cardiac output. That increases to six leaders. Criminal. So what's the best treatment calcium blocker since the main pay pressure dropped with inhaled in uh in the field receptor antagonists Adding possible bastard five inhibitor plus. And in the field receptor antagonists are going with that newer agent that I showed you the oral uh iP receptor Agnes select Spec I'll give you 10 seconds to think about that. And really the evidence would support in a patient functional class three with a lot of the prognostic indicators. BNP watch right heart cath indicating fairly severe disease. To start with initial upfront combination therapy with a PDE five inhibitor and tiara ambition was a trial that showed that multi center placebo controlled a prospective of course randomized that studied to dial a felon amber Stanton upfront versus each of those as model therapy with significant uh clinical reduction in important events such as the worst thing of the ph hospitalization need to go onto infusion therapy. Need for transplant and death. Has a great show 0.5 and yellow bottom right corner And over three years. Uh the event ratio of 68% and uh combination Upfront Therapy vs in the coal mine. Oh therapy was about 56%. If you look at the same sort of uh impact and other efficacy studies. Not an upfront therapy but an add on therapy. I'll bring to your attention. one uh study seraphin where mass attention was studied at two different doses 10 and three mg versus placebo. Again, looking at the percentage of having these important clinical events National Tent and 10 had the best curb with uh less of these clinical events. But it's important to note that 61% of these patients, we're on combination therapy typically with a P. D. Five. So this is really sequential therapy uh showing that two drugs are better than one drug, but it wasn't an upfront start study as was ambitions. We looked at the impact of hospitalization and I'll bring to your attention how I think that should be incorporated and how we follow these patients as well. Uh looking at that reveal population newly diagnosed 960. There were some exclusion that didn't meet thermodynamic criteria. and we looked for hospitalizations among the 860 patients. And 490 out of that, 860 or 57 had hospitalization within the first year. Often multiple hospitalization and over one half were directly attributable to the ph and that had implications in terms of survival. So if you did have a hospitalization for feei Your survival 57% vs 68%. If you did not have a hospitalization per ph so it really should be rolled into how we think about our goals for treating cory hypertension. Certainly we want to reduce symptom burden. I think all the patients would agree they want to stay out of the hospital. We would certainly agree with that as well. I would hope ah we want to do this with minimal treatment burden. That's not always possible. But that's part of the balancing of the equation. And of course we want to improve survival and avoid transplant if at all possible. So did any of these studies show an impact on hospitalization and indeed they did. And that's why it really sort of reinforce the work we had done with the reveal registry and time. The first hospitalization has a great show Just Under .4. Uh And if you look at this with connective tissue, disease related ph uh it had the same sort of impact. So uh that up front dual therapy helped avoid hospitalizations as well. The mass attempt in study that I showed you to surf and trial again dose related uh in comparison to placebo reduction in hospitalization. So the drugs certainly work on this end and make it a reasonable goal of therapy. The 2015 European Society of Cardiology, European Respiratory Society Guidelines are listed here in terms of the therapy as they showed you Earlier, the 2016. Ah where else imposing my ph deeper a little bit from this. But it's in general, same philosophically and that is that the patient is low risk uh Strong consideration for that initial oral combination therapy makes the most sense and if they're high risk moving to more aggressive therapy uh Typically infusion regardless. Close file up to see what the clinical response is his paramount. Uh You can't just start these drugs and see the patient in a year. They need to see back in a month or two after initial start and probably every three months thereafter. And then you may need to add therapy. If you started with two drugs, you may need to add a third or if they're really feeling engage our transplant colleagues. one of the ways to monitor Clinical response and prognosis in a more detailed, well way is revealed. 2.0 published last year in chess, we helped design and develop this with the reveal investigator group that's available online. But it's basically points that would be added if your markers such as functional class and BMP show worsening or high levels. Uh and you start with a base of six and as you get higher and higher. Obviously with that numerical score, The risk of death at one year uh increases significantly. So you really want to keep patients and uh you know 67 or lower because you can subtract points. So for example, if your functional classes one you stop subtract one or if your BMP is less than 50. Subtract two. So keeping it at six or seven or lower is part of how we track our patient's done a fair amount of work in conjunction with our cardiology department. Looking at ways uh prognosticating one of which is cardiac M. R. This is worked by Jordan ray and brian Shapiro that they were kind enough to include men. Uh That shows if you looked at pulmonary artery pulse utility, uh somebody needs to mute their mike, please getting a lot of feedback. If you look at pulmonary artery pulse utility which is changed in pulmonary artery diameter with cardiac sisterly. Uh If the pulmonary artery is uh compliant and can receive the cardiac output without much in the way of diameter distinction, then obviously that's what you want. You want to uh pulmonary circulation that's recruit herbal. Whereas if this is uh doesn't dist end and the pulse utility is low then that does correlate almost quasi sort of dose dependent or diagnostic parameter dependent way between mild and moderate to severe chris Austin and brian Shapiro. Uh looked at a simplified eco score to help predict for the holiday which looked uh with the driving perimeter being right atrial pressure but also including peak trikus speed reduced at jet velocity As an example. That with four or 5 Parameters to each of which would gain a point. And if you had a very high right atrial pressure, the very high tr jet velocity, you know, you would get a couple of points as an example and it did break down quite nicely with the very simplified point score to show uh that you can help prognosticate with what you get out of the echocardiogram thick lab. So we use that extensively in our practice. Let's switch gears just a little bit where we are with uh clinical research. I'll focus on those things in which where most active here bail clinic florida triton study looked at triple upfront therapy vs two drugs up front. Looking at mass attention to Dallas Phil and CeleXA peg. So all three pathway targets vs just mass attention into Dallas fell, which are the two pathways that were shown in combination in the ambition study to impact clinical events. And both groups did remarkably well. So to drugs and three drugs the patients did very well and so well that there really wasn't a difference between starting the third drug up front. So I think we start with two drugs and we can add the third drug as needed. Would be the implications of that study. Southpaw was looking at a group to pulmonary venous hypertension with uh heart player preserved ejection fraction, looking at oral trip arsenal, otherwise known as a renter trim. A very difficult study to enroll. We had a couple of patients, but ultimately, the study was stopped due to limited enrollment. Uh, We had one patient who felt significantly better on it. I don't know that's anecdotal. Uh, but it really uh, was not able to get to a point where it could show benefit versus not. Certainly there's a lot of negative studies using these drugs in group two. Uh, and uh, I would caution you against in parent trials in these patients if you produce a lot of upstream bas oh, dilatation and your problem is downstream, you will congestive pulmonary circulation where some symptoms or some fluid retention and even in some cases, put patients into flash pulmonary edema, which can be life threatening. Uh, so that should not be something that's done on a routine basis without uh, referral to formally hypertension center or in roman. In a clinical trial. In my opinion, Increase looked at group three. So we know yeah. Group to pull the venous hypertension with heart failure and group three with lung disease. Or that statistically quantitatively the two largest groups of patients who have pulmonary hypertension And they far outnumber group one pP So we're continuing to explore ways of treating these patients. So recent trial that's been presented american thoracic society, not yet been published in print, looked at it inhaled too personal. Uh in patients with interstitial lung disease we had three patients in the trial. Overall there was Improvement in the six minute locked us into the 21 m, which was statistically significant. You could argue back and forth about what that means clinically. But for these patients they certainly felt that improvement because they were so limited otherwise. So it may be been held to personnel will develop a role in treating ph associated with print from a lung disease and hypoglycemia. We'll see how that plays out And then revealed. 2.0 I pointed out as being a very useful tool that's been now well validated and published and available for use in the clinical practice for following clinical response and prognosticating. Perfect. Now builds on what we saw with the increased trial but it's focusing on COPD associated for hypertension. So the same concept an inhaled drug versus placebo to see if there's improvement in six minute walk and other parameters of ph ah got put on hold with Covid 19 and there's an amendment uh to allow it to reopen. That's going through the processes of review for approval. Select as a trial that we do have open CeleXA Peg for inoperable crumbling Bilek disease, pulmonary hypertension. Building on the idea that if Real sick, what should benefit, perhaps CeleXA peg will too. There was a trial with massive tent called merit that show benefit. Uh, there's not FDA approval for that drug. However, uh, G B 00 to uh, is an inhaled platelet derived growth factor inhibitor and the tyrosine kinase pathway that we're participating in a trial. We've had one patient go through another being uh, recently consented and it's an early face trial looking primarily at safety and cholera bility with an opportunity to go into an open label extension that the reason I bring it up is we need other target pathways and this would be a Fort pathway. If we can show benefit would be very exciting. Then we continue to look at different ways of delivering the same drugs uh, inhaled your personnel requires a proprietary dispenser and nebulizer, which is uh, fairly large. I mean, you can take it with you but certainly wouldn't fit in your pocket or your whatever uh side bag you would carry around. And so powdered formulations have been studied by a company called liquid idea uh was recently purchased and also by United Therapeutics. So we've been participating in those trials and they look quite favorable. And then dr Shapiro continues to actively recruit looking at the respiratory biomom uh in patients with ph Yeah, So in summary, I wanted to call your attention to the updates from the Six World symposium on polling hypertension, particularly to change an evo dynamic diagnostic criteria, Lowering the threshold of being territorial pressure to 21 but still emphasizing that you need elevated formerly vascular resistance in order to meet this criteria. uh there wasn't a change in treatment in this 21-24 range. All the treatment Diagnostic algorithms applied to 25 or higher screening for CT pH is done with VQ scan and is recommended because there are interventions particularly for example and Directory that can be curative and a growing row for pulmonary balloon angioplasty Upfront. Therapy for Functional Class three, I believe has been well demonstrated now to be the approach for these patients if at all possible, particularly with combining P. D five and an E. R. A. And hospitalization with its impact on uh general quality of life as well as mortality. Now to me should be firmly embedded a goal of therapy to reduce hospitalization that's transparently discussed with patients and incorporated in future studies. And so for those of you joined late, I suppose you can still get your seeing me. If you text, I will stop there and if there's any questions, I'll just put up some of the references that I used. If you have any interest in joining those down or you can send me an email and I can send those to you. Thank you very much. A great lecturer, great update of many things that, you know, definitely feeling has been advancing in the past few years, so we'll open for some questions on on the audience.