Good morning, everyone. Why don't we get started? My name is Tim Morris, and congratulations to me, the survivalist, for being on here on a Wednesday morning at CHEST, and I thank you very much for getting up early to come listen to us. We have a real treat for you this morning. We're going to be talking for the next hour about follow-up after pulmonary embolism, and the CHEST organization has assembled the group to my right here, who are really the world's experts on these various aspects of the work of after pulmonary embolism. So, immediately to my right is Eric Klock, who is a pioneer in the understanding of symptomatology after acute pulmonary embolism. To his right is Jenny Yang, and remember that name? She is a rising star in the field of chronic thromboembolic pulmonary embolism and follow-up after acute PE. To her right is Jeanne Chung, who is a cardiologist but has a special expertise in cardiac imaging, both in echocardiogram and MR and CT, and has a special interest in visualization and measurement of right ventricular and right atrial problems. And to her right is Dr. William Stringer, who is the one who taught me everything I know about exercise testing and understanding of formal cardiopulmonary exercise testing. So, it's really going to be a lot of fun to go through things with them. So, let me start off with the premise that this top diagram right there is pretty much what I was taught when I was a fellow, is that after an acute pulmonary embolism, you either went all the way up and had a full recovery, and the whole thing was just a bad dream, and you got over, et cetera, or you develop CTEF. And so, if you developed pulmonary hypertension so bad that if you didn't get an operation, you're going to die. And I think over the years, that diagram there is probably about 25 years old. And over the years, I think we've become more comfortable with the fact that, just like every other biological process, there's some gradations, and you go all the way from, you know, full recovery to a terrible residual disease. And in the past few years, there's been a recognition that each of these gradations actually has some specific physiological and anatomical problems that can be characterized. And it's probably a good idea, if we're going to try to do things to prevent the development of disease, diseases, or to treat them once we identify them, to give them a name and specify how you can find out whether these things are there. And that leads us to this algorithm that we're going to be talking about today, called the search algorithm. And I know this diagram is a bit complicated and funny. We're going to go through it today. But it's an algorithm whereby, in a cost effective manner, people can be evaluated and going down in a really hierarchical fashion, test by test, and find endpoints at which we can assign people into these various different categories we just talked about there. And I'm going to do this with a sort of a variation on everybody's dad's favorite joke. You know, two, you know, something walked into a bar and one of them says, and, you know, so you fill in the blank. I think I can know jokes for half of these things. I can make up the other half if you want. Now, the funny thing is, true story, when I submitted this, I got a message from Chest and said, do you want this to be an audience response, you know, thing? And I thought, like, no, I probably don't have to do that. So each of these steps, we're going to kind of follow this joke here, but we're going to have two PE patients coming in for an analysis. Now, the PE patients are actual patients, and they're patients that are derived from what's called the University of California Alliance on Pulmonary Embolism, which is a registry that was created in order to to formulate this search algorithm. So so as we go through each of these steps, I'm going to ask one of my expert consultants here to help us look through exactly what are we looking for and what what are the items that we should be paying particular attention to. So two PE patients walk into a clinic and one of them says, and so for that, we're going to go to our expert in the follow up of symptomatology after Pulmonary Embolism, Dr. Klopp. Thank you, Tim. It's a really honor to be here. And let's presume that one of them says, I didn't feel completely recovered. I have dyspnea, right? So this will not come as a surprise to you, hopefully, but one of the most important presenting symptoms of acute pulmonary embolism is dyspnea, mostly exertional dyspnea. But not all patients have it, right? 30% of patients does not report at least dyspnea and could be pain, chest pain, or syncope, or hemoptysis. And the natural course of disease, as nicely shown here in two graphs from publications from the ELOP study, a U.S. study on a group of, let's say, about 100 PE patients followed during the first year of disease. You can appreciate from the graphs, the upper graph, so it says SOPQ, it's a questionnaire for dyspnea, that dyspnea actually improves because the score goes down. This is a natural course of disease until one year later. The six minute walking test increases, as you may expect. And PAMQOL is a quality of life questionnaire, improves because the score gets lower. So this is a natural course of disease and patients usually recover even when they're only treated with anti-gravitational treatment. However, a large proportion of patients still reports to have dyspnea or limitations because of shortness of breath despite adequate anti-gravitational treatment. And this is a figure from an unpublished meat analysis of studies that studied the prevalence of dyspnea and the prevalence of abnormal VQ and CT scans in follow-up after pulmonary embolism is gonna appreciate from all those studies that approximately one in three or even more patients report some form of dyspnea. This may be mild, but also may be severe. So despite the fact that we see improvements over time, not everybody completely recovers. And that has impact for the patient. It's not just a question in your office, do you feel okay? Do you have dyspnea? It means something to a patient. And patients with dyspnea report poor quality of life, as you may imagine. And this is a Dutch study from Amsterdam, which they looked at the presence of dyspnea. And again, the PEMQOL, so the quality of life questionnaire, with all kinds of dimensions. And almost all dimensions, interestingly, work-related problems seem to be okay. But all the other dimensions, so emotional complaints, intensity of complaints, ADL limitations, they all were worse in patients reporting dyspnea. So dyspnea is important, in fact, it's important for the patient, and something you as a clinician would want to know. Because it's not just quality of life problems, behind the dyspnea there may be all kinds of rare or less rare diseases that determine the prognosis of the patient. So of course we have CTEF, very rare, deadly if not identified. Probably the most important reason why we have to ask our patients whether they recover or not. But also CTBD, as just mentioned by Tim, for me, there's no common definition in literature. For me, it's symptoms, abnormal, or still persistent clots or perfusion defects, and measurable abnormalities in the cardiopulmonary function on CPAT or echo. We have chronic RV impairment. One third of patients have abnormal RVs in the follow-up of pulmonary embolism. But the most prevalent reason for being unhappy after PE is functional impairment due to deconditioning, persistent pain, anxiety, depression, or other psychosocial issues. And it's very difficult but important to distinguish those from symptoms related to pre-existing comorbidities, such as asthma, COPD, chronic heart failure, anemia, or cancer. Sometimes it's impossible to differentiate between the two, but it's important to at least try to do so, because of course, if you have severe anemia of heart failure, everything has a different dimension. So we want to know whether there's dyspnea. And if I talk to colleagues, they say, well, I asked my patient, and it's fine. But for me, just asking the question is not sufficient, because you want to know this in a proper, reproducible way. And this is Mr. Calvin, Lord Calvin. We know him from his efforts to measure temperature. And one of his statements was, if you can't measure it, you can't improve it, you can't work on it. So you must measure it, and make sure you measure it over time in all your patients. And the importance of this was highlighted by the ITEM set for VTE. So it's a standard set of outcomes important to patients. And one of the items here in the middle is dyspnea, next to pain, functional limitations, quality of life, and others that are recommended to be measured in all patients. An ITEM set suggests to use the PROMIS dyspnea questionnaire, which is a very long list of questions that really help you to establish in which part of life, or which moment of the day, or during which activity patients experience dyspnea. This set suggests PROMIS, because they work a lot with PROMIS questionnaires, but perhaps it's not the best questionnaire, because it takes a lot of time, and you do not get a single answer. You just get a lot of answers that helps you to determine why the patient faces problems. Something much easier would be the modified MRC, which is a scale rather than a score. So the patient can only be put in one grade. There's no possibility to be in two grades. And it's very easy to assess. It takes you less than a minute with your patient in your office, or before a patient comes to your office, and it can be reproduced, and it can be measured over time easily. And there are many other dyspnea questionnaires that can be used. To be frank with this, it would be a good one, although if you really want to know a little bit more details, you would probably need something like the PROMIS score. And if you ask me, and today you do, I would not only measure dyspnea, but also the impact of dyspnea on your patients. And for this, we have the so-called post-VTE functional status scale, which is as easy as the MRC. It's a scale. Patients can only be in one single scale grade, and it measures the limitations patients experience. So if you know the limitations patients experience and the amount of dyspnea, it's easier to establish the next steps, which we'll do in the next presentation. Thank you, Eric. So Eric, I'm gonna go back just one slide here. And I just want to point out, and I'll see what your comment about this is. One of the reasons that the modified MMR, or the MMRC score is nice, is that you see they're asking people to recall a specific thing each time. They're not saying, you know, do you get really short of breath, and how far can you walk? But you know, if you're walking with your friends, do they have to stop for you? When you're walking alone, can you keep on walking uninhibited? Is that an advantage, do you think? It does, it does, but it does not give you the amount of specific circumstances as the PROMIS score. But of course, you have to make the decision on this. Completing the PROMIS questionnaire will take 10 minutes, perhaps. And this is the time we don't have. So if patients complete these PROMIS before they get to your office, it would be fantastic to have something as PROMIS. But if it's, you want to be short and efficient, this is an excellent skill. And again, because it's not a score, but a skill, which is an important difference, there's only one way to get it into way. And if there's some improvement or some worsening, you will measure it. In a score, you may improve some things, you may get worse in some other things, but the score will remain the same. That's why skills are an excellent way of looking at these things. Great, thank you, Aaron. Can I ask one quick question? Is there a qualitative aspect to dysthmia that helps you understand pulmonary vascular disease? Because I think fatigue and exercise limitation and dysthmia mean a lot of things to a lot of people. So what is it that gets your ears up when a patient starts talking about dysthmia? Honestly, anything. Anything, okay. So you are a physiologist, you are an expert on these things, and you can explain this, but for a patient in your office, it's more difficult to grasp. And the definition of the terms you have in your mind does not apply to your patients. So either you have to lecture him on the difference between breathlessness, or dyspnea, or tiredness, or you just have to try to catch up whether there's something limiting the patient in his activities and something to do with the lungs or the heart. Sounds good. And scientifically, it would be fantastic. In practice, I'd say a harsh job to differentiate. No. Sounds good. Great, so back to our two patients here. And these are, as I said, these are actually two patients from a register. And patient A there says we ask him to recall his MMRC score before the clot. And so he has to do a little bit of recall. And then we ask him the same question for, how about this week? And so in both of those, he said there was essentially a zero on that scale that you saw before. And then we asked separately, do you feel like you've fully recovered? He says yes. The patient on the right, patient B, had a zero on the MRC score before, but now in this last week, after seeing him six months after his clots, comes up with a three, which means that he's walking with people his own age, et cetera, that he has to stop. And actually, when he's walking on it by himself, and not trying to keep up, and then he still has to stop because he shortens his breath, and he says he hasn't recovered. So we then will, for the patient A, we would say, well, you've recovered from your symptoms. I think doing a workup of, you know, going on to doing expensive tests, et cetera, would be a waste of time. Patient B goes on to the next step in the search protocol, which is the exercise function. So now continuing on our little dad joke here, two symptomatic PE patients walk into the CPET lab. And for that, we're going to go with our resident expert on CPET, Dr. Stringer. Well, thank you. First of all, this is fantastic. We're talking about CPET at 7.30 in the morning. Second thing is that on that flowchart, usually CPET is down in level below us, and they've had every test known to man, and then they've been sent to the CPET lab. So it's wonderful to see this on the top of the list. The third thing is that, you know, CPET gives you an idea of different organ systems that are actually causing limitation. And so it gives you an aspect to focus on. So I'm going to try to detail that. So if there's sort of one slide you leave with, this is really it. As the emboli are not resolved, there's ongoing obliteration of the pulmonary vasculature, change in pulmonary arterial resistance, and elevated pressures, which we're going to see a little bit later. But when you're looking at CPET, you're going to find some very specific things. The dead space increases. So there's areas that are not being perfused that are being ventilated. So that's wasted alveolar dead space. So that's very important that that goes up. So on a non-invasive test, BEBCO2 and BEBCO2 slope would be the two things that you would look at. If you have transcutaneous or blood gases, calculating a B2BT around the anaerobic threshold would be a good thing. So that's looking at wasted ventilation. If you look at cardiovascular function, O2 pulse is basically an indicator of stroke volume in somebody that has a normal hemoglobin. So if that doesn't at least double during the exercise test, there's something wrong with the stroke volume. And finally, in pulmonary vascular disease, you can see right to left shunting, which has a very distinctive presentation. I'll show you that. So remember, there's anatomic dead space, which is just conducting airways. And then there's areas that are actually being ventilated but not perfused because of the embolus. So those two add together to do your VD. And then the tidal volume, VDBT, is your dead space. And then low stroke volume is seen in less frequently on CPET, but it's also important. And we're gonna talk about that anatomically in a little bit, so I'm gonna leave that alone. But a normal CPET, you would see a marked increase in oxygen uptake, CO2 output as work rate increases. This would be somebody with pulmonary arterial hypertension, very flat, very slow kinetics, meaning the rate of change of oxygen uptake and way away from their predicted values. So just on this panel alone, you're gonna be thinking, something's wrong with this. This is a shunt mechanism. This is saturation here, a marked dark and saturation here. Looks like there was a start of a shunt and then a marked increase in the shunt. And you can see the end tidal oxygen and end tidal CO2. Oxygen goes up, CO2 goes down because there's diversion of that blood into the arterial system and away from the lungs. So there's not delivery or uptake of oxygen. So that's important. But it's not exactly the same. This was actually an interesting study where they took people with pulmonary arterial hypertension and CTEP and looked for differences. And they actually found higher changes in venator equivalence at the AT, VEVCO2 slope, and also lower end tidals. All sort of markers of more severe pulmonary vascular disease than even the PAH group. So that's important. This is a really good review here that you can take a look at as well. So finally, this is a more recent article. This is 12 months CPET findings in people with persistent post-PE impairment. I actually did say that correctly. So anyway, if you look at no impairment, these people still have their heart, lung disease, whatever got them into trouble in the first place. But most of them don't have cardiovascular limitation on CPET. But this is the group that has post-PE and very marked cardiopulmonary limitation and in need of further evaluation. So last thing I'm going to talk about is this graph. Basically, this is looking at the doubling or more of your O2 pulse. And then actually a B to Bt that drops below about 0.27. So ideal group is up in here. And then if you look at people that have, so this is normal here. This is people that have high B to Bt and they need to be evaluated. These are people that have low stroke volume reserve, but their B to Bt is normal. So they need to be evaluated. And finally, these are people with both, which is a reasonable number of group two. So anyway, this group probably can go back and they're deconditioned. They need something done with them. This is actually a study that is in the two patients we just talked about. These numbers on this side are actually very normal from the CPET and these things are very abnormal from the numbers we just talked about. High valentor equivalent, high B to Bt, very low augmentation of their stroke volume, et cetera. So this would be somebody that would need to go on for further evaluation. And this is somebody that has a normal increase in O2 pulse. This is somebody that has a very, very normal B to Bt. And then this is somebody with normal ventilatory equivalents here, dropped down into the mid 20s. This is somebody with abnormal augmentation of their O2 pulse. You can see that's very, very small amount of increase there and actually the B to Bt remains elevated throughout exercise. So either of those findings, if you sort of walk out here, those two things, abnormal B to Bt, high ventilatory equivalent or low stroke volume augmentation should make you think that there's abnormalities and this is high ventilatory equivalents. So I'll stop there. Good to see this at the top rather than the bottom. And I'll turn it over to my other colleagues with some other thoughts about chronic CTEP. Eric, please. Yeah, thanks. Fantastic to show us these graphs. I agree with you that CPET should be high up in the algorithm because it really helps you to determine the cause of the dyspnea. And it depends, I think, on who's writing the guideline, whether it's a pulmonologist or cardiologist or an internist, what ends up in the first step. But do you think that CPET should be the first test in all patients, or do you see patients that may, you know, need another route through the algorithm here? Okay, you're asking the CPET guy, right? So, no, I don't think so. I mean, there's people that have marked abnormalities, and we're gonna see those in some of the imaging and other things, so you know that they haven't resolved, and whether a CPET's gonna add much to that, but I like the idea of documenting the level of functional impairment, and then looking at improvements as you go through the algorithm of treatment, and does that actually improve these things, and have we got them back to a normal physiologic function? So, I would say most times, yes, but there are people that aren't safe to do studies on, that they're still very ill, et cetera. You're not gonna get much out of the CPET. Yeah, we actually do it on everybody that can do it. Yeah, exactly. So let me actually, we're gonna have some chance for the audience to participate in this. We're trying to get through this in 45 minutes, and then we'll have some time for you to respond, but I'd like the audience to consider if those two patients, patient C and D, so patient C had a perfectly normal CPET, and would you be comfortable saying, look, if you're perfectly normal, you're perfectly normal, and go out and get some exercise, and that's it, and then maybe come back and talk with us later on, see if you have this resolved, whereas the person that has a physiological defect that's identified by the test should go on to do something more in detail. Absolutely. I think that I love the idea of doing a test that actually answers the question you have, so the question is, you have a patient post-PE dyspnea, can be anything, we do the CPET, it helps us differentiate, but some patients have, well, more or less pH on their head, right, so they have right heart failure, perhaps even the CT scan at the moment of the PE diagnosis showing signs of chronicity, RV hypertrophy. I would say that in such patients, you want to go for where the money is, and then the echo, perhaps, would be the better start, because your primary differential diagnosis, pulmonary hypertension. So this, I think, what is important, again, make your differential, and depending on your differential, get the test that will give you the answers. Well, I totally agree with that, only that it's a lot easier, I think, to reassess multiple organs later with CPET than it is to keep repeating one test and maybe ignoring the other organ function, so I think that there's a role for those people either they're not safe or there's just obvious abnormalities, and you should just go for where the gold is there, and we have an echo person that's gonna defend that, so. But if I'm out of place here, correct me if I'm wrong. Oh, please, no. Do you do CPETs at all CTEF patients, because they usually do not exactly determine the treatment? Well, so if some of you, I guess, from our standpoint, where we are in the food chain, is that we are seeing people just after pulmonary embolism, and so the answer is yes, we're seeing them six months afterwards, we almost always do a CPET. Now, on Jenny's end of the equation here, she has people that are flying in from Switzerland who have known pulmonary hypertension, and so she is trying to, they've already made that conclusion that they're gonna need to have an operation or something like that, and so they usually don't put this step in, but if you're talking about just people showing up saying, yeah, I'm short of breath, yeah, that's our next step. So now, if I went back here to this algorithm here, we'd say that now we have the people that have a physiological defect that we could demonstrate, I think now it's time to rule out that there is a problem that's related to the pulmonary embolism, because of course, people can have problems with dyspnea and physiological defects that have to do with the cardiopulmonary issues they had before they had the blood clot, so it's time now to rule it out by a perfusion scan, so two symptomatic PE patients with physiological deficiencies walk into a new med department, joke's getting a little more complicated here, and so this is actually the easy part, which I think gave it to me, so this is kind of the standard ventilation perfusion scanning that I learned when I was in medical school, so you can do a planar scan, you can see this person here started off with a 34% defect, and then after six months, went down to a 0% defect, that's full recovery, that's most of patients, about three quarters of patients will do that, some patients will go from a big defect to a small defect, and some patients didn't seem to resolve at all, so you can do this with just a planar scan, I think the piece of information I'd like to share with you is that this is no longer your father's Oldsmobile for VQ scanning, and there's been a lot that's happened since I learned this stuff in medical school, and now you can't buy a VQ scanner that doesn't look like this, and the reason it looks like this with this kind of rolling gantry is they use the same strategy that you use for CT scans, and make a three-dimensional image out of multiple different new med scans, so that's what a SPECT is, and this is a really nice study showing the same patient getting a planar scan, and then a SPECT scan, so the planar scans are up on the top, there's the RPO on the left, and then the LPO on the right there, and then you can see with the SPECT perfusion scan, you just have so much more detail, and especially if you can look at the parts of the lung that are kind of on the inside, the medial basilar segments of the lung, which are surrounded by healthy lung, and if the defect is there, it's probably gonna shine through in a planar scan, but you can really see them well on this tomography, and we did this study where we looked at folks that had endarterectomies, and so we knew it was pulled out, and then we reassembled them at the end, and looked to see what was really obstructed, and we compared in the same patients a SPECT scan, a preoperative SPECT scan and a planar scan, and it's really just a matter of pushing two different buttons, so you have the same injection, same everything, same scan, or you just, you know, a SPECT scan just takes five minutes longer, and you can see that the SPECT scan was like white columns there, much, much more accurate than the planar scan was for finding these defects here, so in our, you know, patient E and patient F here, patient E came through, had a SPECT versus CT scan, I'm gonna show you that in a second, that's another advantage of the SPECT scan is you can line it right up with a low-dose CT scan and look at what's being done at the same time, and you can see whether all the inflated lung is also perfused, and patient F, who I'm gonna show you here, had multiple mismatches there, so the nice thing there is you can do, you know, coronals and axials and sagittals, et cetera, just like you can with a regular CT scan, and look to see that there's an awful lot of inflated lung that did not have any blood flow, so this fellow here had multiple mismatches and would move on, so in our algorithm, once we've established that, there's a person who's symptomatic and has the positive exercise test and persistent perfusion defects, then that's when we start taking a look at the echocardiogram, but we renamed the echocardiogram for this algorithm with an R, not just to make it work so that, you know, the search, you know, thing comes out and there's an actual word, but to emphasize the fact that the echocardiogram is done at rest, so it has no ability to evaluate what's happening with the heart at exercise, you're looking for resting changes, so two symptomatic PE patients with physiological defects and unmatched perfusion defects walk into an echocardiogram lab, and so we're gonna go to our resident expert, Dr. Chung, to tell us about echocardiogram, what to look for. So as a cardiologist, it's a major treat to be sitting amongst the multidisciplinary panel, including internists who's defending for the use of echo earlier in the process, but in any case, am I advancing it? Great, so I think there's 10 parameters here that are selected from various European and American guidelines in pulmonary hypertension, PE, and RV dysfunction, so I think most of the audience members are familiar. So the top six are assessments of the RV pressure overload. I won't go into the details of each one, but basically it's elevated pressures in systolic, mean, and diastolic pressures, as well as D-shaped septum and the flow, impeded flow across the RVOT. So it's been, the Doppler echocardiography has been useful to measure pressures noninvasively in RA pressure, what I just talked about, in terms of PA systolic pressure, mean, and diastolic pressure, as well as the LA pressure. Now, if you were that simple and you get the findings in the echo for the pulmonary hypertension, it also sheds some light into post-capillary etiology, such as LV systolic and diastolic dysfunction, significant valvular disease on the left side, or congenital heart disease. Now, if you don't get findings on the echo for pulmonary hypertension, it doesn't quite stop you because it doesn't rule out necessarily for the pulmonary hypertension at rest, as well as, of course, exercise, since this is a resting echo, as Tim had mentioned. The problems with this, you know, chamber measurements with the echo is that, as you know, RAP measurement in the calc lab will be continuous variable, but in the echo lab, we just go through three numbers, three, eight, and 15, so you can imagine the limitations right there, especially in the intermediate and the high range. The PA systolic pressure relies on a well-developed and well-defined TR jet velocity, so if you have somebody like this, or no TR, you're not gonna get a good assessment of the PA systolic pressure, and trying to get a well-defined envelope in the mean pressure for the RV or TVTI, that's also not that easy, so there's multiple technical issues, both in acquisition, as well as measurement. The next two are assessments of the RV dysfunction, the systolic dysfunction, as you're all familiar, probably, with the TAPC and fractional area contraction, and these are corresponding images, by the way, from the 2022 Permanent Hypertension Guideline from European Societies. Next two are the dilation of the RV, or PA, and again, the corresponding pictures from the guidelines. So why are there so many variables, and why is it so difficult to just go with one or two? Well, as you all know, the RV geometry is fairly complex, and clearly, it's hard to characterize completely with one or two variables. This is an endocardial definition from the 3D echo of a patient who had a PE. Now, if you have a decent endocardial definition, this correlates very well with the cardiac MR, but as you know, patients with acute or chronic pulmonary embolism, patients, their endocardial definitions can be very hard to obtain. So what we end up doing routinely is a TAPC, which is a 1D measurement. However, it does characterize the longitudinal predominant contraction of the RV. Now, that doesn't characterize the free wall motion of what the fractional area contraction measures. So 3D, if it's acquirable, then there's no geometric assumptions, but at the moment, with the current technology, there's quite a bit of limitations with the spatial and temporal resolution. But I would say, given what's happened in the LV side as well as mitral valve side, there's been a tremendous improvement in technology over the last 10 years or so. So in five years from now, maybe we won't have all these characteristics to measure and maybe have a little more reliability on the 3D measurements. But we're not quite there yet. So there's some other, I won't go into the details or techniques, but there's some measurements you can do on the LV-UTV-TI and RV-UTV-TI to assess the stroke volume and using the heart rate, you can get the stroke volume and the cardiac output on both the LV and RV side. And there's some studies showing correlation as an independent predictor of mortality and bad outcome after acute PE. So one thing to note, technically speaking, is a good, well-defined, and non-4-chamber images are critical to assess function as well as the size. So if I show you these three images, you might say, well, this one looks like RV's dilated. Clearly the RV-LV ratio will be more than one. This looks pretty normal. This one looks like RV's tiny. So these are actually three images acquired from the same patient. I'd ask my tech to go ahead and do, give me like really foreshortened views on purpose. So the properly measured and non-foreshortened view would go through, this is a short axis, so wedge-shaped RV, you gotta go through a little bit of a tip here, and then go to the midpoint of the LV. That will lay out without foreshortening of all four chambers. But, you know, residents and fellows who are doing the overnight focus on these PE patients, or even later in the follow-up echoes, if the indication is RV and PE, they may focus much more on the RV without realizing or unintentionally foreshortening it. In any case, this is not the image that you wanna be measuring, the ratio or the fractional area contraction. So it is very important to recognize where it is that you should be measuring and imaging and interpreting the findings. So this one will be, if you foreshorten LV here, and that's, like I said, foreshortening the RV. Just a quick case of a 40-year-old. Somebody who actually had lupus and APLS and multiple PE underwent an endarterectomy and had more PEs after, unfortunately. So this one, properly done short axis and four chamber views give you the assessment of the RV function in that TAPC is normal, but then if you do the fractional area contraction, you highlight the fact that the FAC is not quite normal. The cutoff is 35-ish or so. RV size, clearly larger than it should be. An abnormal septal motion, D-shaped, and the bad eccentricity index, or increased one, as well as the dilated PA. This patient, Doppler's would show the similar findings of pulmonary hypertension that are pre-capillary. This patient did undergo, oh, got overlapped there, but anyways, it's not simultaneous, but it was about two months apart. So there's some loading condition that are different, but similar findings of the PA pressures, peak, diastolic, and mean as well. Okay, so we're back to our two patients here who come into the lab. Patient G looks like all of those parameters that we talked about, at least the numerical categorization of them, looks like it's fine. And patient H, Gina, would you mind just kind of reminding us what these highlighted numbers mean? Yeah, so, oops, sorry about that. So peak TR velocity assessment of the gradient between RV and RA during systole. So 3.8 is highly elevated. 2.8 gives you about 32 millimeter gradient. So anything above 2.8 is considered high. The LV, RV, the ratio, less than .901, so this is definitely RV enlargement, or dilation. No septal abnormal motion there, and then, as most of the ECHO lab reports go, some fields are gonna be empty. But TAPC is decreased. So clearly some findings of LV dysfunction as well as LV dilation. And then I just wanted you to show, this is just the ECHO report that those numbers came from, and I was telling Gina before, I'm so used to just reading everything after the word summary. In other words, like, I don't know, like that's how you read an ECHO, is read the English words there. But maybe you could show us about where those numbers come from up here. Yeah, so it is unfortunate, sometimes you have to go up there and find those numbers. So if you're looking for the RV, LV ratio, assuming that there's a certain location that you should be measuring these RV and LV at the basal diameters, so assuming that is how these numbers are acquired, you need to do this 5.55 divided by 4.85. But you can tell that's well over one. TAPC here, so TAPC there, 14 millimeters, that's normal. Yeah, 1.1, so a little bit dilated there. I'm sorry, reduced below the 17 or 1.7. And then, let's see, what other? Yeah, and then elevated TR velocity there, well over 2.8. So this patient has all the findings of dysfunction, dilation, and elevated PA pressure. Great, thank you. So now in this algorithm, this is actually a comment on Dr. Clark's question. We don't stop if the echocardiogram is normal. We make a decision about whether to continue based on clinical grounds. And really, that has to do with two different factors. One is that a person can still have problems with their dead space, the stuff that Dr. Stringer was talking about, without any reflection of cardiac dysfunction on an echocardiogram. And the other is that the very first part of the RV's response to persistent obstruction is compensation, not decompensation. Everything that you saw just now was pathology. But people do compensate for the RV by increasing the volume of their right ventricle during diastole. That's what you do when you run up the stairs. And at least our hypothesis is that patients who are developing this disease before they develop pathology are actually using that compensation to increase their own RV diameters and return their stroke volumes to normal. So if that happens, then it's possible, and of course, you couldn't do it again during exercise. You'd still have exercise intolerance. But we rarely will take a normal echocardiogram and say, okay, you're done. And that's actually, Dr. Klok, the reason that we put that farther down there, because we don't want to make the mistake of having a normal echocardiogram and say it's nothing. So the next thing that we do then is to make a decision about whether or not to proceed. And now we're getting more and more involved in things. And some patients along the way will say, you know, it's not that bad, you know, whatever, I don't want to go on, you know. And so we do our best to try to get them to proceed, but at this point, you know, some do, some don't. Well, let's just say that we do have people that will proceed. The next thing that we do in this algorithm is to do a CT scan. And again, this is kind of an easy one, so they allow me to do this one here. So two symptomatic PE patients with physiological defects and unmatched perfusion defects walk into a CT scanner. And so there are some findings that you can use to determine whether a clot is new or old. The major use of these things actually is so that you don't make a mistake of seeing somebody acutely and thinking they have an acute clot and they just want to try to, you know, stick something in there to suck the clot out or put a medicine in and try to dissolve it when this thing has been there for years. And these are some, you know, quite well-known signs of chronicity on CT. And we just organized them here in our group into a mnemonic that's the same mnemonic as the whole thing, which is a search. And so what we're looking for is smaller arteries with the lesions. You know, if a defect is from embolization from another area, then the clot will work its way into a pulsating artery and we'll just kind of, you know, give it a wedgie. You know, we'll kind of keep on going in there and keep the pulmonary artery bigger. Whereas the clot has, you know, shriveled up, is now replaced by fibroblasts, et cetera, it tends to make it smaller. The defects tend to be eccentric or web-shaped. You tend to have anastomosis of the bronchial arteries because the lung is putting out signals that it needs perfusion. The bronchial arteries will answer the call. A right-sided enlargement, either on the right atria or right ventricle or the pulmonary artery enlarged. You have contracted lung regions, which are really reflections of old infarcts and the body's repair of that. And then there's heterogeneous or mosaic lung perfusion. I'll show you a couple of pictures of that. A lot of these are courtesy of Dr. Roget, who lent me these slides here. So there's an eccentric defect there. These are the anastomosis of the pulmonary arteries. So I'm gonna back this arrow off so you can kind of take a look at them. I'd like to think of this as kind of a starry sky through the mediastinum, where, you know, you expect to have the big fat arteries, but if you see a lot of, you know, kind of these smaller guys in there, then be suspicious about that. So there's some chronic, and here's some more folks there. There's an eccentric defect there. There's an enlarged pulmonary artery. This is the bronchial artery anastomosis here, and then this is the heterogeneous lung perfusion or the mosaic look. So now, these are patients from the UK peer, and so that's the blue circle there is an eccentric web-shaped defect, and the green circle is through the bronchial artery anastomosis. So now, this is another example of where, if we see those findings, then, okay, good, that confirms in our mind that this is probably chronic thromboembolism of some type. If we don't see them, that's not a stopping point for us, because these things are not 100% sensitive for the presence of chronic problems here. But in this case, we had patient I, who had none of these problems. Patient J is the photo I just showed you, and had all kinds of problems there. So I'm sorry, so this is patient J there. So there's a small, here, I think I can do this thing, on the left side, the blue circle there is a small eccentric defect there. The green circle there are the bronchial artery anastomosis. The blue circle on the right is another look at that eccentric defect, which is a bit smaller. And then, down on the bottom there is one of these parenchymal scars, but that's not an artery. If you follow it back up and down, it's not an artery. That's shriveled up lung that was shriveled up in the distribution of the artery feeding it. And this is an angiogram of the same patient. Eric, do you have a question? Yeah, Tim. So what kind of CT scan do you order? What do you ask your radiologist when you have such a patient? Because I think it's very important what you write down on the choice of the actual scan parameters. Right. So we asked for the standard CTPA, and not a CT scan with contrast. So the difference between the two has mostly to do with just the timing of when you put the contrast in, and when the film is done. And so the CTPA will trigger off of the pulmonary artery lighting up. And when it gets bright enough, then the scan kind of starts, and that's what we order. Exactly. Because if you do a true acute PE scan, then the timing of the contrast is before it gets into the left vesicle. And it's more difficult to really appreciate these bronchial arteries if there's no contrast in it. You're absolutely right. At least I've learned this from my radiologist. If I want to have a CT scan with a question whether there's chronicity, I have to put this down in writing, and they will delay a little bit the scan time to make sure that also the bronchial arteries are filled with contrast. Yeah, that's an excellent point. I'm just going to repeat that. So if you do a standard CTPA, they were trying to time the scan so that the dye is all in the pulmonary arteries, because that's where all the action is, et cetera. But if what you're looking for is that one specific finding of saying that the bronchial arteries are lit up, then you'd have to wait a little bit longer because the bronchial arteries are branches off the aorta. You need the dye not to be entirely in the PA, but you need it to get out into the aorta and light that up. We considered doing a delay just like you're talking about. The issue is I think that those bronchial artery anastomosis is just kind of icing on the cake. And we usually, if we see them, great. If we don't see them, it doesn't really tell us not to do things. So we haven't gotten brave enough to change our protocol yet. Okay. So now we're at a point where our patient has gone through all the steps leading all the way up to the CT scan. And so now we're going to evaluate their hemodynamics. And so to evaluate their hemodynamics, so two symptomatic PE patients with physiological deep disease and unmatched defects walk into a cath lab, and of course they meet Dr. Yang in the cath lab. All right. So at this point, yes, we are concerned for possibly CTEF, so we just will start with a regular right heart cath. And so the hemodynamic definition of CTEF is just like any other pulmonary hypertension. So we're looking for a mean pulmonary artery pressure of over 20, wedge pressure of less than 15, and at this point a PBR of over 3. That may go down to 2 with the most recent ESC guidelines. So for this patient, so you can see patient K had normal resting hemodynamics and L had elevated mean PA pressures, normal wedge, and then an elevated PBR. So patient L then went on to get this pulmonary angiogram and had confirmed findings for CTEF. So that person we would sort of confidently say had CTEF. However, going back to this patient, they got to this point in the algorithm because they're symptomatic and they have these objective findings on testing that we were concerned about related to their prior PE. And just because they have normal resting hemodynamics doesn't necessarily mean that they don't have limitations related to these defects. So we can then, with the algorithm, what we then would do next would be a combined right heart cath and CPET. So this is how we do it at UCSD. So we do this invasive cardiopulmonary exercise test. So we bring these patients into the cath lab, we do a, we place a radial arterial line, and then we do a sort of a regular right heart cath as well. But after we get some baseline resting measures, we then get them to exercise. And so we can do that either with a recumbent bike or upright. And we've moved more recently towards doing it with an upright bicycle. It just seems more physiologic. And then we bring in a portable metabolic cart so we can measure exhaled gases throughout to determine their VO2. We also have a transcutaneous CO2 monitor so we can monitor that throughout exercise. And then we can obtain direct fit cardiac outputs with the ABG and VBG at various points during exercise. So what are the, you know, the possible causes of dyspnea? You know, we've covered a lot of this already, but the two sort of phenotypes that we see are one is increased dead space, which Dr. Stringer already covered, and then the other one is related to RV limitation. So we'll go over both quickly. So with increased dead space, so essentially there's inefficient ventilation due to these regional defects. And so we've sort of already seen this, but the red dots represent the dead space. And so normally we expect that to fall. But in an abnormal patient, you see that dead space is much more elevated. It does decline a little bit, but not to below 27%. So this is an example of a report that we generate during these invasive CPETs. And so you can see, you know, the mean PA pressure goes up a little bit, but the PVR goes down, which is a normal response to exercise. However, the VEVCO2 and the VDBT go up with exercise, which is abnormal. So this person has more of a dead space phenotype related to CTED. And then with RV limitations, so, you know, with the typically, you know, the pulmonary artery compliance when you exercise improves. You know, the vessel distends, relaxes, and to accommodate the increase in flow and increase in cardiac output. But with CTED, and there is this chronic thromboembolic material in the vessel. So the vessels are stiffer, so you have poor pulmonary compliance, poor RV reserve, and you're unable to augment your stroke volume. So this is, you know, the RV afterload is a product of the pulmonary artery compliance and the pulmonary vascular resistance. And it exists on this hyperbolic curve, where up in this sort of top left corner is normal. So they have low PVR and high pulmonary artery compliance. And then on the opposite end, or on the opposite end is CTEF, where they have very high PVR and poor pulmonary artery compliance. And in the middle, and in the sort of lower left, are the CTED patients, where they have normal PVR, but poor pulmonary artery compliance. So this is some data from UCSD looking at our CTEF and CTED populations. And so in the blue dots are our CTEF patients, and in the red are CTED. And so you can see they follow on that curve. And then, so this is looking specifically at that same population, but looking at the pulmonary artery compliance. So we expect the pulmonary artery compliance normally to improve as we exercise. But you can see here, sort of overall, between rest and exercise, the compliance worsens in this population. And what about the mean pulmonary artery pressure? So we expect that to rise with exercise. As the cardiac output increases during exercise, we expect the mean PA pressure to also rise. But the degree of rise is pretty low, so that the pulmonary vascular resistance with exercise decreases. However, in CTED, because that pulmonary artery compliance is poor and the vessels are much more stiff, the rate of rise of the mean PA pressure is much steeper. And so we've, you know, the definition of this sort of exercise pH is a slope of the mean PA to cardiac output slope of greater than three. So in these CTED patients, we see that the rate of rise of the mean PA pressure here is much steeper than normal. So this is an example of one of sort of the second phenotype, the more pulmonary hypertensive response. So you can see here the mean PA pressure goes from 19 to 61, and the pulmonary artery compliance goes down with exercise. The PBR, as a result, also increases. And then we can calculate a stroke volume augmentation, and it is, you know, we expect sort of a set number, a set increase of at least 128% usually, and it does not meet that criteria. So this patient, we would say, has more of a pulmonary hypertensive response to exercise. And then when we calculate out the slope of the mean PA to cardiac output, we see that it's about four. So for this patient, you know, despite having a normal hemodynamics at rest, they then went on to get an exercise right heart cath, and here you can see the slope is five, and so our threshold is about three, and that the PBR at exercise increases from the PBR at rest, which is an abnormal response. And then here is the, and then the report of the right heart cath, which similarly shows all the data here. So you can see the, you know, at rest, the mean PA pressure is only 12, but with exercise increases up to 26, and then that the PBR increases as well, and then when you calculate out the slope of the mean PA to cardiac output slope, it is, it's over three. Great. Well, thank you. So you can see, with the help of my expert friends here, that we were able to take people right from the get-go, and take all comers that would come to a pulmonary embolism clinic at six months, and then with this series of what we hope is a logical sequence of tests, sort them as rapidly as possible into those triangles on the right of diagnoses. And you can see that most of these things are definitive diagnoses, and the only time you have a, or, you know, and those are all underlined, is if a person were to stop at some point and decide, you know, the person themselves, or the clinician decides that for some reason they don't want to continue on in the workup. So this is a way of sorting patients into these categories that we started with, and I'll finish with a slide, and it's a little bit complicated, and I apologize about that, but it's the different various conditions are all up there in the top, and on the left side here are all the various tests that we discussed today, and this is a nice way of saying, you know, plus, minus, whatever, and if you can put those into those categories, then you could look up at the top. So I will end by saying mahalo for coming here early this morning. I'll put this back up, and we purposely wanted to finish a little bit early so that we could give you plenty of time to ask us questions. So if you have any questions, please show up to the microphone. Please identify yourself and ask your question. Thank you. Hi. I'm from London, New York. Yeah, I have a question. We used to do exercise echo to see if we have a patient exercise-induced pulmonary hypertension, and we faded away from that, but doing this metabolic exercise test with right heart cath, area line, a little bit more invasive, is there any role for stress echo before you jump to be more invasive? I think the parameters you're trying to get from the exercise stress echoes are similar to what you're getting in the resting echo. Of course, with exercise, that is PA, systolic pressure, with assumed RA pressure being either 3 or 8 or 15 or so, right? And then you could do the, you know, estimation of the PA mean pressure and diastolic. So I think if we're trying to do the compliance and resistance and, you know, change of slope that we just looked at from the CPAP, I think it's a bit of a stretch. We, you know, I think one of the main problems is trying to get the profile of the PTRJ adequately to make the accurate assessment. So those things are somewhat of a limitation. And again, we're not able to get a whole lot more than the RA pressure estimation, RB pressure. So I think, yeah, we're missing some of the parameters that I guess Tim and his colleagues are able to get. So that was very helpful and interesting. Dr. Chung, I have another echo question. He asked one of my questions. You know, some tests never change over the years, serum sodium. But echo, several other things have been suggested. So Nelson Schiller, a famous echocardiographer at UCSF, maybe 10 years ago, did a series of patients and showed that what they called the right ventricular time velocity integral was a highly reliable measure of pulmonary vascular resistance. But I haven't seen that sort of take off. And then subsequently been told by echocardiographers that if you really have any concern about what's going on and how much velocity is real and so on, use contrast. You're not stuck using saline bubbles anymore. And echocontrast is safe. It's widely available. But I didn't hear that mentioned. And I haven't seen that crop up for evaluation. And as this other doctor pointed out, it's, you know, it's usually an accessible test. It's noninvasive. So could you address those two? Have they been discredited or just not used? I think those studies work really well for people who have great emissions. I think when we're talking about the patients we're interested in with the RV dysfunction and PA pressure elevated, trying to get the RV OT VTI as a person who does this all the time and we have a special protocol for EE, it's not easily acquirable. So you've got to train the techs properly and try to get to a study where it's a reliable number. I think it's a bit of a challenge, to be honest. The second question was about the... About contrast. Oh, yeah. So... Echocontrast, not just bubbles. Yeah. Actually, bubble is just adequate to get through the RV assessment if the RV is difficult to see. So the advantage of DFINITY or other contrast that goes through the pulmonary vasculature into the LV, it is really for the LV endocardial definition. So it doesn't really add a whole lot to the RV. In fact, if you have a lot of contrast in the LV, it's going to not add a whole lot to the RV endocardial definition. So I must say it's not adding too much to get that 3D volume and it makes it a little harder actually to evaluate the RV. So I think actually sometimes if we can't get the TR jet and you think there is there, you got to align it right with the ultrasound probe to get the incineration angle right. Sometimes you do inject the bubbles. We deal then with some of the bubble artifacts. But there are ways where if there's a trace TR and you really need to get that TR jet, bubbles are just as adequate. So you don't really need the DFINITY or other contrast that goes through to the LV. Tim, could you go one slide back? So I think it's important, there was an excellent discussion and yes, we are all algorithm fetishists and we want to understand what's going on. But ultimately for the patient, this helps us to give them some idea on prognosis and also on treatment. And there are not too many flavors on treatment for these patients. So they receive antibacterial treatment often, but that's not because of this, but to prevent new clots. We have rehabilitation, we have BPA, and we have balloon angioplasty. So does this algorithm, maybe a question to you or to any of you, help us to make this decision? So do you make treatment decisions based on where these patients end up in this beautiful color scheme? Yeah, I think for our CTED patients that have some sort of defect, whether it's ventilatory inefficiency or small stroke volume or that pulmonary hypertensive response, as long as their invasive C-PIT shows that they are limited due to that, we will offer surgery or BPA depending on what is more appropriate for them. And most of them, we've looked at our results of our CTED patients who've undergone surgery and they tend to overall, you know, they're usually younger and so they tend to do better than our CTED patients. This might be a tiny bit simplistic, and please Jenny, correct me about this, but while we have sent people that had only dead space ventilation to surgery, and they've done great and it's changed their life, we typically would say if there's no problem with stroke volume and no problem with pulmonary hypertension, then we tend to veer a little bit more towards BPA and say, maybe that's a less invasive thing to treat. And of course, if they're pulmonary hypertensive, then if they can tolerate the surgery, they should. But even as I say that, I mean, it's a little bit more simplistic than the actual approach, right? Yeah, I think it's sort of, you know, dependent on where their clot burden is, you know, if it's more proximal, but they don't necessarily have all of these, you know, we might not offer BPA just since it will be less effective, but if they're not that symptomatic and we see, you know, these clots in their vessels, we might just monitor them and sort of, you know, observe and wait and see. If they do develop symptoms, I think, you know, they just out of the UK published sort of a paper on their CTED patients where they just observed them over three years and they did fine, you know, in terms of they didn't develop overt RB failure over three years. So I think it is safe to observe them if there's no functional limitations based on their disease. One more thing to that is that, you know, this really is the search algorithm, right? And the whole point is trying to get these people front and center so you can think about what they have and what's the therapies for them. So I like the idea you're going some sort of, you know, minimally invasive from symptoms to, you know, CPAT to, you know, further studies and sequencing those. So you really understand what the patients are doing. So I think it's really trying to get the knowledge that these people are out there, they're not being recognized and to pay attention to dyspnea. And that should trigger a workup. And this is a way to do a workup that should help you really understand their pathophysiology. Great. Yeah. I fully agree, of course. Maybe if you may, one final question. So if you have CTEF, of course, you need the surgeon or the interventionist. But if you do not have CTEF, what do you think of the role of rehab in those patients? But ultimately, you're not treating them to live because they won't die from CTED. You're just treating them to get improvement in their daily activities, right? And sometimes, depending on the patient, rehab can really help achieving that so that you can avoid doing all these invasive expensive treatments. What's your view on that? I think the poster child for people that rehab would have a ton of benefit for is that second one there, that you have dyspnea without a cardiopulmonary, you know, you don't have to increase that space, your stroke bonds are fine. And I think that that's exactly the type of person that rehab would help with. We have had some success with people that had dead space ventilation. But essentially, what you're teaching them is to tolerate the dead space ventilation. To say, yes, you know, when you're moving your luggage as you go on vacation, it's going to be harder for you. It's not all in your head. But I'm going to teach you how to tolerate that. And so I've had people that do it for a couple of years. And then finally, they say, I don't want to tolerate it anymore. So I want to go do the operation and fix it. So I think that rehab may have different roles in different people then. Well, let me finish here. I think we're just about out of time. Thank you very much, everybody, for showing up to the session. So really, thanks for your attention. And especially, thank you to this expert panel who's really provided you a world-class look at this disease. Have a great day. Thank you.

pulmonary embolism

chronic thromboembolic disease

search algorithm

dyspnea assessment

echocardiography

CT scanning

invasive cardiopulmonary exercise testing

treatment decisions

rehabilitation

complications