Good morning, everyone. All right, I'm going to talk about a common clinical scenario that we see. So case, a 34-year-old male presented with one year of exertional dyspnea and hypoxemia according to a smart watch. He walks about two miles on most days, limiting dyspnea with walking up hills or walking at a fast pace. No other associated respiratory symptoms. Has those comorbidities, including class 3 BMI, or class 3 obesity with a BMI of 46. Did have COVID about a year and a half prior, hospitalized for a few days. He's a nonsmoker, no known cardiac pulmonary disease. Pertinent medications include metoprolol, which he held the day of his test. So his recent evaluation had echocardiograms, showed normal LV and RV function, no evidence of pulmonary hypertension. Spirometry and diffusing capacity were normal. Chest imaging was normal. And the CPET indication was assessed cause was exertional dyspnea and possible hypoxemia. CPET protocol was a continuous ramp, cycloergometry at 20 watt per minute. And so why is this important? Well, obesity, as we all know, very common in the United States. Most recent data, class 1 obesity, about 42% of the population. Class 3 obesity, 9% of the population. And exertional dyspnea is very common in otherwise healthy obese adults. Study where at low levels of exercise, about 40% of obese subjects reported moderate dyspnea, modified Borg dyspnea index greater than 4. And the healthy lean subjects, very few of them reported dyspnea in that study. So and then obesity is obviously a risk factor for multiple other disease processes that can cause dyspnea. Okay. So which of these is true regarding CPET and obesity? Dynamic VO2 is decreased in obese patients compared with lean patients of the same height. Obese individuals are often deconditioned. Exercise efficiency expressed in change in VO2 over change in work rate is decreased in obesity. Or dynamic hyperinflation is common in obesity. Okay. All right. And the answer is often deconditioned. Well, we'll talk about that. So the correct answer is D. And we normally think of it, we'll talk about this, but dynamic hyperinflation, we mostly think of it as deleterious, increasing the work of breathing in patients with obstructive lung disease, but not necessarily the case in obesity, maybe a positive thing in obesity. And we'll explain why that's the case. So our patient's impertinent results, his resting VO2 is 389, unloaded is high, and we'll explain if that's too high. And that's his peak is 2.8 liters a minute, adjusted for his actual weight, 21.9, adjusted for an ideal weight for this subject would be 39.5. Good study, or good effort, good performance, RQ was 1.22, he achieved 100% of his peak heart rate. Exercise efficiency was normal, this is from unloaded to peak. And his cardiac, once again, cardiac response appears to be normal, he had normal heart rate response, normal O2 pulse, and his gas transfer appeared to also be normal, his VEVC O2 at AT was 30, less than 34, which we use as upper limit of normal. His oxygen saturation, we're at altitude, so this is normal for us. Minute ventilation, he had plenty of breathing reserved, 28%. His tidal volume was less than half of his, we generally want tidal volume to be half of your, or greater of your, resting body capacity, his was a little less than that. His respiratory rate was about 50, so somewhat of a little bit of a rapid shallow breathing pattern. His inspiratory capacity was a little bit high at rest, his body capacity was about 4.8 liters, normally it's about, what, two thirds of body capacity is normal inspiratory capacity, and his actually decreased a little bit. Now it depends on how you define dynamic hyperinflation, some people, multiple different definitions, some people will use a decrease of ICM 100, some index it to minute ventilation, but regardless, a 35 year old should not decrease their inspiratory capacity with exercise, that's abnormal. So here's a nine panel plot, I'll go through some of these a little bit individually, but you can see his heart rate achieved the end zone here, this is a normal O2 pulse, and a normal end tidal CO2 response, end tidal O2 response, I'll talk a little bit about his venatory response. So is his peak VO2 normal, remember his peak VO2 was 2.84 liters a minute, his VO2 to watt relationship here is normal, that's 10, well it depends on the reference equation, right? So multiple different reference equations, we use Hansen, Hansen's what's recommended for obese subjects, and so this, once again, so our measured, this is the reference equation, some of the different reference equations, you can see the difference, and ours reports divides this by his actual weight and this by his actual weight, so the predicted weight adjusted is the same. So if you, you know, these are, you know, appears normal for most of them, Jones, no, if you use, based on ideal body weight, you know, his peak VO2 is low, as we'd expect in a person with a BMI of 130. And the ones in the red use weight in their reference equation, I'll show you some of those, and most reference populations didn't have a lot of obese subjects, a lot of them had some overweight patients but didn't have a lot of obese subjects, I think the Hansen study, I think the heaviest person was about 125 kilograms, but they didn't have a lot of obese subjects. So just to show you how these different equations deal with weight, here it's Hansen does actual minus ideal, and it's a positive, so you add, it increases peak VO2, increasing weight. Jones, Jones 1 doesn't have weight in it. Jones 2 does have weight, but it's a positive factor. Just to make things more confusing, and you have, if you have Jones as your reference value, well, there's four Jones equations that are all different, and the only one has weight in it. And this is Glaser, also has weight as a positive factor, and this is the Friend Registry, actually Friend Registry takes away weight, it's a negative factor, and then the Canadians, Luth Weight adds weight too. So the question is, is most reference, well, does VO2 increase with increasing weight, and most reference equations predict that it does, because it's a positive factor, but most of them didn't have a lot of obese patients, not a lot of class 3 obese patients. And why would we expect VO2 to increase with obesity, you know, lung size doesn't increase with obesity, I'll show you that actually, it decreases with obesity, DLCO doesn't, just recent study, doesn't really increase with obesity with increasing weight, KCO does, but not really DLCO, increases, but not above the lower normal usually. Cardiac output is increased at rest in obese, but really not much difference at peak exercise compared with lean individuals. Most obese patients don't desaturate also, so we wouldn't really expect VO2 to significantly increase with obesity. Here's a study comparing healthy obese and non-obese using a bike, looking at peak VO2, and as you can see, the peak VO2 wasn't different between the non-obese and the obese, using absolute value, weight adjusted, and lean weight adjusted, obviously, there was a difference. It's a little different with treadmill, as you'd expect, you know, for a given speed and grade, obese subjects have a higher VO2, and actually in this study, peak VO2 on treadmill was a little higher in obese individuals, using absolute value, but the weight adjusted was lower. And so what about the VO2 to Watt relationship? So VO2 displaces the, our obesity displaces the VO2 to work rate upward, but the slope is really unchanged, so there's an increased VO2 for any given work rate, and that reflects the oxygen cost of moving the heavier limbs during cycle ergometer, and you can figure that out, it's, see if your patient's in the, where it should be, the oxygen cost of unloaded cycling rate to body weight, which is 5.8 milliliters O2 per minute per kilogram. For our patient, he was 130 kilograms, and he was about 780, so just about right. So what about the ventilatory response to obesity, or in patients with obesity? So our patient had plenty of breathing reserve as MVV, 40 times as FEV1, although, you know, maybe it should be measured in obese subjects rather than calculated 40 times as FEV1, but regardless, here, you know, plenty of breathing reserve, you can see his tidal volume increase then seemed to kind of decrease toward the end, but he didn't achieve 50% of his FEC, and that's a little bit abnormal, he had a little bit of a rapid shallow breathing pattern, his IC decreased, but not, oftentimes people use a threshold of 100, but once again, for a 35-year-old, you'd expect it to increase. And just to review the mechanics of obesity and pulmonary mechanics, you can see that total lung capacity and vital capacity decreased, but usually within the normal range, unless you're super obese, BMI is above 60, and then the ERV is the most affected, ERV and FRC are markedly affected. So then what does the flow volume curve look like? I think we've all seen this, where the tidal curve is shifted to the right, we have flow limitation even with tidal breathing. Just what about airways resistance? Well, airways resistance increases with obesity, and why is that? Well, it's because FRC decreases, and we know that airways resistance is highly dependent on lung volume, so here's the inverse of resistance as conductance. So conductance decreases, i.e. resistance increases with decreasing FRC, and we showed that obesity is associated with decreased FRC, but specific airway conductance is unchanged. So and then just looking at the respiratory system compliance, remember, the compliance curve is shifted to the right with the lung and chest wall are less compliant in obesity, and what are the curves compared to a normal curve, and here's tidal curve in FRC, and with exercise, the normal people use, they decrease the end-expiratory lung volume, increase their end-expiratory lung volume to maintain that steep part of the curve. Now remember, people with obesity start at a lower, much lower FRC, and they're almost abutting their, they have flow limitation with tidal breathing, so it's not necessarily a bad thing that their end-expiratory lung volume increases, and it still stays on the steep part of this curve. So this is not, you know, what happens with COPD is, you know, FRC is way here, and as they increase, they're on the flat portion of the curve, increasing their work of breathing, so that's not necessarily the case. So this increase in end-expiratory lung volume is not necessarily a bad thing in obesity. Just looking at the flow volume curve of, this is, I think, 18 obese and females and 13 normals, and you can see the increasing end-expiratory, or, yeah, end-expiratory lung volume, and, which may be not a bad thing, because we have less expiratory flow limitation. Now, other studies haven't shown, there's some variability in the amount of expiratory flow limitation that's seen with obesity, depends also on the fat, the weight, the distribution of adipose tissue, whether or not people are more apple versus pear-shaped, for example. So just showing you the breathing pattern in obesity, so we, just to speed up a little bit, it's running out of time, there's a little bit of increase, well, we know that frequency, are tidal volumes less in obesity for given minute ventilation? Respiratory rate is higher for a given minute, tidal volume or minute ventilation, and this is the amount of expiratory flow limitation. So, ventilation in obesity, is it an increase in elastic loading due to decreased compliance with the chest wall and lung, is it an increase in airways resistance, an increase in work of breathing, a relative rapid shallow breathing pattern, expiratory flow limitation is present in some, dynamic hyperinflation is present, but that's not necessarily a bad thing, that attenuates that resting increase in airways resistance by increasing end-expiratory lung volume, and it keeps tidal volume really on the steep part of the curve and decreases expiratory flow limitation, and most patients don't exhibit mechanical ventor limitation, but once again, that depends on the severity of obesity. So our patient, normal peak VO2, normal cardiac response to exercise, normal gas transfer, no hypoxemia, had some mild abnormal ventor response, and this is what I said in the report, it had exertional dyspnea, likely to class three obesity, it had COVID, but it didn't have the findings we would see with COVID, weight loss and exercise would really be helpful and has been shown to improve exertional dyspnea in obese subjects. So peak VO2 is not decreased in obesity, really no difference between healthy and obese patients, maybe a little higher in treadmill, obese individuals are usually not deconditioned, they have muscle masses similar, cardiac output increase is similar, they have a normal efficiency and dynamic hyperinflation is present in obese patients, but in respiratory mechanics are abnormal, but the dynamic hyperinflation may not be a bad thing, it might improve the abnormal respiratory mechanics. All right. Thank you for your time. All right. Our 59-year-old man has a history of atrial fibrillation, which he's had ablation for. He also has a history of dilated cardiomyopathy with numerous echoes showing EF range from 8 to 35% with medications, including Carvedilol. He has a history of recurrent ventricular tachycardia, for which he's had cardiac resynchronization therapy with a defibrillator, and he has a history of sporadic inclusion body myositis and asthma. He's had multiple hospitalizations for acute decompensated heart failure, despite medical therapy, and he's starting to get progressively anxious because he can't breathe. Here's an echocardiogram on the left, it's a parasternal long axis highlighting the left ventricle, and on the right is an apical view of the left ventricle. And basically, it's showing global hypokinesis, EF ranged about 20% on average, and he has a dilated LV, left ventricle, of unknown etiology. He's had other studies done, normal coronary angiogram, pulmonary function tests showed mild restriction, and a DLCO modestly reduced, about 60% predicted. So he undergoes a CPET, and you can generate a lot of data from a CPET, and here's a 9-plot. And when you look at the 9-plot, it can be somewhat overwhelming, there's a lot of data, and I feel like it's analogous to going to Costco or Ikea, where you're like, I just need a few things, but you have to go through the whole store, and then you end up with your things and some other things that you didn't expect to buy. So we're going to look at this 9-plot, and basically we're going to be consuming data, and there's different themes to the 9-plot. There's VO2 in the blue, antero threshold in the purple, gold is for gas exchange, and then you look at the cardiovascular parameters that happen during exercise, and in green, what did the patient do as far as ventilatory response during exercise? And so let's look at that 9-plot again, thinking of those themes, a little different. You'll see the green hash bars, it's kind of like when you watch a football game. You want to get to the end zone, so whenever you see the green end zone, you want your data to get to that, that's ideal. So looking at the blue theme, the VO2, the patient's VO2 predicted was 2.5 liters per minute, but you can see the blue triangles is VO2, he doesn't even come close to it. He gets to 0.79 liters per minute on the y-axis. Divided by that is 100 kilogram weight is 7.9 mils per kilogram per minute, which is about 25% predicted, it's supposed to be 2.5 and he's 7.9. His slope of VO2 as a consumption compared to workload is less than that normal range of 10 that Dr. Hagewold spoke of, his was less than 8.3, so normally it's like around 10.3 with a range of 8.3 to 11-ish, and he's below that. So looking at ventilatory response, this is the, he wants to get to the VO2 of 2.5, that green end zone, but this is the one exception where you don't want to reach the blue end zone, the max ventilation, minute ventilation, which is your FEV1 that the patient measured multiplied by 35 to 40. So his FEV1 times 40 was 134, and you don't want to tap out on that breathing reserve, and you can see he clearly doesn't get close to that blue end zone. On the right is the tidal volume, and as you're exercising, you want to increase that tidal volume, and at some point you can, so you increase the respiratory rate, and you'll go to the right on the x-axis, and you'll start going towards that blue end zone, but you don't want to tap out. And you can see he clearly has a lot of breathing reserve from the blue end zone to here. For cardiovascular, that red box, the heart rate on the y-axis, with exercise, it increases. You want to tap it out. You want to get to that end zone at the top. The predicted heart rate is roughly 220 minus your age, so he's 220 minus 60, roughly 160, and he didn't quite get there, but you notice his heart rate stays at 60 because he was AV-paced. So then you're like, what was his O2 pulse? Did it go up? And it gets close to the predicted of 15, and you're thinking, what is O2 pulse? It's that Fick equation, that VO2, and you break it down. The cardiac output is heart rate times stroke volume. You take the VO2 divided by the pulse, you get that O2 pulse, is equal to the stroke volume times the extraction rate of oxygen content. So if your stroke volume is low, O2 pulse is low. But you have the other factor. If you can't extract the oxygen, that venous oxygen content will be a high, so that difference, R2 minus venous will be a low difference, so that will make your O2 pulse low. And if you're anemic, your hemoglobin's low, that whole oxygen extraction will be low. You'll have low O2 pulse. The next graph, I call it my trifecta graph. You want your heart rate graph to go up to here, and you want your VCO2 compared to VO2 to go up here, and you want to reach your VO2 max of 2.5, and you can see he clearly doesn't reach it. This graph is also misleading because it also can tell you anaerobic thresholds, because it's VCO2 on this y-axis, and the gray, and then VO2, which a lot of CPETs will put it on another graph so you can see it better. So just to refresh, how do you calculate anaerobic threshold? Because that's the one thing you wanted to go to Costco for. You wanted to find out when he reached anaerobic threshold, if you did. And there's four ways. The first graph is minute ventilation on the y and VO2. And as you're exercising, your minute ventilation increases. But as you reach, the lactic builds up, you reach anaerobic threshold, your body starts buffering it with bicarb, and then you make H2O and CO2, which CO2 drives minute ventilation. So you'll start cranking up your minute ventilation, and that inflection point is anaerobic threshold. You drop it down, and you say, oh, they've reached anaerobic threshold at two liters per minute. The second way is a V-slope. The slope of VCO2 over VO2, V-slope. Look for that inflection point where VCO2 cranks up relative to VO2 consumption, drop it down, and reached about two liters per minute on that graph. The third one is a valentor equivalent for oxygen graph. And as you start exercising, you start consuming VO2 more than your minute ventilation, so that ratio starts going down. When you reach anaerobic threshold, your minute ventilation, VE, goes up relatively higher than VO2, and you start seeing the ratio going back up higher. That inflection point is anaerobic threshold. You're thinking, well, why doesn't the valentor equivalent for CO2 graph look like the same? Turns out as you're at anaerobic threshold, you do some isocapnic breathing changes. You maybe change your mouth, the way you breathe, you don't necessarily increase your amount of minute ventilation to CO2 production. So that ratio still keeps going down, and at some point, you start cranking up your minute ventilation relative to CO2 production. So that is called valentory compensation. And then you know that means that anaerobic threshold happened earlier. And the last graph is one of my favorite. It's the smiley, frowny face graph, where it looks smiley normally and frowny. And when the p-entitle O2, when you first start exercising, you have a lot of dead space, so that entitle O2 is a little bit low. But as you start exercising, and you reach anaerobic threshold, you've got great gas exchange, increased minute ventilation, great ventilation perfusion, and your p-entitle O2 goes up at that inflection point. And you drop it down and look at your anaerobic threshold there. So here comes your first question. When did the patient, our case patient, reach anaerobic threshold? I gave you four graphs there. And I'm going to turn to the next slide to start the poll. And I'll let you look at these graphs. And I'll start the poll here. Oh, where's the QR code? Oh. Did it show up? Okay. Does it show up on your questions? When did this patient reach anaerobic threshold? I picked the best graph for you guys to look at it. And you can see the O2 is 2.5 liters per minute. Do you guys have the code? The survey? It didn't show up either. All right. Let me see. Oh, okay. They didn't put it on. Usually they put it on the same slide. Sorry about that. Do you guys remember the graph? Do you need me to go back? Okay. All right. So the answer is... I see various answers. Yes. Okay. Good. The answer was 25% predicted. How did I get that? So I draw a line through the data and then I look for that inflection point. Maybe it's there. And then I drop it down. I thought maybe it's .74 divided by the predicted, which is 2.5, times 100 is 30%. And in the game of price is right, you want to guess under, not over. So I would have guessed B. But I got to be honest, when I was looking at this data, I thought, Dr. Lee, this is a little shady. I don't know if there really was an anaerobic threshold. I'm not sure. So I don't blame you if you guessed it D or the other answers. So I thought I wanted you to come away with this talk with something like you accomplished and you learned something. So I gave you another control case. So you can calculate the anaerobic threshold and I didn't give you a shady case. This is a 50-year-old guy who does Ironman triathlons. He's training for a Long Beach marathon right now. And his predicted VO2 max is also 2.5 liters per minute. So can you calculate where his anaerobic threshold is? And that will be on the next graph. But they didn't put the QR on the same, sorry. So I'll let you look at that. Oh, sorry, I'll give you the QR code there. And I might go back a slide so that you guys can see it. So 30, 60, 100 are not detected. I'm hoping more of you will answer this so I can feel better if you get it right. All right, great. Okay, actually, I'm impressed. You guys learned a lot. All right, so I gave you a couple chances to get it right. If you guessed B and C, you were right. So great job. So basically, you saw the first inflection point at 1.5, maybe you saw that. So you divided by 2.5 times 100, that's 60%. Awesome. And I didn't know this, but apparently, if you work out a lot or you're an elite athlete, you can reach anaerobic threshold twice. And so around 2.5 divided by 2.5 times 100 is 100%. So great job. So looking at this other data, just speeding up, looking at the gas exchange is looking at VE over VCO2 slope. And if that slope is under 30, you're golden. Good gas exchange. You can also look at the ventilatory equivalent for CO2, the red triangles. And look at the nadir, the low point at anaerobic threshold, and see if it's less than 34. This is a normal graph. And you can see, I just look at all these red triangles, and they're well above 34. So I know it's weird, it's high. And if you want to know why do I say these graphs relate to gas exchange, it's that modified gas equation that nobody remembers. Looking at dead space as it goes up on the denominator makes 1 minus a high number a low for the denominator, which makes VE over VCO2 higher. So as dead space goes up, the VE over VCO2 relationship is high. And here's a gas exchange. Here's how you can derive it if you're a math geek like me. Alveolar volume times P, alveolar CO2 equals VCO2 times constant. And you know alveolar ventilation is equal to minute ventilation minus dead space. Divide everything by minute ventilation and substitute for VBBT. There you go. It's in the handouts. I put some handouts out for you guys. And the last graph is that smiley frowny face. And I look at his graph and I'm thinking, it doesn't look smiley frowny. It looks like the Mona Lisa, you know, where you can't tell if she's smiling or frowning. And then maybe you don't like graphs. You like tabular data. That's fine. And when you look at tabular data, I feel like with the exercise test, you look for trends. And in general, you don't want numbers to go down during exercise. And if you look at the minute ventilation, you're seeing 17, nine, 14, 10. And if you're for fun, if you put on Excel file and you just graph it, you come up with this graph. This is called periodic breathing, where you see oscillations in breathing during exercise. And there are different definitions for exercise oscillatory ventilation. But one of them is like when you see that cyclic variation and the amplitude is on average at least five liters per minute. And you see these oscillations for at least 60% of during the exercise time. And this is just a summary of what we found in this patient. The low O2, early aneurothreshold exercise oscillation ventilation. And this is just some classic cardiovascular findings. It's not 100% true. There's some exceptions and variations. And then these are the other conditions that I won't go over. They're also in the handouts as well for you. Just generalizations. And this is a pause to reflect on the case. This is a case where CPET's used to diagnose things. But in this case, we already know his symptoms are related to acute decompensated heart failure. It's really to prognosticate his heart failure and say, is there a bridge to something else? He's on medical therapy, but what next? And you can use CPET to prognosticate CHF and see if they're eligible for heart transplant. And that's what this case is trying to highlight for you. So in the 1980s, Weber said, let's look at the CPET's and classify what their peak VO2 is into four classes. The worst class is when your VO2's less than 10 mils per kilogram per minute. You can also look at the VE or VCO2 slope on that graph and say the worst class would be having a high slope. The best class would be having that slope under 30, which is golden. And then you can look, and this is a graph showing that if your peak VO2 is, sorry, this is supposed to be less than 10, you have a lower rate of event-free survival rate when you have a VO2, peak VO2, less than 10 mils per kilogram per minute. And if your VE, VCO2 slope is also terribly high, then you have a lower event-free survival rate. They also, in the study, did echo during exercise. And they can estimate the mean PA over cardiac output on the x-axis. And those in Weber class D, that peak VO2 less than 10 mils per kilogram per minute, had a higher slope, a higher increase in mean PA relative to the CO. And same with the ventilatory class, slope of greater than 45. And they looked at that and said, look, if you had a mean PA, if you had a higher slope compared to greater or equal to 4.2, you had a lower event-free survival rate by echo. So our patient would be considered Weber class D for being less than 10 mils per kilogram per minute and a ventilatory class of one. And so the International Society of Heart Lung Transplant looks at CPET, and that magic number for peak VO2 happens to be 14. 14 or less would be eligible for heart transplant just on CPET criteria. There's more, there's other criteria, but just based on CPET. If you happen to tolerate a beta blocker, they may lower that threshold to 12. I mean, not lower, lower that peak VO2 to less than 12 or equal to it. But what if you can't do the whole exercise test? They may look at your slope and say, well, during the exercise, your slope was kind of high, greater than 35, you may qualify. And what if your BMI is high? They'd like to transplant patients with BMIs of less than 30, but pre-transplant is greater than 30, they might have a different peak VO2 threshold. And so this patient, based on numerous eligibility, underwent a heart transplant at UCLA about three weeks ago. And so this is my last slide. So I don't know how he's doing after that. But this is, I wanted to include this slide and this picture in Busan, South Korea, so that, I thought it was beautiful, from the Gwangalli Beach. So if you ever fly into Seoul, you can take the train to Busan or watch the movie on Netflix. It's a horror movie called Train to Busan. So you could do either one. And then I want to say mahalo for coming to this talk and a special shout out to the cardiologist who gave me this case. We looked through several cases pre-transplant to highlight the learning points. Thank you so much. Thank you. Okay, thank you. You're all congratulated for getting up this early to hear about CPAT. I'll try to stay with my colleagues that have had some great cases there. This is the chest, but hopefully you've already used that. I don't have any conflicts with this presentation, but we do do long haul COVID research. Anyway, so I'm going to talk a little bit about a review of long haul COVID, some of the physiologic findings, talk about a case and a little bit of discussion. So this is kind of where we've been. Well, what happened there? Oh, there we are. This is where we've been with COVID, obviously acute COVID, but the issue now really is this far right corner here. This is very hard to see the actual laser pointer. Sorry about that. Anyway, so this is an area that is just being investigated. We're also doing a study as well on patients with long COVID, but the definition is that they've had these symptoms for at least 12 weeks post COVID. And there's a variety of presentations, including the severity of illness to start with that can increase the likelihood of going on to long COVID. But there's also other conditions, multi-organ COVID, which has specific dysfunction in certain organs, and then a post ICU type syndrome, which we see. So all those are mixed together in various patients. Current studies try to focus either on just ambulatory or hospitalized patients. But in terms of the common systemic manifestations, in terms of neurologic, that's usually things like brain fog, the difficulty concentrating, executive function. The pulmonary is primarily fatigue and dyspnea. And then other areas, especially psychosomatic depression, anxiety, those things are very present. And post-exertional malaise, which we're gonna talk more about. So if you look at the sort of myriad of symptoms you can get a hold of, fatigue is actually the most common in this group. And the colors are related to the various types of inflammatory mediators that are elevated and or imaging abnormalities. So fatigue really is the top of the list. And if you look at either retrospective analyses or longitudinal cohorts, they remain very prominent, both fatigue, post-exertional malaise, and difficulty with cognition. So the etiology is not known at this point. There's a variety of possible contenders. The first is that there's ongoing viral replication, and this is the Recover Vital study using 15 or 25 days of Paxlovid, trying to get rid of some viral reservoir in the body. There's also persistent viral inflammation that can actually either be kicked up by persistent viral replication, or just an overactive immune response that doesn't downregulate. The other possibility is that there's intrinsic viruses that are kicked up, EVV, CMV, et cetera, that are normally existing in your body, and this viral inflammation is causing persistent abnormalities. There's a possibility of dysbiosis, GI tract. The actual biome is actually altered, or there actually may be a viral reservoir in the GI tract, similar as we see in things like HIV. There's also peripheral microvascular dysfunction, which is probably related both to the microvascular structure and coagulation abnormalities, especially hypercoagulable states. And then finally, there's autoantibodies that are detected both peripherally and in the CSF, and may be responsible as well for a part of this. So we don't know which one is actually the correct pathophysiologic mechanism, and we don't know if there's multiple interactions of these that are causing it. So anyway, first question here is, let's see why this is doing it. Okay, so do you have a long-haul COVID-focused Pax clinic in your institution? So go on to the answers here. So good, I think this is really important to have an area that focuses on the patients, that listens to their complaints. They're not a 10-minute visit, I can tell you that. They're very complicated, lots of symptoms, lots of difficulty with psychosocial function, et cetera. So having availability of a Pax clinic is incredibly important. Okay, so this is a patient, 47-year-old. He's a nurse practitioner, actually, and he was starting our long-haul COVID rehabilitation program. That's the clinical trials number. He'd had Pfizer twice, not without a booster. He'd had a COVID infection, but it was ambulatory, not inpatient. He was an active swimmer, but now found that he was dyspneic and unable to complete strokes without going up for air. And he also had comorbidities, hypertension, hyperlipidemia, and wasn't a smoker. So 2021, the acute COVID, he had a lot of symptoms at that point. So multiple symptoms is actually a risk factor for going on to long COVID. And he was having those, primarily fatigue and brain fog, as one of the entry criteria for this study. He was on medications for both blood pressure, his lipids, and prostatic. And his BMI was normal. He was comfortable at rest. Blood pressure was just a little bit high. Sat was okay. His cardiovascular function was normal. We do a mini mental status exam, and that was 26 out of 30, which would be a little low for a healthcare provider. But we found a lot of these patients that are in our long COVID clinic are our healthcare providers due to their degree of exposure. So his hemoglobin was normal. We checked for TSH to make sure that that isn't responsible to their long COVID symptoms. We also do a BNP and high-sensitive troponin looking for myocarditis to make sure those people shouldn't be exercising. And then inflammatory mediators, which were not elevated in this person. Chest X-ray was normal. We do overnight excimetry to exclude sleep disorder breathing. And then EKG is actually normal. This is a copy of it. So this is pulmonary function test. His spirometry was normal. His blood pressure was normal. His MBV was actually super normal. That's his flow volume loop there. This is his lung volumes, again, normal. And his gas transfer is normal. So what do you think about that? All right, good, I like that. Just making sure you guys are awake. All right, so my favorite topic. We did a CPET on this person, 20 watt per minute. Did a peak of 189 watts, 79% of predicted. We're just going to go through the actual panels here. So starting with this panel one, Gene was just talking about this oxygen uptake. CO2 output is a function of rest, unloaded cycling, peak exercise. You can see there's some flattening and a lot of CO2 production here towards the end of exercise. This is heart rate and O2 pulse. O2 pulse becomes flat and a little bit of steeper heart rate there. And this is the V-slope here. It's going over here. We got about an AT of just a little bit above a liter, 1.1. So the blood pressure peak exercise was about 185 over 90, which is not high. And then, as I mentioned, the peak oxygen uptake was about 80% of predicted. In terms of the middle panel here, his ventilatory equivalence and his VWT by transcutaneous CO2 is normal. Blood pressure was a little bit elevated. Ventilatory response was normal. And then last thing is the bottom panel here. One tidal oxygen goes way up here. CO2 is pretty stable. That's consistent with his anaerobic threshold. Here you can see his R value goes way up as that CO2 increases relative to oxygen uptake at end exercise. And then maybe actually some falling in his tidal volume towards the end of exercise. Okay, so these are just tabular data. If you're more a fan of tabular stuff, you can see his oxygen uptake at peak exercise was about 80% of predicted. He's about 26.9 mils per kilo. In terms of his AT, it was normal. His peak work rate was just right at the predicted value. Heart rate was normal. His O2 pulse was a little bit low. And then his MBV relative to peak exercise was normal. It didn't seem to be any evidence of ventilatory abnormalities. So let's go back here. This thing has kind of a delay time. Okay, so what do you think the etiology of this patient's intolerance is? So you can have cardiac, you can have ventilatory, you can have gas exchange, you can have motivation, or you can have that he's a typical long-haul COVID subject, which might be the type of person we're looking for this study. All right, so let's see what we got here. All right, so most of you folks are down here at the typical long-haul COVID. That would be the obvious choice. Some of the others, cardiac and gas exchange and motivation. Okay, so a little bit of everything. Good, that's good. Okay, well, what I didn't show you was his EKG. And it's important, I think, to look at EKGs. They do get done during exercise. And this is 1, 2, 3, AVR, AVL, V5, V6. And you can see, if you go over here, lateral, there's marked ST depressions here in this person, both inferior and lateral. So we were a little taken back by that. So this was the readout as decreased peak oxygen uptake, reduced O2 pulse, normal LAT. The O2 pulse and peak oxygen were very flat later in exercise. There seemed to be some degree of deconditioning relative to that CO2. But there were ischemic changes. So he was a nurse practitioner. He actually had a cardiologist on speed dial. And he went to see him. And he didn't spend more than about 15 minutes before he went to the cath lab. And this is his cath lab report. So he had a 90% LAD and a 90% right coronary artery. So, you know, you can imagine that that was something that was important to detect. And he didn't continue with our study. But he got three stints. And I followed up with him after my email. And he says, regardless of the outcome of your study, you helped save my life. So for me, this was the best possible outcome I could have gotten from being enrolled. So that's not quite the answer that the clinical trials people want. But I'll talk a little bit about cardiovascular disease for a second. There is actually an increased risk of cardiovascular disease with COVID, both acute COVID and long COVID. Atrial fibrillation actually is pretty common in this group. But myocarditis, pericarditis, which we look pretty hard for, both bradycardia and tachycardia, as Matt mentioned. And then postural orthostatic changes. We look for that using a NASA lean test, basically leaning against the wall for 10 minutes and a blood pressure and a heart rate, just making sure there isn't orthostatic changes before they enter the study. And then there is definitely accelerated cardiac disease. So this was a VA study, Gina, from a whole bunch of people in the VA system. And they had two different cohorts, historical to COVID and then after COVID. And what they found was that there was a marked increase, about a doubling of the risk of almost everything, atrial fibrillation, bradycardia, tachycardia, V-fib, ischemic cardiomyopathies, et cetera. And then if you look at the excess burden per thousand, the highest one was atrial fibrillation. But acute coronary disease actually was in there as well. So COVID by itself, separate from long COVID. And then whether they're hospitalized or not. So these are three groups. The green is non-hospitalized. The red is hospitalized. And then the purple here is ICU. You can see the risk goes up dramatically with hospitalization and then ICU care in terms of all the ischemic and heart failure type outcomes. So the first thing really is that CPET's an excellent screening test for long COVID. I think it's important if you're going to be exercising these people and they present with dyspnea to think about a cardiopulmonary exercise test. The exercise limitation can be cardiac. And looking at that, not only O2 pulse and the VO2 flattening, but also the 12 ADKG. And then the COVID can certainly accelerate arteriosclerosis. And then finally, enrollment clinical studies does have secondary benefits, specifically looking for risk factors that were unrecognized in this particular person, even though he was a healthcare provider. So anyway, thank you. Thank you. So, this next case, and we've chosen these cases to look at different perspectives of exercise testing and the capabilities and the findings. This is, I'm not gonna save a life here, so I'm kinda envious of what Bill shared. But nonetheless, we're gonna talk a little bit about some exercise. But I should have included this at the beginning, but I didn't wanna mess with people's presentation. So if you could just, what best describes your experience with CPET? A is what does CPET stand for? B, I supervise monthly, weekly. I'm an expert. D or E, I don't supervise, but I wanna become better. All right, so we have a 57-year-old male with documented amyloidosis with documented vocal cord infiltration, central airway involvement, so that's a given. Has had hoarse voice for five years with increasing shortness of breath on exertion, and activity limitation, now walking about three blocks before he has to stop, and that's been for about the best year. And they're considering surgery, major reconstruction upper airway, because the feeling that the upper airway obstruction, the amyloid, is contributing to his symptoms. On exam, he does have stridor with forced inspiration, has a background of hypertension, has seen the cardiologist, investigated the cardiologist, says nothing wrong with the heart. And how often do we hear that? So amyloid with worsening activity limitation, central airway cause, so pretty good reason to do an exercise test. These are the pulmonary function studies. I'll show you the full volume curve next. And these are kind of, oops. Apologies. These are 85 and 84%, 69% normal TLC, RV, diffusing capacity. So we did do a cycle, ramp 25 watts per minute while breathing room air. This is the full volume curve. This is reproducible with flattening here at about six liters per minute on the expiratory, and consistent, again, flattening here at about four liters per minute. So we do have evidence of central air obstruction, little bit of variability between expiratory and inspiratory. So I'm gonna show you some numbers first. This is the resting data, the end exercise data, and then the percent predicted. Work max was 170 watts, which is 70% of predicted, so the maximal work capacity is reduced. Peak VO2 is 62% of predicted, 1.86 liters. The anaerobic threshold was low, 40% would have been 1.23. Breathing at the end of exercise was 68 liters, which was 61% of predicted with a breathing reserve of 43 liters. So lots of breathing reserve here. Did not desaturate. Came close to maximal heart rate, 91% of predicted. The O2 pulse was 66% of predicted. Reported discontinuing exercise because of seven and seven for shortness of breath and leg fatigue. Nothing on the ECG. I have to stop, I can't do anymore. That's the reason that he attributed for stopping. So I'm gonna show some relationships. These are one minute, 30 second averages. So just cleaned up a little bit to make it easier to see. This is, if I can get this, this is VO2, predicted maximal VO2. Work rate, predicted maximal work rate, line here from resting VO2 to where they join. And so it's going up and up. When I look at this, I'm wondering whether this slope is falling down a little bit, which sometimes you can see in people with inotropic, you know, reduced ejection fraction heart failure, or even preserved, but for other reasons. So I'm kind of wondering about that. Here's the VCO2, VO2 predicted maximal line of one. You can sort of see the slope probably changing around there, which was consistent with reduced anaerobic threshold. This is, I'm gonna put this in my left hand. This is the heart rate in blue. Maximal heart rate, so came close. The O2 pulse is climbing, but again, you might say to yourself, geez, I wonder if that's starting to flatten absolute about 11 or 12 here. Ventatory equivalence, and idea here is around 30, so they're not elevated. Ventilation, here we used at this time 35. This is the slope of 35, and again, it's good, lots of reserve. Breathing pattern, nearly tripled the vital, the VT, the tidal volume. Respiratory frequency at the end of exercise was less than 30, so that's how the breathing pattern the patient chose to achieve that ventilation. No abnormalities there. Estimated dead space ventilation's falling, it's not high, and tidal CO2, as you would see, and no evidence of desaturation. So unlike, I like Gina's comparison about the Costco, this is kind of the corner store data. So we've selected some data that I think are important, enough to allow us to kind of have some impression. And then here's where some of the money is. This is the flow volume curves. Again, this is the resting flow volume curve. Inspiration, expiration, at rest, middle of exercise, end of exercise. Little bit abutting here, but did not come close to expiratory or inspiratory, and no stridor during exercise. So the question for you, why did this patient with amyloid involving essential areas most likely discontinue exercise? A, abnormal ventricular mechanics, B, chronotropic insufficiency, C, inotropic, D, deconditioning, or E, pulmonary hypertension. So, I think the correct answer was D, deconditioning. However, if you don't believe the cardiologist, and also, we'll talk a little bit about this. There were clues in this test that might suggest there might be some heart disease, and we'll talk a little bit. So I've actually identified both C and D as correct. And we'll talk a little bit about why A, abnormalities, but likely not limiting. So this patient, a physiologically maximal study, heart rate 91, or more than 90% of predicted. There was exercise limitation, reduced work and aerobic capacity. But the respiratory system, while there were abnormalities, there was evidence of mechanical reserve, normal gas exchange, normal breathing pattern, good tidal volume response, no stridor that you would see, and did not come close to the boundaries of the flow volume curve. And so we concluded that surgery was unlikely to enhance activity limitation. Those symptoms consistent with deconditioning, plus or minus cardiac, as did you on that answer. So again, just going to, and what typically happens when for surgery, anyway. So this was the flow volume curve before, and this is the flow volume curve afterwards. So in fact, there was an improvement, near normal, of the expiratory curve, but no change, rest, during, and at the end of exercise, but no change in peak VO2, maximal workload, ventilation, or symptoms. So you had a solution which really didn't fix the problem. But quite aside from that, and just to give you some background, this is a young woman who had a traumatic intubation, with, you know, at about two liters per minute for both expiratory and inspiratory, marked symptoms limitation, breathing at rest, and then at the during of exercise, you can see that it's abutting here, and abutting here, and that's when you develop stridor, and then the only way to increase ventilation is to increase an expired lung volume, decrease, because you can't increase expiratory and inspiratory flow. That's hard, it's no fun, and it leads to activity limitations. So that is, that's a very characteristic case of what you might see in this setting. And just to give you an idea here about what happens with the respiratory responses during exercise, this is minute ventilation with normal breathing capacity, someone who has lung disease, and VO2, predicted VO2, normal anaerobic threshold, you stop, hopefully with the normal VO2 with reserve. If you're trained, your cardiovascular system responds, your anaerobic threshold gets pushed to the right, and so you go farther, but you may encroach upon that reserve, and in fact, in very fit, you might desaturate and come very close to your limit. In someone with lung disease, the slope is up and to the left, and you're limited by the capacity. But what our person was, was right here. So they were stopping for reasons other than the respiratory system, and in fact, what we want to do is to get them back here, and that's where reconditioning and things like that. We can also try and increase this line with medications, but that's not the instance in this patient. So it's possible in this patient with reconditioning, pulmonary rehab or whatever, and then the surgery, you might actually be able to get gains, but the place to start would be pulmonary rehab. And just to talk a little bit about our person, this is where I was talking about the cardiac. This is the heart and the O2 pulse, and we were talking about how it's flattening. This is a 43-year-old male with an ejection fracture at 31%, and you can see this is kind of a more characteristic, and then once O2 pulse flattens, heart rate goes up. So this was, you know, you're kind of wondering when you see it, is that the beginning of this? So I think it's appropriate as a clinician to think about that. So I'll stop right there, and maybe I'll ask our panel members to come up to the stage, and we'll be able to take some questions. Thank you.

cardiopulmonary exercise testing

CPET

obesity

exertional dyspnea

pulmonary mechanics

long-haul COVID

fatigue

coronary artery disease

amyloidosis