Case Review Dynamic Assessment of the Fontan Part II: New Horizons in Medical...

All right. Um, I'll take up the second part of this talk of dynamic assessment of the Fontaine. And really what I'd like to focus on is more non-invasive, uh, assessment of, uh, the Fontaine circulation. So, essentially, before they get to Brian in the cath lab, and how we can best screen for this. So, I'd like to start with a, just a case. This is a real patient of mine, um, that was sent to me, uh, about 6 months ago. He's a 45 year old gentleman with transposition associated with tricuspid atresia. And he had Fontaine revision surgery done a number of years back for, uh, for, uh, uncontrolled atrial tachycardia. And he's actually been relatively stable over a number of years until recently when he had a decline in his functional capacity. And you can see his peak CO2 is certainly quite significantly diminished, although not perhaps in the worst category. And this is his MRI scan, which just shows that there's really no obstruction in his circuit, and his pulmonary arteries were also of a good size. Now, part of our screening of all our fontans is, uh, a systematic look at the end organ function and clearly, the liver is one of the important ones. Um, and this gentleman had very high liver stiffness, uh, associated with this decline in functional capacity. So, his, uh, uh, measure of stiffness, the AI or acoustic radiation force impulse, was really very elevated. Remember, in you and me, this will be probably up to about 1 m a 2nd, 10.5 to 1 m a second or so. Uh, so, a value of 3.5 is really quite stiff. So, the question is, is why and what is it about his physiology that's different? Now, of course, we could send him to the cath lab, uh, straight away, but then every single Fontaine patient that we, uh, have in the outpatient clinic will end up in the cath lab, and maybe that's the right thing to do. But what we've developed here is, uh, sort of relatively non-invasive screening in the, in the first instance. So I sent him to the exercise lab and, um, uh, and what we do is to put in, in the antecubital vein, a large bore, uh, cannula. And then we connect that to a pressure manometer and we are able to then transduce venous pressures as exercise progresses. And what we're able to measure at the time of exercise is this incremental change in venous pressure. But also we can deduce from this, um, uh, uh, mean capillary filling pressure, which gives us an idea of, uh, the stress volume of the veins, and we know that, uh, this is very abnormal for fontine, uh, for fontine population. And then also we can measure, uh, uh, an indirect measure of perfusion, which is, uh, NEs. And then also at the same time, we can measure stiffness, um, in response to exercise. And there's some very nice data from, again, from Hideki Senzaki's group, uh, verifying the utility of doing this kind of thing. So, peripheral venous pressure is highly correlated with central venous pressure, as you can see in the top left-hand graph. And also, uh, doing measurements of, uh, uh, mean capillary filling pressure is highly correlated with the values that you can obtain in the cath lab, as you can see in the right lower panel. And, uh, in this instance, the way that it is done is that you apply a, a cuff in the, uh, upper portion of the arm and you completely occlude, uh, arterial inflow and you wait for venous pressures essentially in the arm to, uh, equalize, uh, with. The arterial pressure and that corresponds very well to the mean capillary filling pressure and that is a measure of the volume status of the patient, the intravascular volume, but also the uh uh wall tension and compliance of the veins. And very often in Fontaine circulation, uh, patients, this is very abnormal, so the compliance is reduced. And this is some work, uh, uh, that we, uh, did, uh, earlier and published. And you can see there's a vast array, uh, variety of responses in venous pressure. The red, uh, graph indicates, uh, patients with a fontan circulation, and the blue is really normal, uh, control patients, or, or normal controls. And you can see that. Some patients with the Fontaine will respond very rapidly in terms of their venous pressures, and these patients tend to have diminished exercise capacity. And those who don't change their pressures very much tend to go longer during exercise, suggesting that there's something very fundamentally different about their physiology. And if we look at nears associated with this, uh, the Fontaine patients drop their renal nears very precipitously and very early, uh, during the exercise phase, as compared to normal controls. And if you look at the recovery phase, it does not return to normal, even after 56 minutes of exercise. Uh, it's still abnormal. And if we look at cerebral, uh, news, uh, you can see a similar effect. There's an early drop in cerebral nears. Uh, but this, uh, uh, in contradistinction returns back to normal pretty quickly, uh, by the 2nd minute of exercise. So coming back to our patient then, you can see that his venous pressures started off at about 17 to 18 millimeters of mercury, and this rose pretty quickly and went up to 35 and then to 40 millimeters of mercury during exercise, which is really quite astronomical. And there's data suggesting that once your venous pressures transduced to the hepatic veins, exceeds 25 millimeters of mercury for any. Uh, length of time that you do get subclinical evidence of hepatic or hepatocellular damage, uh, because of a perfusion problem. And when we measured his liver stiffness, uh, a baseline, uh, as you saw, his, uh, stiffness was 3.5 m a second. And during exercise, not surprisingly, that increases to 4 m a second. And, um, one of the advantages of this technique is that we can actually test, uh, like Brian does in the cath lab, the effect of different drugs, uh, and we can look at uddenafil, uh, uh, tadalafil, um, in, in this instance, uh, traprostinol. Uh, inhaled traprostinol, and we can see that that makes a difference in the stiffness response, uh, in the liver as it did in this particular patient. So, Brian did take him to the cath lab, uh, and his fontan pressures at rest were 17. His wedge pressures were elevated, um, with, uh, to 12 with a transpulmonary gradient of 7 or so. And with this fluid volume challenge, he really responded very dramatically, and his fontan pressures elevated to 25 and his wedge pressures to 18. So clearly his venous compliance is probably abnormal and also his diastolic function in the ventricle is very abnormal. So, I'd like to conclude and say dynamic assessment of the Fontan patient is essential. Um, even in well-functioning Fontans, I think this technique and strategy gives us really good insight to pick up occult abnormal physiology that we would not appreciate until much later when the patient becomes, uh, ill. And I think, uh, this kind of assessment allows us to to test in a relatively non-invasive way. Uh, uh, potential therapeutic targets. So, I will finish with that and, um, we can take up the discussion, uh, from this point. I have a question for you, Doctor Feldman, um, which is. There's data to suggest that exercise participation. Whether it's formal or informal, begets improved exercise capacity, such that exercise should be seen as a good thing for a population that in many cases may have been inappropriately restricted by caregivers or parents, etc. And yet you've just shown that with exercise comes central venous hypertension, which begets liver disease amongst other things. How do you counsel patients with those two competing. Uh, findings, yeah, I think this is, uh, something that, uh, uh, our patients wrestle with equally as well as, um, uh, as obviously physicians involved in the field. And I think like with any form of exercise, uh, if you take the extremes of any form of exercise, the detrimental effects of exercise may well outweigh the beneficial, uh, effects. So, what we're looking at here is really stressing patients to the extreme. And if you've seen what the exercise tests are like, which you've, I know you've seen, you know, we really take patients to their, to their peak ability. And um I suspect that, you know, if using this kind of technique, we may be able to show that patients are able to adjust exactly to, you know, good levels of exercise, prior to the sort of really peak levels of exercise and that they're able to adjust and adapt to that and we can shift that you could actually argue that we could use this as a, as a barometer for the individual patient to say, look, When you were feeling, uh, you know, doing that amount of workload, you were optimal in terms of your human dynamics, but potentially by using a submaximal protocol going to improve your exercise tolerance. It is complicated because submax has most of the rise already incorporated into it, so it's tricky, but it would be very interesting to understand, and maybe you have these data or maybe you're, you're doing this, if patients go through a formal exercise rehabilitation program, which I know we offer and are are very invested in. If their hemodynamic response to exercise actually shifts after training, yeah, we've not done that, but I suspect that is true, uh, by clinical experience. I think patients change, and also I think the, uh, be careful about that. I mean it, they change and and the benefits of exercise are protein and in, you know, you can take somebody on a transplant list and they get better if you exercise them, but they get they get better largely because of skeletal muscle function and oxygen extraction. This set of human dynamics may or may not change, who knows, but, um, you know, it may be that they feel better and they can do more, that may actually, you know, following up on Brian's point, be worse for them because now they're gonna be pushing themselves up to CBPs that that. But I think Andrew, one of the things that we've observed, at least in the, in, in histological series, uh, and I think you've done some of this with the ultrasound work, is that. It seems that the vessels themselves actually change in, in their histopathology. In other words, the vessels adjust, uh, so as to accommodate these higher pressures. And certainly, if you look at the liver, the sort of perivannular changes are quite striking. And also in the SVC and the IVC there seems to be a sort of a vascular adaptive response. That is true, but there is virtually no data in any condition suggesting that if you change vascular biology acutely, you change exercise function. And so, you know, I think you might well see some better vascular health, but I don't think that necessarily will ultimately change your fonta. I think it's a fascinating question and I think you could use this as a, as a sort of alternate, a hemodynamic stress test to tell a patient where they potentially could sit uh in terms of the the optimal exercise that they do. This actually goes right to a question from. Uh, Cynthia Cuido, who says exercise is a broad term, and I suspect the physiologic responses would vary depending on the form of exercise. For example, cardiovascular load, treadmill, bike, or, uh, ergometry versus weightlifting or isometric exercises. Do you have data on this? Uh, Cynthia, thanks for the question. Uh, very important question. We don't have data yet, but, um, uh, hopefully, in, uh, you know, over the next, uh, next couple of years, we'll be collecting some of that, uh, some of that data. What we're first starting with is seeing if we can actually assess, uh, uh, pharmaco pharmacologic changes. In responses to exercise, um, but I think one of the, uh, one of the next things will definitely be to assess different forms of exercise. OK, I know I, I just to address that, um, uh, we were interested in this question specifically to understand if supine exercise like swimming, uh, we did supine cycle ergometry because that's eminently testable. Um, if there would be a benefit from taking gravity out of the equation, and a lot of patients were interested in sort of swimming as a, as an exercise, as, as you know, um, in biventricular patients, supine exercise is limited compared to upright exercise, um, and we were interested in testing the hypothesis that maybe in Fontaine patients they wouldn't be limited or they might actually be improved and. Um, we did not find that. We found that their exercise limitation looks the same as biventricular, so there's certainly not a particular advantage to things like, uh, swimming or other flats exercises. Well, at least in terms of ultimate performance, the gravity does affect, uh, flow patterns, um. TY Shah showed when I was at Great Ormond Street, um very, very different patterns of hepatic venous flow, for example, depending on whether you're lying flat or standing up. Yeah, that was the motivation for that study, I mean we were really interested in motivation for Fontan patients staying in bed longer I think. Well, one of the, one of the things, uh, that we pick up increasingly with this kind of testing is occult, uh, problems and, and oftentimes we pick up, uh, obstructions in the Fontaine circuit that we may not have, uh, known about, uh, with, with just an echo and, uh, clinical assessment. And, uh, uh, Brian has been very instrumental in helping out with, uh, the trans catheter intervention, uh, uh, in those patients.