How Does the Blood Go Round in Single Ventricles and Fontans? New Horizons in...

And the first one, probably doesn't need any introduction, uh, is, uh, Doctor Andrew Reddington. Um, and Andrew is my boss, uh, and he's the co-director of, um, of the Heart Institute here at Cincinnati Children's. Um, so, Andrew, uh, is going to talk about how the blood goes around. I did give him a whole range of topics to speak about, but he wanted to take this particular one. I look forward to hearing what you've got to say, Andrew. Thank you very much, Grucian. Um, Doctor Tweddle here, my co-director at the Heart Institute, uh, very kindly pointed out that, uh, of the 15 or 20 slides that I have, none of the data I'm going to show you is any more recent than about 15 years ago. So this is a bit of a, uh, a walk down memory lane for me. In fact, um, this title. Uh, pertains to my first contact with a Fontan patient for the want of a better word, and my boss, when I was a fellow, um, and I'd been doing echocardiography for about 3 months at that point, sent a patient over who'd just had a Kawashima operation at the Brompton Hospital in London, a Kawashima operation being the natural total cave of pulmonary anastomosis where in patients with left isomerism you do a bidirectional glen and that carries the Asagous vein. Uh, and the SVC blood into the uh pulmonary arteries directly, and his, uh, echo request was how does the blood go round? And so that sort of summarizes where we were 30 years ago. I'm, I'm almost embarrassed to say it was that long ago. Uh, and we ultimately brought 2 or 3 of those patients back. In fact it was 3 patients back, and we did a formal study to understand how the blood went round because at that time our understanding of Fontan physiology was really quite rudimentary. Uh, what we did was we placed a phonocardiogram, that was in the days when we had phonocardiograms, an electrocardiogram, and that was in the days when we used to put an EKG on patients when we did an echocardiogram, and a respirometer onto the patient and basically showed that there was very little effect of the cardiac cycle on blood flow into the fontan circuit. And in fact, as you can see, blood flow into the fontan circuit mirrored and mapped uh respiratory effort. er and you can see that as a patient takes a breath in, in this very streamlined circulation, uh, essentially all of the blood flow is occurring with the work of breathing, and so I wrote back actually on the first report that I sent Elliott Scheinborne, breathing makes the blood go round, and we tried to. Entitled this paper that was published in Heart in 1990, Breathing Makes the Blood Go Round, and we were told that that was flippant and not correct, and it probably isn't correct because in fact around about 40 to 50% of the cardiac output at baseline in your Fontan patients and my Fontan patients is driven directly by the work of breathing. Worth bearing in mind when you think about what we do to patients and what they do to themselves sometimes in terms of respiratory effort and the like. Now we also were able to show that um essentially mean airway pressure makes the blood go round, a negative pressure during normal ventilation draws blood into the fontan circuit. This is what happens when you do a valsalva maneuver. This was a controlled valsalva taking up the mean airway pressure to 20 centimeters of water. And you can see essentially it cuts off all of that spontaneous respiratory flow, and you get this tiny little *** of blood flow occurring now with ventricular systole. This is like the X descent, this is suction pulling blood around the pulmonary vessels. But you can see very little blood flow indeed and and of course the fontan circulation is one of the few situations where constipation can be fatal. Now to do that, um, uh, you have to have a low pulmonary vascular resistance. If you had a high pulmonary vascular resistance, the work of breathing, which is essentially driving a 2 or 3 centimeter of water, um, pressure transient, uh, could not, uh, impose, uh, energy to the circulation. And we all know that the prerequisite for a good outcome for the fontan circulation is a low pulmonary vascular resistance preoperatively. And this study that we did a few years later is going to be picked up I'm sure as we go through the morning. This is looking at the pulmonary vascular resistance postoperatively in patients after the fontan. It was one of the first studies that did that, and most particularly looking at what happened to the pulmonary vascular resistance in patients when we gave them nitric oxide. Now in you and I, if I give you nitric oxide, the pulmonary vascular resistance doesn't fall because we're maximally vasodilated in the pulmonary vascular bed. The fact that there was a significant fall with nitric oxide, statistically significant and, and, and probably physiologically significant, about a 1 index wood unit fall in pulmonary vascular resistance, shows us that for at least some of the patients, and in fact this was only seen in about half of the patients. There wasn't maximal vasodilation, and they were potentially going to benefit from nitric oxide therapy or nitric oxide donors or managers, things like sildenafil. We made that point, whatever that was 1314 years ago. And of course we're going to be talking about other therapeutic options in terms of sildenafil and neenafil today, but I would make the point that only half of the patients, and they were all teenagers. Showed a benefit from nitric oxide and that might inform some of the questions that we're going to ask about the use of these pulmonary vasodilators in this circulation. If only half of them have a benefit from nitric oxide, it's unlikely that they're going to further benefit from, for example, PDF inhibitors. Uh, now I asked at the beginning, I don't know whether we've got any polling results, um, whether, uh, you thought out there, er, the right ventricle was a risk factor for outcome after the Fontan operation. And do we know what what the polls not 100% of the people said false. 100% said force, and they're all right, um, so it's rather interesting if ever the right ventricle, which is traditionally thought to be the somewhat weaker ventricle, was gonna expose itself as a weaker ventricle, it would be in the fontan circulation. And there's lots of data to prove that we're all right when we say that the right ventricle isn't a risk factor after the fontan. This is CHOP data which asks the question as to whether hyperplastic left heart syndrome is a risk factor after the Fontan procedure. Many people have said that this is going to cause a tsunami of late Fontan problems. I would suggest only on the basis of a numerical tsunami there was no difference in outcomes, at least in the 1st 10 years, depending on whether you had hyperplastic left heart syndrome or a systemic left ventricle. This is even more controversial. This is Boston data. This shows that if you're born with a systemic left ventricle with normally related great vessels or a single right ventricle, you do better than all other diagnoses, suggesting that a single right ventricle clearly is not a risk factor. And this is data most recently from the Melbourne group. They point out that right ventricular dominance is a risk factor if you're born with it. You can see that if you have a systemic right ventricle, you do badly, but in general terms, better now than you did in the preceding decade. But all of this risk, as you can see, is upfront. As soon as you get past the first couple of years of age, once you've got past your fronton, uh, these curves are essentially identical. Uh, so after the fontan, if you can get through a fontan with a systemic right ventricle, you're likely to do as well, at least in the first, uh, decade or so, as any other patient. And that's because the right ventricle, and in fact the systemic ventricle in the fontan circulation in general, is not a weak ventricle, it's hypercontractile and it's hypercontractile to match its increased afterload. This is some work that Michael Chung did when he was in Toronto with us. Looking at force frequency relationships, comparing the force frequency relationships generated with a change in heart rate, this was induced using esophageal pacing, and you can see compared with normal, both the systemic rights and the systemic left ventricles in the univeventricular circulation outperformed the normal ventricle. These are hypercontractile. And when we measured that directly, this is work done by Sachin Cambatone looking at n systolic elastance. Look at n systolic elastance in the fontan patients, orders of magnitude higher than normals and even greater than in the systemic right ventricle of a mustard patient, for example. We'll come into some of the other stuff as we go through the talk, but these are strong ventricles that are pumping against, albeit a high resistance. You can see arterial elastance is high, uh, but relatively well coupled. The problem seems to be in diastole, and this is work that Dan Penny did uh looking at the early transition after a fontan procedure. These were in patients that in those days, this is how old I am, did not go through a primary bidirectional glen prior to their fontan. So this. Was transitioned from shunted circulation to fontan really exposing the physiology, but this physiology exists no matter how you do it and whether it's staged or not. And I'm going to cut to the chase here. You can see in this trans mitral flow pattern in this single patient that underwent a fontan procedure, that it's not late diastole. There's the P wave on the electrocardiogram, there's the A wave flow that you see through the mitral valve. It's not late diastole that's affected. In the early post-operative course, it's early diastole that is completely undermined the E wave flow here going from a relatively normal EA ratio to a very abnormal EA ratio with virtual abolishment of early rapid filling. And we were able to show that going along with that, other things like the time constant of relaxation and isoboluminic relaxation time were all prolonged er indicative of er impaired relaxation of the ventricle. We subsequently were able to show that that was due to incoordinate wall motion. We showed using in those days, uh, plots of angiograms, and that incoordinate wall motion during isovolumic relaxation, if you have one part of the ventricular wall moving in, this is basically post systolic shortening of one part of the ventricle. Blood's incompressible, so another part of the ventricle has to move out, and you get this squirming during early relaxation. You can see that on this color M mode, this is blood flow within the ventricle, uh, moving from base to apex. This is blood flow flow through the mitral valve, and you can see this rather perverse triphasic pattern of inflow velocity, the E and the A wave here being the transmitral flow, this being the isovolumic relaxation flow as a consequence of this squirming nature of the ventricle. Now that's not unique to the left ventricle, it's not unique to the uh direct fontan patients. This is work that Mark Fogel did with the chop uh population, systemic right ventricles as well as left ventricles. He was able to show using MRI tagging of wall motion. That there were some segments of the ventricular wall that were 180 degrees out of phase to other uh parts of the ventricle. They were in systole when the rest of the ventricle was in diastole. And of course that screws up early relaxation. Now that er I would suggest doesn't have a lot of implications, although there are studies, and I'm gonna go through this fairly quickly, showing that the longer your eyes overlimit relaxation time, the longer your towel, the longer you stay in hospital immediately after the operation, that adaptive phase is slower, the worse your er early relaxation. But fundamentally, er we can overcome that as long as we stay in sinus rhythm, er and our patients do. Now the astute of you will have noticed that I just said that the E wave velocity is reduced in patients early after the fontan and the A wave velocity has a compensatory increase. And then I showed you this where the E is bigger than the A. and this is of course not from a patient that is early postoperative, this is from a patient who is late postoperative and a patient in fact who's got protein losing enteropathy, and now he has pseudonormalized but still has incoordinate relaxation. Pseudo means that your left atrial pressure is essentially going up. So if your left atrial pressure goes up and your compliance is going down and you still have problems filling in early, uh, relaxation, that is a very potent, uh, adverse effect. And this is likely to be an adverse effect that all of our patients after the Fontane face because uh in all of us, our uh left ventricular end diastolic pressure is rising by about 2 millimeters of mercury per decade, uh, every decade after the age of 30. So Doctor Tweddle's left ventricular end diastolic pressure is probably about 20 as we speak. But if that occurs in the normal left ventricle, imagine what that's going to do to our Fontan patients in terms of gradual and progressive deterioration of cardiac output, and we can see that in our patients and just in the last couple of slides just to set the scene for thinking about fontan failure. And uh ventricular performance. This is an 8 year follow up study looking at Dan Penny's original cohort, but Ringo Chung in this case, uh, looking at their changing ventricular performance over that 8 years of follow up. Patients maintained their eyes over a limit relaxation flow so they stayed in coordinate, but now they were developing a shortened IVRT suggesting that their left atrial pressure is rising. Faster E wave deceleration suggesting that their compliance is falling, and I'm not going to go through this in any great detail, but again, Sachin Kambad Koni showing directly using pressure volume analysis and conductance catheters was able to show surprisingly compared with for example the mustard procedure. Where diastolic compliance does not seem to be a problem in the systemic right ventricle, that the diastolic compliance of the fontan ventricle, and this was predominantly left ventricles in this study, uh was highly abnormal, uh setting the scene for a patient having a very low cardiac output, cos if you can't fill in early diastole and you can't fill in late diastole, you're not gonna fill at all and you have a low stroke volume and a low cardiac output. And it's just worth remembering as we go into the next few talks that of course the patient may not show that in the traditional way. Their diastolic stiffness is very high, but their end diastolic pressure may be rather low, because what they do is, because their preload reduces, they don't have a right ventricle to preload their left ventricle, their preload reduces and they drop down their pressure volume curve, their ventricle gets smaller. Uh, and their pressure falls, so in the presence of really profoundly abnormal ventricular compliance, these patients can have a normal left ventricular and diastolic pressure. So how does the blood go around? Well, it goes around because the ventricle pumps it around, it goes around because the lungs suck it around, uh, but it doesn't go around predominantly either because of plumbing issues or I believe abnormalities of diastolic function. Thanks very much. Thanks. Um, uh, we'll have I've seen a few questions maybe from the panel and, uh, encourage, uh, the audience as well, please, uh, to submit your questions. So, um, for the audience, um, if, if you wanna be able to participate in the chat or the polls, uh, you have to leave full screen. It's beautiful to watch it in full screen mode, but to get access to the polls and everything, just minimize it and interact and you can go back to full screen. Andrea, I want to uh just uh take up, uh, just on one issue and your slide with the Valsalva maneuver is absolutely stunning, isn't it? And only yesterday, I saw a, a Fontaine patient who showed me a video clip, and I became Braddy Carig and dizzy seeing what he was doing. He, he was showing me, um, lifting 400 pounds of weight, um, and holding it on. And I have to admit, it was only literally for about 1015 seconds that he held the weight. What's your advice to patients who want to do that kind of thing with the Fontaine circulation? Uh, well, I, I, I suggest to them that, and you're gonna show some other data that, that in normal activities, this, this mechanism may be at play. Uh, but I suggest to them that things like that, I, I always say bench pressing 500 pounds may not be so good for you, uh, because it really essentially cuts off your pulmonary blood flow. Now the, the interesting thing is that it seems to be somewhat addictive to patients and, um. Uh, you know, there is, I think there is an endorphin rush from feeling dizzy and not having much blood going around because quite a lot of our patients seem to enjoy that sort of, uh, behavior. But nonetheless, um, I think you can say from first principles that ultimately that is not going to be ideal for them, if it was prolonged over the course of years or decades, um. Uh, uh, of course, uh, it may have been even more, uh, disadvantageous in the old days of the atrial pulmonary fontans that we still see in your adult population, uh, because the, the, uh, because of the direct effects on atrial stretch and the potential for chronic atrial arrhythmias and, uh, as a result of right heart dilatation. Uh, maybe slightly less important in patients with a total cave of pulmonary anastomosis. But as I say, if you're doing it every day, uh, one can only imagine what it's doing to your liver under those circumstances, agreed. Any other comments from the panel? Yeah, I, I have a question. So, Um, you showed some, uh, relatively, uh, uh, modern series of, uh, thank you very much. You're welcome, um, patients, uh, undergoing Fontan comparing right and left ventricular morphology. I'm a little disappointed you didn't, uh, show our paper, which also showed that in the short term, well, it was more recent, so perhaps that's why you missed it, um, but, uh. At least in, in a decade of follow up, it appears that right and left ventricular morphology are not a factor. But if you look at some of the Fontan series that have a little longer follow, the Mayo Clinic in particular, their right ventricular morphology does appear to be a risk factor late. So when, when does it start to be important? So I think it's, that's a very interesting point, and it sort of reinforces. The, the, the message I'm trying to give that this uh change in diastolic compliance might be a, a driver of poor outcomes, and I'm just gonna show you one slide, thanks for teeing this up, Doctor Toy, it's unlike you to be helpful. But this, this, this is uh PHN data looking at uh some of the things I've mentioned, mass volume ratio, systolic function and the like, early diastolic velocities after the fontan in 500 patients. Uh, and I'm gonna point you to the difference between the left ventricles at the top here and the right ventricles here, and they're pretty much identical in terms of this abnormal mass volume ratio, T index, reduced early rapid filling. But look at the tail here in terms of E to E ratio, which is essentially telling you about left ventricular stiffness. Um, they are stiffer than the normal population when you have a systemic left ventricle, as we've pointed out, but look at the right ventricles. Far more of the patients have an increased E to E ratio. So it might be that this late diastolic failure, this was about 10 to 12 years after their fontan on average, is going to bite the right ventricles late on. So I think there is a signal there that would support what you're saying and what we're potentially seeing. Um, and a signal that, uh, potentially is a therapeutic target, which I'm sure we'll get into during the morning. Um, Andrew, I have a couple of questions from the audience. Uh, and actually, while I'm reading those to you, can we also get, uh, pull up the next talk, so you have that ready. That's gonna be, uh, Brian and Grushin's talk. Um, they both seem related. The first one, is from Kate, who really, first of all, says she loved the talk and wants to have a better understanding of the pathophysiology of the diasto Is that Kate, my daughter? I didn't know you were watching. Uh, she wants to have a better understanding of the diastolic, uh, pathophysiology in these patients, and, um. Sanjita Sharma says, what are the factors that created the diastolic dysfunction in the fontan ventricle? So the same sort of question asked two different ways. So, um, I think if we look at what, what drives end diastolic pressure rise in normals, it gives us quite a good clue in terms of what might be driving some of these changes in the fontan. So we know that that rise in N diastolic pressure that affects us all is more rapid if we have hypertension. Uh, it's more rapid if we're diabetic, it's more rapid if we have other risk factors. Uh, but, uh, it's also much more rapid if we have any ventricular volume load like AV valve regurgitation, aortic regurgitation, for example. What do the Fontan patients have? They frequently have some degree of volume load, and they've had volume load for the first few years of their life, uh, for sure. So that in and of itself could drive some of this stuff. They all have a very raised er arterial impediment, systemic vascular resistance, and Brian has done some beautiful work showing that uh arterial function actually has a a significant role in terms of overall er performance of the fontan circulation. And there's a beautiful paper just recently written in the last year or so that shows that if you relate arterial elastance to ventricular and diastolic pressure, there's really quite a tight relationship between the two. That's conductance catheter work done in Europe, in the Netherlands, so. Uh, I think, uh, in the long run, although I don't think there is a role, and one of the polling questions was should we be treating patients with ACE inhibition, I don't think there's a role that can be suggested on the basis of evidence, uh, of, uh, arterial, uh, vasodilators as being beneficial, at least in the in the short term. Management of left ventricular end diastolic pressure and the things that drive that, essentially fibrosis, and potentially management of vascular biology, not just. Systemic vasodilation because that just drops your cardiac output, have real potential as therapeutic targets in the long haul. The real problem is that um, to understand the potential impact of those therapies, you're gonna have to wait 10 or 20 years, it's gonna be, it's gonna be for the likes of our fellows over here to, to take that sort of study on. So, uh, before you started your talk. I told you that 100% of the people said that mortality after the Fontan procedure when we hire in patients with systemic right ventricle was said false, but since you gave your talk, now 30% say true. So maybe we should do the talk again. I give up. I give up. I'm going. Thank you very much. But it's an it's an important distinction is the difference between 10 or 15 year outcomes and 20 and 30 year outcomes and that's where I think a lot of the abnormalities in diastolic relaxation will start to be clinically manifest is is later on and and we don't have the 30 year RVLV data to know the answer, but I, I, I don't know that they're wrong.