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

OK. Right. It gives me great pleasure now in, uh, introducing, uh, Brian Goldstein, and Brian is our associate director of the, of the cath lab. And Brian's had a very long standing interest in the fontan circulation and particularly Brian has done a lot of work on vascular function and that how that relates to the ventricle. Uh, Brian, I, I've learned a lot from you over the, over the years, and I look forward to hearing some more about dynamic assessment of the content circulation. Well thank you Doctor Veltman uh for the introduction and the opportunity to uh speak with you and all of our virtual audience uh today throughout the, uh, the states and the world, um. I'm happy to have learned that my left ventricular and diastolic pressure is not 20, uh, facing my 40th birthday in a couple of weeks. Uh, maybe that hasn't even risen yet, but we're going to talk a little bit today about, uh, dynamic assessment of the Fontian circulation. So before we get into dynamic assessment, I'd like to begin by talking about the circulation. Dr. Reddington just gave a beautiful series of slides on the physiology at play, and I'd like to take a step back and look at the macro circulation in Fontan patients compared with typical biventricular physiology patients. In any circulation, blood flow per unit time is dependent upon the drop in pressure across the vascular bed. And the vascular resistance, of course, Ohm's law. Therefore, pulmonary blood flow is dependent on both the change in pressure and the vascular resistance. In a typical biventricular circulation, the right ventricle does the work to generate the pressure gradient across the pulmonary vascular bed. And a pulsatile circulation, the resistance is typically dynamic, speaking of endothelial responsiveness, and resistance is typically maximally vasodilated with exertion, times at which uh stress occurs. Therefore, biventricular circulation is characterized by low right ventricular pressure, low pulmonary arterial pressure, and low pulmonary vascular resistance. There are two pumps in series in the circulation, and you can see those pumps generating both aortic pressure here with the left ventricular left ventricular work, as well as right ventricular work generating pulmonary arterial pressure. During exercise, cardiac output can increase to something like 5 times baseline cardiac output, and the right ventricle does much of this work by generating increased pressure. The pulmonary vascular resistance also falls characteristically during exercise, allowing for substantial augmentation of pulmonary blood flow. In the Fontan circuit, however, the change in pressure is the difference between central venous pressure and the ventricular and diastolic pressure in the absence of a subpulmonary ventricle. Further, the pulmonary vascular resistance is typically both fixed and elevated, as we just saw nice examples of. The pressure gradient is reduced compared to a biventricular circulation. The resistance across the pulmonary vascular bed is increased, resulting in decreased net pulmonary blood flow and therefore decreased systemic output. Thus, even with a moderate elevation in central venous pressure, the pulmonary blood flow is limited, which limits systemic blood flow. In this circulation characterized by the presence of only a single pump or ventricle, the baseline cardiac output is typically near normal but a bit reduced, 70 to 80% or so. Central venous pressure, as you'll see, is chronically elevated because there is no ventricle to do the work of the subpulmonary blood flow. Pulmonary vascular resistance is typically elevated. With exercise, cardiac output increases quite a bit more limited than in the two ventricle population. And this circulation is characterized by increased central venous pressure and increased pulmonary vascular resistance compared to their biventricular peers. This has substantial implications to both how much cardiac output can be augmented, as well as the central venous pressure where the liver and other organs that require fair bits of blood flow face chronic venous hypertension that's worsened during exercise. So this hypothetical set of curves by Mark Velli and Dave Goldberg really demonstrates some of the abnormalities in Fontan circulation. At rest with zero exercise, cardiac output in typical or good Fontan patients seen here in the green, really 70 to 80% of a normal biventricular patient, and identifying differences between these two populations, especially in a high performing Fontan patient, may be subtle. However, with augmentation of cardiac output or with stress or exercise, the difference between the Fontan patient and the biventricular patient becomes substantially increased, and identifying abnormalities or limitations in the Fontan circuit becomes quite a bit easier. Of course, in the low performing Fontan patient or the patient we'll call with failing Fontan physiology, their baseline differences become more obvious. So the limitations of cardiac output in the fontian circulation can essentially be distilled down to pulmonary vascular resistance. Diastolic function of the ventricle and systolic function of the ventricle. I placed the systolic function in gray because typically systolic function is preserved, at least preserved until very late in the clinical presentation with difficulties, and so I think most of these problems boil down to problems with the vascular resistance across the pulmonary bed, probably in the systemic bed and diastolic function of the systemic ventricle. To the extent that rest and cardiac output is near normal, as we just talked about, most or all of these variables may be pretty typical or near normal at rest. And thus to understand these limitations, one must evaluate these variables in a dynamic or stressed state. This is a slide that shows a couple of images of a patient who's in our catheterization laboratory. Who's undergoing an upright cycle ergometer test and in addition to measuring typical cycloergometry variables, including work and uh VO2, the patient has a neckline in with a wedge catheter that's been advanced out to the pulmonary artery, and at each phase of exercise we're able to measure saturation, pulmonary artery pressure. And pulmonary arter wedge pressure indicative of the of the left atrial pressure, and we're able to make calculations of cardiac output and pulmonary vascular resistance throughout exercise and help understand where this patient gets into trouble in their presentation with clinical limitations. A series of patients who underwent supine exercise previously had the same invasive hemodynamics measured, and we demonstrated that not only was pulmonary vascular resistance elevated at rest, as we've seen in the early post Fontian group that Dr. Reddington showed, but with exercise, the pulmonary vascular resistance is quite static. It does not decrease as one would expect with maximal exercise. Importantly, if you compare this graphic to patients who have biventricular circulation, their pulmonary vascular resistance begins lower and falls with exercise. This of course has major implications to limitations of cardiac output with this population and treatment strategies. So abnormalities in the Fontan pulmonary vascular resistance are clearly multifactorial in etiology. We haven't gone into that in this particular talk. This has become a very hot topic of study in our field for a couple of reasons. I think the largest is which we have an entire category of pharmaceuticals now aimed at treating abnormalities in pulmonary vascular resistance. Thus we have relative ready access to specific pharmacotherapy for this problem. We eagerly anticipate the results from the Pediatric Heart Network Fuel trial, which is the Fontan Uenofil exercise longitudinal trial. This is a trial of 400 Fontan patients who are undergoing uh randomization. 200 of them will have therapy with udenafil, which is a novel PDE5 inhibitor, and 200 will have placebo therapy. It's a blinded trial, and after 6 months of therapy, they'll undergo a series of tests baseline and at 6 months with exercise and vascular function, echo, etc. to try and understand if chronic use of a PD5 inhibitor has efficacy in improving or at least maintaining exercise capacity, which we know declined substantially over time, especially through the teenage adolescent years. Um, I know Dr. Veldman will talk a little bit about pulmonary vascular resistance and a lot about exercise in his talk to follow this, and so, um, hopefully these dovetail nicely. We've seen this slide already today. The take home message from my perspective is that with echocardiographic assessment of diastolic function of both right and left and mixed ventricles, nearly 3/4 of Fontan patients demonstrate abnormalities of early relaxation or elevated atrial filling pressure by echocardiography, suggesting problems with diastolic function are really quite prevalent in the Fontan population. Our own data, we took a look at the differences between supine and upright exercise, but we subgrouped the patients into those who were control patients. These are two ventricle controls, patients in the dense checkers here who have normal diastolic function and patients with the more granular checkered pattern who had diastolic dysfunction by echocardiography. And what we demonstrated is both with supine and upright exercise when looking at peak VO2. Or at peak work that the patients with diastolic dysfunction had implications from that diastolic dysfunction, at least association between the presence of diastolic dysfunction and reduced functional capacity. Now the the diagnosis of diastolic dysfunction, as we've heard earlier from Doctor Reddington, may be difficult. Um, first, we don't have population specific validated non-invasive measures. The echocardiographic measures we've talked about have not really been validated in a Fontian population. Invasive assessment of the end diastolic pressure, the gold standard for diastolic dysfunction, even in the symptomatic Fontan patient, it is frequently unrevealing in the resting state. They're often a bit preload starved because they've been NPO in advance of their procedure. They're lying supine, and they're not undergoing any stress, and measuring the filling pressure in that state may not reveal the true nature of their diastolic dysfunction. So locally we generated a protocol of rapid volume expansion to perform what we'd call a ventricular stress testing to evaluate for what we've termed occult diastolic dysfunction, which is just diastolic dysfunction. It's not revealed at baseline under those non-stress conditions. And when we looked at a cohort of patients, patients, these are the 1st 46 patients we put through this protocol, we found that while the transpulmonary gradient, the pulmonary vascular resistance, the cardiac index was not significantly affected by this volume challenge, ventricular filling pressure, the end diastolic pressure, was significantly increased after exposure to volume. Moreover, when you look at the individual patients, uh, most patients demonstrated some increase in end diastolic pressure, as you'd anticipate with volume loading. However, many of those increases were subtle. What's important, however, to note is some patients generated substantial increases, and some patients had significant uh increased slopes of those difference between baseline and final and diastolic pressure, suggesting their ventricular compliance was impaired. And they are more likely to get themselves in trouble at times of increased demand, such as with exercise. On the whole, about 35% of patients demonstrated what we termed occult diastolic dysfunction, which was defined as a post volume challenge and diastolic pressure of greater or equal than 15 millimeters of mercury. We tried to understand factors associated with the presence of occult diastolic dysfunction, and in the uni analysis, we found that a higher baseline and diastolic pressure, not surprisingly, but longer duration of Fontan circulation and lower baseline cardiac index were both associated with higher fluid challenge and diastolic pressure. And this makes some intuitive sense that the longer duration of exposure, just like the longer duration of life in a standard biventricular circulation, is associated with a progressive increase in filling pressure and diastolic stiffness. The longer duration of Fontaine's circulation was also associated with a greater change in filling pressure. And baseline EDP was the only finding in multivariable multivariable analysis associated with the the final EDP. Um, we've published the 46 patients, we've now performed testing in over 100 patients, and we've shared this protocol with a number of other large congenital heart centers, uh, who are interested in utilizing this to really tease out who has and who does not have that degree of diastolic dysfunction. Um, we're in the process of using the population for a couple of other studies that we're very interested in pursuing and and are ongoing. And I think one of them that's very important is to understand the relationship between those filling pressures and diastolic stress response to longer term clinical outcomes, so our cohorts being followed over time, and then more importantly, we're interested in understanding the potential causes of this diastolic noncompliance and looking at stiffness, looking at fibrosis of the ventricle are important targets for potential therapies. This is just showing one of the projects we're working on, specifically looking at myocardial fibrosis in this population. Now of course, not only is diastolic function impaired, but systolic function can be quite dissynchronous. These are quick echo clips demonstrating what Doctor Reddington showed earlier, talking about impaired systolic function in terms of the order of systolic function of the mechanical synchrony, even if overall ejection fraction is not particularly diminished. And we know that Fontaine patients can have the presence of mechanical dissynchrony without electrical dissynchrony. This contributes to overall ventricular dysfunction, both systolic and diastolic, and reducing that dissynchrony could improve mechanics, which could improve symptomatic patients. This is work that uh Doctor Doctor Feldman and Doctor Choick, who you'll hear from later, and myself and others have worked on uh with Doctor Reddington as well, uh, looking at the concept of pacing to improve mechanical dissynchrony even in the absence of electrical dissynchrony. We can measure the acute impact of proposed pacing sites on ventricular mechanics in the catheterization laboratory. And in theory, acute improvements in ventricular mechanics could translate to long-term clinical benefits. Of course this is an unproven assertion. Also using pressure volume loops with conductance catheters, um, we've tried to translate work performed in patients with normal biventricular circulation, ischemic heart disease, left bundle branch block, and the concept of using pacing. And multiple sites to identify ideal sites in this case biventricular pacing proved to demonstrated to improve ventricular mechanics the most. And in our cath lab we are able to utilize a multimodality setup that has both conductance catheter feeds, electrical, electrical anatomic mapping, as well as fluoro and ECG, voltage mapping, etc. in order to identify ideal sites, in order to pace and then demonstrate the ventricular mechanic changes at each of those sites. In this particular patient, we identified a couple of sites that were associated with potentially improved DPDT and reduced and diastolic pressure. So in conclusion. Dynamic assessment of the Fontan circulation might provide substantial insight into what can be beyond what can be obtained in the resting state. By combining disciplines and expertise across uh cardiology domains, we may be able to offer complex Fontan patients improved insight into the mechanisms of Fontan limitation and Fontan failure and hopefully uh translate these mechanisms into potential solutions to improve both functionality and quality of life. Uh, and pathologies and pulmonary vascular resistance and diastolic function are likely to play critical roles in the limitations of our Fontan patients. With that, I will stop and see if there are questions both from within the room as well as from the audience at large. Thanks again. Um, I just wondered, uh, uh, Todd, if we, if we should call the questions together after because they're, uh, both, yeah, on, on dynamics, and, and just as we load over the talk, Brian, maybe just one question I wanted to ask you. One of the things that always puzzles me is, uh, you know, it's becoming very clear that there's preload deficiency in the, um, in the Fontaine circulation, and much of that may well be related to, um, Uh, what happens in a form vascular bed for a number of reasons. So, I wonder, you know, what do you think is, uh, the way forward of how we can tease out The diastolic abnormalities that we see in the ventricle, which may well be related to just preload deficiency, is there a way out of that, or, you know, will this still take a little bit of time for us to figure that out? Yeah, I think that's a great question, and clearly preload insufficiency is a loaded term because it implies everything before the ventricle, which could be a problem, and that includes both ventricular compliance, it includes really atrial compliance, but it includes pulmonary vascular resistance and volume status. Um, and, and probably several other, uh, aspects of the circulation. I think one of the issues with large scale trials, for example, the fuel trial, which has 400 patients, is that we haven't, uh, uh, made efforts to identify those patients who specifically have problems with pulmonary vascular resistance before inclusion in the trial. And so giving patients who have relatively low pulmonary vascular resistance, but for example, substantial ventricular noncompliance, if the PDE5 inhibitor drug in the trial, udenafil, doesn't have lots of luotropic effects, that isn't able to overcome ventricular fibrosis and noncompliance, then that patient may look negative as a result. But really that patient probably wouldn't have been expected to look positive with a PDE5 inhibitor therapy. So I think it's incumbent on us at this, right, it could make them worse. I think it's incumbent on us at this stage to to treat patients as individuals and utilize a combination of non-invasive and invasive testing with stress to tease out if the primary problem is a vascular resistance problem through the lung circulation, if the primary problem is ventricular stiffness, or if the primary. The problem is a substantial combination of both and target their therapies towards what we have and what we can use to those specific problems in our future. It's a great question. Can I ask you a quick question because I was fascinated. I've seen the data a few times and it just struck me, you may have, may, you may already have looked at this. But obviously when we're looking at diastolic function, we essentially in and stiffness, we're looking at the rate of change of pressure for incremental volume, swap, and it's very clear that even when uh the pressure doesn't go above 15, some patients have a bigger slope, and when it goes above 15, some have a, Lower slope, OK, did you look at smoke as an index of uh occult diastolic dysfunction and any, and, and maybe when you start looking at the impact on, you know, exercise performance and fibrosis, that might be another thing to look at. Yes, absolutely true, um, we did look at both overall change in EDP per unit time and everyone's unit time. is the same, so that reflects slope. We also looked at those who got to an absolute higher number. Both populations are known to us, is it? It's it's per unit volume, right? Yes. Both populations are obviously known to us, and both all of the patients will be tracked to understand their implications. But yes, there's clearly patients who have evidence of noncompliance, even though their absolute final number doesn't get all that high. There's a couple of questions. Do we have time for that now? Uh, first one, actually, I think Sanjita, I think, uh, Doctor Goldstein pretty much answered your question that was for Andrew at the end of his talk about is it ventricular, uh, stiffness or VA impedance of the inherent problem, which, um, I think it's a little bit of everything. Yes, yeah, yes, for both, you're right. Um, and, uh, the question for you, Doctor, uh, Paul Kantor says, Doctor Goldstein, did you measure resting and post-exercise NTRBNP levels in your exercise-invasive cohort? Might this be a useful non-invasive biomarker of diastolic responsiveness of the fontan ventricle? Yeah, so this is a great question. We did measure BMP. We measured BMP after exercise, and almost universally it's a meaningless measure. Um, we, every patient's number was between 15 and 40, and it's hard to tease out substantive differences in relatively modest sized populations, 50, 60 patients between numbers that are that small. So, um, we did, but it didn't prove meaningful in our cohort, and I think that unfortunately may be a lesson from. You know, Fontaine patients in general that the easy biomarker has proved difficult to identify because their EDP is probably quite low and it's not straining their atrium if you like. Hi Paul, good to hear from you. I hope the snow has melted up in Edmonton. There is something else that circulates in the blood that might be quite interesting. We haven't looked at it enough. Hidiki Senzaki's group has looked at profibrotic markers in the blood in the fontan circulation. It's all over the map, but with. Some of them having very, very high levels of circulating effectors of uh of of fibrosis and uh and I think that combined with some of the the material that you've just heard, looking over the long haul may actually turn out both to be an interesting biomarker of response, but a biomarker of this abnormal physiology. So I, I don't think there's a single paper out there and it was fascinating. I think we, we should be doing that more often. Yeah, stay tuned. I think we have access to all of these data with this specific cohort of 100 patients, so we have all these invasive stress data for us, so we'll see how that plays out, what we identify. OK.