Dr. Rajeev C. Mohan presents emerging data on the effectiveness of intra-atrial shunt devices for treating heart failure.
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Dr rajiv Mohan, who you met virtually earlier. Um So Rajiv's a colleague of mine and a fellow heart failure transplant cardiologist here at scripts. Um Rajiv did his training cardiology training here at scripts and then went up to see does did a year of his transplant fellowship um an advanced heart failure um and then came back to scripts and it's been um I've been here for five years I think, and he's been here for 33 to 4 years. So it's been um yeah, I know it's been quite a journey for us and it's been um absolutely um great to work with roger Rogers and uh amazing colleague physician a friend and we've done uh and doing a lot of stuff here in terms of developing our program. And uh Rajiv is absolutely spectacular physician as well um and has really spearheaded developing the cardiac amyloid program, the Health Best program. And I think today is going to speak to us on heart failure with preserved ejection fraction um and more specifically on inter atrial shunt devices. Thanks raj. I was going to say that the years are going by pretty fast here. Um, I think it's seven years for you in uh, five years for me at this point. Um, but thanks for that warm introduction, I want to echo your comments on Dr Azmi is in stock. That was wonderful. Thank you so much for sharing your morning with us. Really appreciate that. You know, there's gonna be a lot of questions for you as we move into the the panel. So that's great. But you had to echo what you were saying earlier. Dr Rasmussen, I think uh, you know, twitter has really exploded as a, as a way for all of us to connect with each other, particularly over the course of this past year. Um, and some of these new reforms are quite interesting too. I haven't quite yet delved into a the clubhouse uh uh seen I guess enjoining those conversations, but it seems like there's a lot of great meetings and sort of just small group chats about certain topics that are going on by that format as well. I don't know if you've had a chance to join any of that. I have and I've really enjoyed that. I really think that it's exciting to be able to um learn about different things in different ways. You know this just audio on clubhouse is really interesting. There's no slides, there's no visual, it's just audio and people talking and I quite enjoy that. So you ought to check it out. Yeah, yeah, we'll do. Okay, so I'll be talking today about inter atrial shunt devices for the treatment of heart failure. These are my disclosures. We work with two companies that are presently um involved in clinical trials. So we are sites for these clinical trials. So we'll start with the case. This is a 71 year old female with a history of Hyperloop academia, sleep apnea arthritis with progressively worsening exertion, all Dystonia. Um And I put these two echo images up here just to highlight the fact that they're relatively normal. When you look at the sort of structure and function of the heart. We left atrial volume index is basically normal sort of on the top end of normal in this particular echo we were not able to measure her right ventricular pressure P. A. Pressure. Her RV. Sorry I. V. C. Measured essentially normal. So her are a pressure was measured as normal. She had a pretty extensive work up including this echo, a chest X ray and nuclear profusion scan and ultimately arresting right heart catheterization, coronary angiogram at all came back normal. Unfortunately, she continued to be significantly short of breath and so was sent to us for evaluation. Um We decided to perform an exercise right heart cath and what you can see here to start with or her resting pressure. So we're filling pressures at rest Essentially normal wedge pressure mean of 11 with the D wave up to 13. Her blood pressure was a little bit on the higher side. Certainly her map was 115 Cardiac output and index are normal. And then when she began a recumbent bike on the Cath lab table with the Swan Ganz Catheter in place, we saw pretty dramatic increase in her pay pressure with a mean up to 38 And wedge pressure up to 31 with a v waves up to 47. And this is in the absence of any mitral regurgitation. Um So significant elevation and her filling pressures which we felt were responsible for her shortness of breath. So what are treatment options for her? We could increase diuretics, but her filling pressures at rest or basically normal. Um which is it's just challenging. Is Doctor Mendy mentioned earlier, um These these medications in a relatively you've olympic patient can make can cause a challenge, can cause hypertension, that kind of thing. She certainly is hypertensive in this sense. So we do have the opportunity to increase her after load reduction given her hot map. So we'll talk a little bit more about what kind of options are out there for for for her at this point. Um So I'd like to spend some time talking about half past for heart failure preserved, ejection fraction. And this is a table that just shows a number of different large cohorts looking at hospitalized patients hospitalized for heart failure. What we know now is that FPF really comprises about 50 of patients who are admitted for heart failure and many of us here we'll probably find the same thing that really in our heart failure clinics, half the patients are Hedgpeth patient. What we also know is that the mortality associated with hospitalization secondary to FPF is just as bad as it is for those admitted with reduced yet heart failure. You can see on the right side of the screen there. This is this is data, this is older data from the Mayo Clinic and it's sort of broken down into five year segments and you can see on the top with reduced ef heart failure with each five year increment, there was an improvement in the outcome of those patients with reduced ef heart failure and that's just due to the fact of the advent of improvements and guideline directed medical therapy I. C. D. S. And even L. VADs in the beginning or towards the end of that time frame. Whereas with preserved fr fellow there's really no change over that same period of time And this is sort of played out even in more recent data is from 2019. That shows that patients with preservative heart failure just as high risk in the short term for mortality as their reduced, you have counterparts. So if we look at the path of physiology between the two, between half and half for f what we can see is that there is a little bit of a difference in terms of what causes the actual problem. If you look on the right side of the screen reduced to have heart failure, it's sort of an external um insult or injury to the heart, whether it's ischemia infection or a toxicity from uh illicit drug or chemotherapeutic drug, that kind of thing that causes uh necrosis of myocardial cells and eventually collagen deposition and scar formation within the cardio. Whereas with it's a sort of constellation of a number of different pro inflammatory comorbidities that can cause an up regulation of an inflammatory cascade. That then leads to changes in signaling pathways in the heart muscle cells that leads to hypertrophy and increase passing uh passive resting tension within the myocardial. Um So these are those sort of this kind of a delineation of the same thing. Just shows what these chronic inflammatory states are all the sort of comorbidities that we see in patients with heart failure that include hypertension, obesity, diabetes. That leads to corner micro vascular inflammation, increased reactive oxygen species production. This pro inflammatory cascade again causing signaling changes in the myocardial that ultimately leads to diastolic dysfunction. So there's a variety of different sort of Fiona types of HEP F. As we all know. It's a very heterogeneous kind of umbrella of disease states, but Fiona typically, how does it present? Um Some of those things are more common, regardless of what the ideology of the Fpf is. What we see initially. What we're seeing more of is this phenotype is exercise induced diastolic dysfunction. So these patients may have certainly have risk factors for so long standing hypertension. They're they're somewhat symptomatic heart association class too. But they're eco parameters may not yet reveal significant changes. So they may have some left atrial enlargement, some diastolic dysfunction, but they're resting, filling pressures are normal. Um These are the patients that we want to try to intervene on early because as you can see on the bottom part of the slide as they progress from a to be and then be to see their clinical course deteriorates and their risk profile goes up quite significantly. Um What we want to avoid is those patients eventually progressing to find a Type C, which is overt right ventricular failure, pulmonary venous hypertension. These patients have significant risk for hospitalization and death and they have, you know, clinically three plus Dema sides frequent heart failure, hospitalizations. These are the patients that are much more challenging to manifest to manage and once they have over manifestation of RV dysfunction, then we start running into renal dysfunction, liver congestion and all those kind of things. Much harder to treat those patients. This was an interesting study done by the group at Mayo Clinic looking at patients who were evaluated for dystonia. So these are patients with normal ejection fraction and disappear. They all had an exercise right heart catheterization. So this was 55 patients that were in this study and they defined FPF as those patients whose wedge pressure elevated With exertion to greater than 25 mm of Mercury and those with normal wage pressures were were considered non cardiac distance. So what you can see is that early on, even on the right side, you can see is early on in their exercise, even when they have their feet up in the pedals, the filling pressures in the fF groups start to go up and just one minute into exercise. Their their filling pressures are already more than double what they were at rest. So you can kind of get a sense how these patients can get quite symptomatic pretty quickly. This is another similar study looking at exercise right heart catheterizations and patients with shortness of breath. And if you focus just on the red line, so the red solid line and the red dash line, you can see that this was actually a survival uh studied. So looking out 10, 12 years after the time of the right heart catherization, those patients who had an elevation in their wedge pressure where the exertion had a significantly reduced survival as compared to those whose wedge pressures did not increase with exercise. So very important to know and understand that these patients at rest may have normal pressures. We are evaluation is often at rest, the right heart catheterization, the echoes, all those kinds of things. But if they're they're very symptomatic then and then often we need to delve in and do more of an investigation. Here is another case a 45 year old woman, a younger woman with the history of a fib for 10 years and she's had multiple a fiba relations in the past. And she's had progressive having progressive destiny as well On her Echo. Her filling pressures were quite normal pressure of 29 and are a pressure of three. And you can see her Um Echo pictures below. You get a sense that her left atrial volume is enlarged. So this was her exercise, right heart catheterization again, her filling pressures at rest normal, somewhat normal though her wedge pressure is elevated with the mean pressure of 18 and be waves all the way up to 28. You can see those sharp the waves here on the left side of the screen when she exercised, Her pressure's went up quite significantly. So pay pressure of 70 with the men of 42 And wage pressures with the waves as high as 60. So we had changed the scale when we were exercising her on this particular study. So significant increases in her left atrial pressure. Um This is an MRI study looking at left atrial myopathy. Um and the fact that there's there's some amount of scar that develops at the time of the ablation itself. And you can see that that often. This was actually an electrophysiology study looking at um the lack of scar uh causing recurrent atrial fibrillation. But what we tend to think is that the more scar there is in the left atrium, the stiffer that left atrium is going to be eventually cause more shortness of breath issues. So what are treatment options for half past? Well, they're pretty limited all the same drugs that we've looked at for reduced the heart failure has been studied across the board with preservative heart failure, with Arnie clasping the most recent and it narrowly missed its primary endpoint of heart failure, hospitalizations and cardiovascular death. So our options are somewhat limited. What are the guidelines say? Well, number Class one education class one recommendation is to control filling pressures with diuretics and control blood pressure. That's really what we do. We give diuretics, we control blood pressure. Class. To recommendation is to revascularization. We think ischemia is calling causing the diastolic dysfunction. Um If they if we think a fib is the primary issue, we try to keep them in sinus rhythm. Um and then we want to control their blood pressure with beta blockers, Aces and Arbs. So this is really what we do. For the most part we do use this device is called the cardio members device, an implantable device that helps monitor filling pressures at home. So patients can have this device at home and we can monitor what their pressures are and adjust their diuretics accordingly. And in the pivotal study that looked at this device, those patients with preservative heart failure actually had a more profound effect in terms of reduction in heart failure hospitalizations than the group with reduced f heart failure. So our in our practice we do use this device quite regularly, particularly in patients. So we talked about left ventricular dysfunction, diastolic dysfunction, elevated filling pressures. We talked about atrial dysfunction stiffness of the left atrium due to a fib and even Catherine based ablation. The common pathway here is an elevation, the left atrial pressure, which ultimately leads to pulmonary venous congestion and the symptoms of shortness of breath? Well, what if there was a way to reduce the left atrial pressure directly? And that's when that's how these shunts became developed. So this is some modeling data looking at changes in left atrial and right atrial pressures with at baseline and with the shunts of blue line is baseline and red line is the shunt. And these are under resting conditions on the left and under exercise conditions on the right. So you can see at exercise the left atrial volume and pressures go up pretty significantly. But with the shunt in place, those pressures can be modified and this is all this. This this concept was based on a condition of that was well known in pediatric cardiology of those patients who had congenital mitral stenosis. Those patients who had an asd at the time of birth actually did much better than those patients who had the congenital mitral stenosis alone. So the thought was that while the left atrial pressure was elevated due to the mitral stenosis, if those Children were born with an asd to help offload the left atrium, um then the mitral stenosis didn't have as much of an impact on their functional status. And so that's the concept behind creating these atrial septal shunts in order to unload the left atrium. So this was this is one of the shunts made by core via, it's a 19 millimeter external diameter with an eight millimeter internal diameter. And we use these 16 french delivery system. It essentially creates a stent ID uh shunt between the left atrium and the right atrium. Um this was studied initially in the reduced left atrial pressure heart failure study. This was a 64 patient open label study That was published in 2016. Looking at patients with normal yet or EF is greater than 40 who were quite symptomatic and they had to have an elevated filling pressure at rest in or with exercise. um and no preparing procedural, major out adverse events were noted. So what were the outcomes? Well, there was a significant reduction in their work indexed palma Kappler wedge pressure. So this was how how what their pressures Went up to, based upon how much work they were doing. So, significant reduction that was sustained at six months and 12 months and functionally uh they did much better to see an improvement in New York Heart Association class and improvement in quality of life scores as well as an improvement in their six minute walk test. So this is uh you know, looking at the Chemo dynamics at six and 12 months. Um Right atrial pressures did not increase significantly, which is sort of a consideration when we're thinking about entering entering a patient into one of these clinical trials. They have to have relatively normal right ventricular function to start. That kind of highlights what I mentioned before about wanting to catch these patients earlier and earlier on. This was a phase two randomized trial for the same shunt. So this was 44 patients randomized to the device or a sham procedure. And again those patients that got the device had a reduction in their filling pressures with exercise as compared to those who did not. Um And this again held out in terms of the differences in the new york heart association functional status between the treatment group and the control group. So um the pivotal trial to reduce LAPD heart failure to study has just completed enrollment uh 68 months ago or so. So we're collecting to your data on these patients. Um This included those patients with again, E. F. greater than 40 had to be significantly limited in terms of New York Heart Association class and had to have at least one heart failure hospitalization in the last 12 months or the need for escalating diuretics or ivy diuretics and clinic that kind of thing. So this study again has completed enrollments are looking forward to the results of this study. But in the meantime there's another clinical trial going on looking at this device from the V Wave company, a different Shape of the device but similar concept. The internal diameter here is 5.1 mm same concept, shunting blood from the left atrium back into the right atrium. The initial study, 38 patient open label study had both reduced EF heart failure and preservative heart failure patients. The initial design of the device had a valve on it. However, because of the size of the valve, those valves were becoming cyanotic and so the current device does not have a valve on on the device. But even in those patients that were studied in the initial generation of that device, there was a significant improvement in their new york heart association functional class as well as their Quality of life questionnaire and six minute walk test. So that is now in its pivotal trial phase. In a large randomized double blinded study we are currently enrolling in that particular study with a goal of getting about 400 patients nationwide. Um This is looking at both preserved and reduced E. F. Patients. They have to be on proper G. D. M. T. With the least one hospitalization in the last 12 years. And the primary outcome is a 12 month composite of death, heart failure, hospitalization or the need for advanced therapies such as um el batter heart transplant. Now this space is becoming more and more populated because of the fact that you know there's a need for some sort of treatment for patients in this court. Again it's it's very we're very limited in the guideline directed therapy that we can offer aside from diuretics. So this is another device called the atrial flow regulator. This was studied in a perspective open label study with both preserved and reduced cF patients, same clinical criteria, sicker patients and their initial primary land point was just device related. An interesting thing about this particular devices that it's modifiable so you can adjust the size of the opening so how large the shunt is between the left and the right atrium and that's kind of dependent upon what the resting filling pressures are. Um at the at the time of implantation. So there's data again with this device showing an improvement in functional class based on new york heart association as well as six minute walk test. They just published their one year data which sort of confirms this initial data as well. There is another catheter, a stent lys asd creation Catherine. So it's basically a radio frequency ablation catheter that creates a an asd within the septal wall there to allow shunting of blood. The thought behind this catheter is that there would be no um stent or device left behind. This is just a radio frequency ablation so it just basically burns a hole in the left atrium in order to allow blood to shunt across this data was presented at T. C. T. A. Number of years ago. So a number of different kind of devices in the works in this space in order to help treat these patients. But again even in this group in a small cohort of patients they did show some improvements and functional class as well as objective data. Last device is a catheter based device that goes into the coronary sinus that creates a n roofing of the coronary sinus into the left atrium so that left atrial blood can flow into the coronary sinus and then empty into the right atrium. So another type of deployment but same concept just basically unloading the left atrium. So another type of device that's being studied presently and again, small group of patients but improvement in functional status as well as an improvement in human dynamics. So more data to come on on that type of device. So take home points important to recognize left atrial hypertension early to prevent right ventricular failure. We want to capture those patients in Vienna type A. And B before they progress the genotype C. An elevated pay pressure on echo is abnormal and must always be evaluated further. Um exercise echoes or exercise. Right heart cath scan help, unmask left ventricular dysfunction or left atrial dysfunction. That may help uncover when patients have elevated filling pressures due to exertion. Um And there are, you know, are guidelines recommend essentially controlling volume status and filling pressures. But again we are limited in how much we can do. Um And that's where it's important for us to follow the emerging data that's coming out with these shunt devices that are presently showing improvement in human dynamics and functional status. So we're excited about the possibility of additional treatments for this complex group of patients.
