Talking Tall Rounds®: Heart Failure with Preserved Ejection Fraction: Old Challenges, New Advances

Podcast Transcript

Announcer:
Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart Vascular and Thoracic Institute at Cleveland Clinic.

Dr. W.H. Wilson Tang:
Hi, my name is Wilson Tang. I'm a staff cardiologist at the Heart and Vascular Institute at the Cleveland Clinic. Today, we have our Tall Rounds that is involved heart failure with preserved ejection fraction, all the challenges and new advances. This is a hot topic. There has been a wide range of research and clinical activities related to this really challenging clinical conditions and today we talk about the new insights in phenomapping, understanding the different subclasses of heart failure preserved ejection fraction, diagnostic evaluation, particularly in terms of exercise testing and advanced imaging, as well as some really innovative therapeutic approaches, particularly with drugs, devices and new devices that are in the horizon. I invite you to watch it and thank you.

Dr. Sanjeeb Bhattacharya:
Good morning. I'm Sanjeeb Bhattacharya, one of the new heart failure staff, and I'm going to talk about defining subtypes of HFpEF with phenomapping. So just for quick objectives, a brief overview, very brief overview of HFpEF And we're going to talk a little bit about phenomapping and then the use of phenomapping in the HFpEF population. So looking at HFpEF, the prevalence has been increasing in terms of hospitalizations. This is looking at the Get With the Guideline registry and it shows that the incidents of hospitalizations for HFpEF has been rising. And this was actually published in 2010 and looking at the trajectory, they thought that it was actually going to overtake HFrEF in 2020. There's some epidemiologic data that shows that the actual hospitalization rates were about the same, but still elevated fairly high.

Dr. Sanjeeb Bhattacharya:
And survival by age is still fairly poor. So red is looking at life expectancy for normal individuals in that age range, and then looking at HFrEF in blue, the borderline EFs in orange, and then the gray are the HFpEF patients and you see their actual age and year survival is actually pretty low looking at the decades or the age gaps.

Dr. Sanjeeb Bhattacharya:
And then in terms of outcomes with HFpEF trials, we all know that all the trials have been fairly negative looking at drugs and interventions looking at HFpEF. Not really moving the needle in terms of survival. Maybe some signals for reduced hospitalizations but nothing that's been really a game changer in the HFpEF population. And why is that? It's because it's a very complex pathophysiology, initially thought mainly driven by hypertension but we know now that this is sort of a constellation looking at the lungs, heart liver, adipose tissue, kidneys, metabolic issues like diabetes, all leading to milieu causing this actual presentation of HFpEF.

Dr. Sanjeeb Bhattacharya:
So, looking at phenomapping, the thought was, is putting everyone in these clinical trials for HFpEF hasn't really shown anything and maybe the problem is not every HFpEF patient is the same. So how do we further delineate? Well, some of it is using machine learning. So actually Sanjiv Shah over at Northwestern, back in 2007, started a registry at Northwestern of HFpEF patients in their clinic. They followed about 400 patients longitudinally and they looked at various markers looking at biomarkers, ECG data and echocardiographic data, and with machine learning, analyzing these large data sets to see if there's any sort of underlying pervasive themes or patterns that might further subtype these patients a little bit further.

Dr. Sanjeeb Bhattacharya:
And they looked at a lot of variables. So this is a heat map looking and actually across the top, these are the actual patients that were analyzed in the registry. And then going down in the rows, these are actual variables that we're looking at, and you can see it's looking at QRS at GFR, some lab values and echocardiographic data as well. And what they found is using phenomapping, they were able to find three sub-group of patients in their clinic. The pheno group one showed the BMP deficiency syndrome, which showed the least cardiac remodeling, lowest BMP levels. Pheno group two is the obesity cardio-metabolic phenotype, which had the most severely impaired relaxation, a lot of heart failure hospitalizations, high prevalence of diabetes. And then the pheno group three, which had the worst outcomes, which we'll look at the next table, had a lot of cardio renal issues, RV failure, pulmonary hypertension.

Dr. Sanjeeb Bhattacharya:
And looking at this, he then looked at Kaplan Meier curve and he showed that that group three RV failure, cardio renal syndrome had the worst outcomes. And then pheno group one, which had the least cardiac remodeling, did the best of all three, but still had a lot of incidents for survival free from CV hospitalizations or death.

Dr. Sanjeeb Bhattacharya:
So this is just looking at one data set from one institution. There has been a lot of validation of this most recently coming from the group from UT Southwestern and then in particular, Dr. Tang, which is actually just recently published in the heart failure journal and what they did was actually pretty smart, they looked at validating machine learning in a randomized controlled database. So they looked at Top Cat. They looked at people who had echocardiographic data, people who didn't. And they also look to externally validate this in the relaxed trial.

Dr. Sanjeeb Bhattacharya:
So looking at multi different variables, but also looking at different sub-group of patients which were very different across the type. And with their data, they still came up with three pheno group subtypes. Group three, meaning that the least cardiac remodeling and group one, having more cardiac remodeling, but also more have those carotid disease burden. And they looked at primary end points and they showed that the group one had the worst end points across the board looking at all cause mortality at those carotid burden, hospitalizations and such and such.

Dr. Sanjeeb Bhattacharya:
And this is just looking at cumulative incidents plot and it just shows that pheno group one, which had the highest degree of atherosclerotic burden, heart failure hospitalizations, did the worst across the board when it came to cumulative incidents of death, atherosclerotic events, heart failure, hospitalizations, everything like that.

Dr. Sanjeeb Bhattacharya:
Just to briefly talk about beware of phemo copies. So the one thing we always have to be aware of are the cardiac amyloids, the hypertrophic cardiomyopathy, the other infiltrative restrictive cardiomyopathies that mimic HFpEF, which I'm sure we'll get into a little bit in the next talk. And then overall, what does this mean? It means leveraging phenomapping to further delineate. So in my mind, looking at phenomapping it's to first understand the pathophysiology, breakdown in subtypes using phenomapping precision medicine, and then trying to do targeted clinical trials on these subtypes individually to lead to more personalized medicine and maybe more positive outcomes on clinical trials.

Dr. Sanjeeb Bhattacharya:
And this is the hope, trying to get a therapeutic target using a tree like this. This is Sanjiv Shah's thought process and the way that he subtypes but I think having more data will be a little bit better in terms of how we treat these patients.

Dr. Samir Kapadia:
Thank you very much. So this is an exciting topic for the interventional cardiology also in the cath lab, that with Dr. Starling, we are doing some work, particularly with the hemodynamics in the cath lab. So the idea is that people who have mitral stenosis and Lutembacher, or you have ASD and diastolic heart failure and if you close the ASD, they get worse or if you have Lutembacher syndrome, if you have mitral stenosis, you typically do better with a small ASD.

Dr. Samir Kapadia:
So there was the concept based on that, that the idea was that can we create a small ASD in patients with HFpEF or HFrEF to see if we can improve their symptoms. So this is the concept. There is a lot of information available on what exactly happens with the pressure volume curves off the left atrium, as well as left ventricle when you create a small ASD. The curves move, as you can see here, that the patients before and after the introduction of a shunt, you can see that the curves moved to the down and the right.

Dr. Samir Kapadia:
So the device that is available currently are in the clinical trials, there are two devices that are in clinical trial, the Korea device, this is the device which is very simple. You do a transseptal puncture and place a little stent into the left atrium in the interatrial septum. So this device is placed as you can see, this is the device and it is placed, this is by intracardiac echo, or this can be done with TEE. It is a 14 French sheath it's a relatively simple procedure.

Dr. Samir Kapadia:
There's several trials that have been done, small, and now we are on the pivotal trial. So the several trials that if you can see, this is the reduced LAP trial, reduced left atrial pressure heart failure trial. They are the one, two, and right now we are on this particular trial at the pivotal trial, which is a 608 patient two trial.

Dr. Samir Kapadia:
They have been published, so again, the literature is available. This was published fairly recently in Jack looking at the effects of interatrial shunt on pulmonary vascular pressures. What it shows, and see this is at rest, so this is the rest hemodynamics. So the trial is done fairly rigorously. So we bring the patient in the cath lab. We put them on supine and there is an exercise bike. We have a supine exercise bike also, just like Dr. [inaudible 00:10:15] showed you the vertical bike. We have one that fits on the cath lab table. Then we exercise the patient. First we do it at baseline and the baseline wedge pressure as you can see, the rest pressures are very, very similar before and after the shunt.

Dr. Samir Kapadia:
There is a little bit of shunt creator, so the PA saturation increases and the shunt is 1.2 to 1, typically with a seven or eight millimeter device that we place in the heart. What happens really, which is the part that is not very 100% clear that what is exact mechanism of this, is that exercise tolerance increases. So if you look at the exercise tolerance, so these are 75, 78 patients before and after the ASD placement. So if you see that it's 7.4 minutes to 8.4 minutes, a one minute exercise tolerance is quite a bit of exercise tolerance increase. And as you can see, the hemodynamics shows that at least the RA pressure, the wedge pressure increase are not that different in the sense that when you have the intact septum versus not intact septum, you increase your exercise tolerance without increasing your pulmonary capillary wedge pressure.

Dr. Samir Kapadia:
So this is the idea that you can go a little bit further with the same amount of filling pressures. And as you can see, the pulmonary flow increases so when you exercise, actually your shunt gets a little bit worse and the pulmonary pressure increases. This is the concept that the idea is that if you have a little bit of more QP pulmonary shunt, pulmonary flow, that recruits more of the pulmonary capillaries and that decreases increase the pulmonary compliance, and that improves your exercise tolerance.

Dr. Samir Kapadia:
So this is the concept on which we are working on. And so this is several publications for this particular device and interestingly enough, it shows that you have fewer heart failure admissions, fewer events, which require diuretics, IV diuretics dose decreases. So all of the clinical endpoints, although small numbers, these are very, very small number of patients, did show favorable outcomes. So this is the reason why we are doing the randomized trial. We have enrolled probably six or seven patients in this particular trial, but if you can see, this is a trial where we exercise the patient. If the pulmonary wedge pressure increases about 25 and between the RA and the LA or the pulmonary wedge pressure, there is a five millimeter difference. There's no RV failure. So a very, very, very detailed exercise protocol. It takes almost an hour or hour and a half to do this procedure and then after that, we randomized them to say that the patient is really a candidate or not.

Dr. Samir Kapadia:
And it's a sham controlled trial, double-blinded trial. So Dr. Starling, for example, looking after the patient does not know that the patient actually had a shunt or not, and then we follow the patient. So it's a very interesting concept. This V-wave is another device, which is also very, very similar inter atrial shunt. And then we place the device on both sides. There's music there, but I can turn it off. When I was capturing the thing, there was music playing on the television, I guess so that's why there's music. There was actually no music but now with the PowerPoint, you can capture the screen where it records the music.

Dr. Samir Kapadia:
And they also have fair number of... This is also paper published in Lancet, showing that the exercise tolerance increases and the quality of life improves. There's one other device that is, not one, but there are several devices for neuromodulation in HFpEF patients. Some of our newer recruits that we are trying to recruit in this particular field, because this is a very important expanding field in heart failure is neuromodulation and we are looking in some of the young colleagues to join us, to particularly help us with the neuromodulation and especially Wilson is particularly interested in this field. So this will help us in general. And thank you.

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