In this presentation, Sanjiv Shah, MD, discusses precision pentoypic of HFPEF.
Hi, my name is Sandy Shaw and today I'll be talking about precision for genotyping of Hef Hef here. My disclosures, I like to start with this slide Which shows a paper published in 1985 by Eric Topol and colleagues on hypertensive hypertrophic cardiomyopathy, the elderly. This was not the first description of hefty, but one of the first and at that time we typically thought of Hef's diastolic heart failure, a thick L. V. A small LV cavity and an upward and leftward shifted and diastolic pressure volume relationship. However, as we have seen with dedicated health programs like ours and others across the country and the world, once you see all of these patients, the full spectrum of hefty if we see something different. And now in 2021 we recognize that Hef Hef is not just diastolic heart failure involving the heart. It also involves the lung, the liver, the visceral adipose tissue, the kidney and the skeletal muscle. It's truly a systemic syndrome there, of course is hypertensive remodeling and ventricular and vascular stiffening. But coupled with this is a sedentary lifestyle and poor fitness, which we know is a major risk factor for Hef. Hef, but not half ref obesity and metabolic stress are increasingly common and important in the syndrome and coupled with aging, this causes a global loss of cardiac, vascular and peripheral reserve, culminating in the Fpf syndrome. So what's our current treatment algorithm for Hef Hef. Well, first we've got a diagnosis and once we do we have to see is the patient volume overloaded If they are, we need to decrease them and I think that we should be using cameras and s guilty two inhibitors. Now, once there diaries or if they weren't falling overloaded to begin with, we have course treat their comorbidities as a way to manage the syndrome. Next we want to do heart failure education, exercise training as I'll show you. And recently we've understood that if the E. F. Is in the lower range of normal, so ef less than 55 to 60% and they have a congested genotype, they likely will benefit from ski patrol, val certain. Some patients will have persistent symptoms and heart failure, hospitalizations and in those we really need to refer to a heart failure program. We also need to reevaluate for zebras. Did we miss an atypical ideology like cardiac amyloidosis are their worsening comorbidities. And here is really where implantable hemo dynamic guided management can be very helpful and of course have passed clinical trials. So let's look at that first step of reducing congestion and heart failure, hospitalization. We know that in the overall top cat trial and especially in America's spironolactone, reduced the risk of heart failure, hospitalization and cardamom also appeared to be beneficial in these patients with a preserved ef. Now there are many ongoing trials, for example, para glide, so secure, travel certain and hospitalized transform, which is torso might versus usual care. There's three trials of cameras including a novel mra nonsteroidal mRA phenomenon in the fine arts trial and then the deliver trial as guilty two inhibitor trial. But we do have some data already on large scale s guilty two inhibitor trials. This is the soloist worsening heart failure trial which gave us the first hint that these drugs may be beneficial. So to go flossing is an S GLT 12 inhibitor And this was only in diabetics and those with worsening heart failure. But in the subgroup analysis, you can see here that if anything, those with an E. F. greater than 50% seem to benefit more from surgical flows in. And now we have the first ever large scale randomized controlled trial and half bath that met its primary endpoint and that is emperor preserved. This was nearly 6000 patients empirical closing versus placebo in patients with heart failure than E. F. Greater than 40%. Now note that about two thirds had an E. F. Greater than 50% and this primary outcome was driven by heart failure, hospitalization and there was a slight improvement in K. C. C. Q. Quality of life versus placebo at 52 weeks. The subgroup analysis, diabetics and non diabetics fared similarly, there seemed to be an attenuation as EF went up, but the interaction p value is greater than 0.1. Now, even more recently as the preserved HF trial. This was a smaller trial. Us only 324 patients capital flows in versus placebo. And look at this. This is heart failure greater than or equal to 45%. A 5.8 point improvement in case the CQ. That's the biggest improvement in quality of life ever in a heart failure trial. And there's about a 10 improvement in six minute walk test. Now, here we look at the subgroup analysis, there's absolutely no heterogeneity by ejection fraction below or above 60%. And as I said earlier, the six minute walk test also looked quite good. Now how can we compare and reconcile Emperor preserved determined preserve, which was another trial similar to preserved HF. And then of course the preserved HF trial, well preserved HF was us only it was really done at FPF and cardio metabolic heart failure centers I think therefore understanding the heart failure syndrome and that syndrome. And making sure that patients treated had the syndrome and they were more often women, about a third black individuals and more white class three much higher. BMI. In fact lower BMPs E. F. Was higher as well. And look at the difference here a much better improvement. So for us in the US, it really does seem like these s guilty two inhibitors are helpful. Step two is diet and exercise training. This is the secret trial. This is a single center trial showing an improvement with both caloric restriction and aerobic training and the combination of the two more recently, earlier this year was the optimum. Exclaim trial. And here we see that whether it was high intensity interval training or moderate continuous training in these health care of patients. They both improved that in person training at three months compared to uh guideline control. This attenuated over the next nine months where it was more telehealth and this shows us that if we're going to do exercise training, it really needs to be in person. There are also significant differences between the secret trial in this trial and that the optimistic Lynn trial were healthier patients. Nevertheless, I think this data supports the use of exercise training in our have best patients and finally, a genotype guided approach and will spend the rest of today's talk talking about why it's important to do precision genotyping to get at FF. And a guide therapy. So how can we resolve the hydrogenated half past? Well, first of all, there's something easy myocardial genotyping of half past. We know that patients have Hedgpeth have elevated filling pressures and preserved EF. But it could be a cardiac cause or an extra cardiac cause. And most patients are somewhere here in the middle. And what we've hypothesis that if we use something like abnormal strain or even ejection fraction within the normal range or tissue velocities, those with worse myocardial phenotype may respond better to cardiac specific medications. And we certainly saw that in the Paragon trial with secure patrol val certain and so we can go beyond the f when genotyping, Hedgpeth is it have pep with reduced longitudinal strength, we have a list of differential diagnosis here. But if there's preserved longitudinal strain of the LV, we start looking at other things the left atrium, the vasculature, extra cardiac volume overload or primary RV dysfunction. So it's really important to you strengthen the management of your patients. But even if you don't have strength, we can use tissue. Doppler to evaluate whether the myocardial is sick or not. Are there low S. Prime E. Prime and a prime velocities. Is there a short ejection time or prolonged ice of olympic times? Even on the G. And increased Q. R. S. T angle is indicative of a sick. My accordion. Let me show you an example. This is a 62 year old man with alcoholic liver disease, this mia and fluid overload. You can see that his ejection fraction is normal and it's 57%. But something about the myocardial looks abnormal. And here we see his strength. This train is 12.3% which is severely reduced. Anything absolute value less than 16% is abnormal. As you can see here with the reference ranges now, what I did was I increased his diuretics started carvedilol and update traded to 25 mg P. O. B. I. D. And six months later you can see a market improvement in strain values. So here the diagnosis potentially was masked alcoholic cardiomyopathy. And because he had end stage liver disease in a low SVR he had preserved ejection fraction. But strain really helped us in understanding we needed to treat him with neuro hormonal blockade. So how do we treat myocardial? Well, Paragon showed us never listen inhibition. Spironolactone may work better in these patients. We can target the metric peptide PDE nine system or the camera system Antibiotic therapy. The pirouette trial recently showed that prevented don't actually decreased the amount of interstitial myocardial fibrosis and healthcare Madison activation or inhibition and china tropes. Here's a study from David Kay's group in Australia showing that a short infusion of mill run on markedly reduced exercise, pulmonary capillary wedge pressure in half of patients. How can this be? Well remember that in the heart the LV apex and the base of the heart are fixed. And so there's this micro angular interaction between the A. And the L. G. If we improve lb longitudinal function with mag metro, we can improve L. A. Reservoir function and the L. A. Can feel more easily. We can also use string patterns on speckle tracking these are the bullseye maps and so we can look at amyloid, a pickle sparing. We can look at the reverse with a pickle HCM. You might have a diffuse process with idiopathic restrictive cardiomyopathy and february disease may have a reduction here locally in the basal lateral wall. So here's another example, 62 year old man with a previously healthy and active. Get no other have pets risk factors and you can see on the still images from his t cardioversion that the myocardial look uniformly thick and sparkling and texture. So he was referred to me for evaluation of cardiac amyloidosis. It's significant diastolic dysfunction with an elevated E to a ratio. His tissue velocities were pretty reduced, but his strange pattern didn't look like amyloid. It looked like HCM with a reduction in the antiseptic and septum. And sure enough on cardiac MRI with late gadolinium enhancement, he had the same pattern and genetic testing showed that he had a TNT to pathogenic mutation known to cause HCM with a restrictive cardiomyopathy pattern. So we need to use these clues to understand the ideology in our patients. So, what about machine learning? Well, what we want to do here is take a heterogeneous clinical syndrome. Use unsupervised machine learning or pattern recognition and identify discrete fino groups, discrete groups that may be more therapeutically homogeneous, but that is not where we stop. We then, as clinicians develop new clinical and biological insights based on what the machine and computer told us and we do further investigation. So we've done this using echocardiography as our method of deep genotyping And what you can see here in our paper on piano mapping of health path is that each of these rows are different prototypes, mostly echocardiography and each column is one of about 400 patients of health red is increased in blue is decreased and you can see there's quite a bit of heterogeneity When we use model based clustering. We find that three groups is the most parsimonious solution. And these three groups are quite different on principle components analysis and they have markedly different outcomes. We've added show that this added prognostic value over the magic risk or BMP. We've replicated this prospectively and here we show in top cat that we see the same thing that's differential risk. And in fact, the first female group, the lowest risk group had the most response to spironolactone. This is a proof of concept that genome mapping can be used to guide therapy. So, what do these groups look like? Well, they all have a preserved ef they all have left atrial enlargement. They'll have markedly elevated plenary Catherine wedge pressure, but they're very different. The first group has the least cardiac remodeling and dysfunction and the lowest BMP. The second group has the most diabetes, the most impaired relaxation. And the third group has the most severe cardiac and electrical remodeling. RV dysfunction and renal dysfunction. So I called the first one, the BNP deficiency syndrome. The second, the extreme cardio metabolic syndrome and the third RV failure. Cardiac donald renal syndrome. So let's go through each of these. The first group is the BNP deficiency syndrome. We are now well aware that many things can cause chronic BMP deficiency, not just obesity but a lack of my party Wall Street's in some of these patients and a host of other factors. And this is present in about a third of patients with Hedgpeth. The lack of BMP results in hypertension, fluid retention and increased at a posse. And that plasma volume expansion is coupled with this para Cardell constraint causing Hedgpeth with minimal myocardial involvement. Here's an example of a lady who's morbidly obese low BNP and you can see the severe pericardial pericardial fat over the RV and a diastolic septal bounce showing ventricular interdependence and invasive human dynamic testing. It looks just like constriction with discordance at peak inspiration. However, on cardiac MRI the pericardium itself is normal and yet there's a ton of pericardial pericardial fat over the RV. So this is the classic obese low BMP patina type volume expansion and pericardial constraint. And when we treat these patients, we need to think outside the box here is an example of a very similar patients who I treated with GLP one receptor agonist. BMI went from 39 to 31. She went from new york heart association class three to Class one and she's off all diuretics and antihypertensive therapies. So in the future we can do some of these newer therapies for weight loss. We can target visceral adipose tissue induced splanchnic nasal constriction. Or we can augment B. NPR's downstream effects because they're Bmp deficient. What about fino group number two? This is the extreme cardio metabolic syndrome and this fits most with the policy paradigm for hef hef where comorbidities cause systemic inflammation that then poisons the end of helium of multiple organs and then the heart causes coronary microvascular dysfunction. Interstitial fibrosis, LV hypertrophy and passive stiffness of cardio maya sites due to changes in titan phosphor relation. So we've studied this with a dentist in Doppler coronary flow reserve of the mid to distal lady and here's what it looks like on the left preserved coronary flow reserve and a half per patient and on the right a severely reduced coronary flow reserve and a half per patient. We studied this in the prospective multi center five site trial across the world called promise Hefty and coronary microvascular dysfunction was present in 75% of patients. It was related to systemic endothelial dysfunction. As noted by albumin area, a worse for genotype with elevated BMP. And more RV dysfunction and end up at reactive hyperthermia index, which is a marker of systemic and ethereal dysfunction. Well, we then sought to understand the proteomics of this Vienna type and so we looked at 250 unique proteins and we sought to understand whether comorbidities burden works through systemic inflammation to influence abnormal cardiac structure and function and half bath. And sure enough, when we did machine learning analysis of the proteins. This weighted co expression network analysis, we see that this turquoise module is the inflammation module and it's centered on TNF are 11 of the receptors for TNF alfa and we found that in a totally separate cohort we're seeing the same pattern of this inflammation module which is very present and have path and not present in patients with comorbidities without Hedgpeth. And sure enough, this inflammation module or a cluster of proteins did mediate at least partly a third of the association between co morbidity burden and echo parameters indicative of elevated filling pressures, like my trolley velocity. And when we network rank it we see the TNF R1 is a hub and this might be what's triggering an abnormal t regulatory cell response which is causing inter social fibrosis in these patients. So further investigation of this final group were doing metabolite profiling of these patients with a multi ah mix approach to combination with proteomics. And we have two trials ongoing the satellite trial and the amateurs trial looking to inhibit proteins known to cause endothelial dysfunction. What about fino group number three, this is the RV cardio renal syndrome. So we know that in patients with RV cardio renal syndrome they have very elevated right atrial pressures and this causes splanchnic congestion and when you explain to congestion, increase the hypoxic environment in the interest sites and they become a sadistic. Well we often forget that there's a major sodium hydrogen transporter in the gut which is how the gut absorbs water. Nhe three. And if you're in Terror site is as idiotic, you're going to exchange hydrogen into the gut lumen and you're going to resort more sodium. So this becomes really prevalent in this RV failure cardio renal syndrome. And what does this do? Well the low ph in the gut increases gut permeability and inflammation susceptibility to infection sepsis and cachexia. And on the other side the increased sodium retention causes water retention, causing worsening venous congestion, renal failure, worsening heart failure and death. And so we studied this in a study called Victory. It was a pilot study of hospitalized heart failure patients versus non heart failure. Hospitalized controls. We collected stool samples and looked at exfoliated colony sites that were extracted from these with flow saitama tree. We see that cell surface and intracellular Nhe three are markedly up regulated in heart failure patients versus controls were hospitalized and that this elevation and Nhe three correlates with RV enlargement and RV. Dysfunction. So there may be something here with right heart failure and augmentation of Nhe three. So we can actually block the gut Nhe three with a drug called Klonopin or we can improve our V. Function and the stressed blood volume in the gut. We showed this in the help trial with Leviosa Mendon. And we can try unilateral greater spanking nerve ablation which also increases splanchnic venous capacitance. Remember that there are fast and slow mechanisms of congestion but slow mechanism is what we typically think about renal and dietary mechanisms but any minor precipitous that causes sympathetic activation can mobilize the splanchnic venous reservoir and rapidly increase effective circulatory volume. And if this becomes constituent lively active venus compliance goes down and we get the cardio renal syndrome. So this is really where greater splanchnic nerve ablation and leave us amended may help these patients and now matchmaking for targeted therapeutics and have faith in the future we'll take this heterogeneous syndrome and we'll do sub genotyping machine learning and hopefully use genotype specific treatment. But in the meantime we use at Northwestern an umbrella designed for Hef Hef trials where we do deep echocardiogram thick and invasive genotyping often with exercise and we assign them to one of these groups and we then target them to clinical trials. And so we've been doing this in the elevated L. A. Pressure the myopathy group with an intra atrial shunt device. Remember that abnormal mechanics is very common in half if I often like to say that Hef Hef's failure of the L. A. And have ref is failure of the LV. But abnormal mechanics can cause chronic pressure and volume overload, resulting in RV failure. And there's reduced atrial emptying which decreases exercise capacity. And what we've shown here is when we look at L. A. Reservoir strain in L. A. L. V. Global longitudinal strain we can see that there's a nice correlation but that there are some patients with an L. A. Myopathy. So they're LV global longitudinal strain is relatively preserved and the L. A reservoir strain is very bad. And these patients have the best LV diastolic and systolic function but the worst team of dynamics. So there's something here and when we did a proteomics analysis there was some overlap with a fib but many proteins are really segregating just to disproportionate ella myopathy and hef. Hef and maybe target able in the future. In the meantime we've got the creation of an SD, it was shown over 100 years ago the Luton bash, a syndrome that a congenital asd in the setting of mitral stenosis may allow decompression of the high L. A pressure into the greater reservoir of the right atrium, great veins and panic veins and help these patients. And so there are at least eight companies that are in this space and many trials are ongoing. So we eagerly await the results of these trials for this particular funeral type of health care. So I come back to the original paper, hypertensive hypertrophic cardiomyopathy of the elderly. And I highlight something in the abstract we conclude that this unique subset of hypertensive patients has a clinical syndrome that warrants recognition and tailored management and I really think that still holds true today. So Hedgpeth is a heterogeneous systemic, multi organ reserve dysfunction syndrome. Resolving hefty heterogeneity with improved classification may lead to improved outcomes in clinical trial results. Machine learning plus deep genotyping of the echo may cause re classification of health and provide new biological insights and future treatment may involve novel targets like the left atrium obesity, gut et cetera. Thank you very much.
