 Good afternoon. I hope that everyone can hear me sufficiently well enough. I am beyond humbled to be in your presence this afternoon. The voice that you just heard is a voice that I first heard as an intern at Parkland and I have gone from having that voice strike terror to having that voice evoke love and I do mean that in the most sincere and heartfelt way. Any of you who haven't had an opportunity to engage with Dr. Wilson please avail yourself of that moment. One of the beautiful things about medicine is that we actually identify our lineage based on those persons who helped to shape us to become the persons that we are now and when you have an opportunity to spend even a few minutes with someone like Dr. Wilson I promise you the effect will be long-lasting and it will be a fact that you will pass on. So I am delighted to accept the invitation and thank you for the generous introduction. Let's talk about heart failure. I realize that the audience is mixed. There were things that we could have done today that would have disguised from translational science were involved in. There are things that we could have done today that deal with some leadership issues that we continue to navigate in Chicago at Northwestern. But one of the things that we do for the community at large is to help articulate how best you provide care for the patient with heart failure. I needn't tell you what the burden of that condition is. But I also need to remind you that whereas a number of years ago we had very limited options. We have many more options now and our new therapies are coming forward at a very rapid rate. So we have the opportunity to really restate, redefine what it is we understand about this condition. I have no relevant disclosures. I have no relationships with industry. So you can feel as if the comments I'm making to you come from a lens that is mostly academic but also involves some editorial responsibilities. Let's begin with the basics. I'd like to take just the first few minutes particularly with the presumption that there are house officers in the audience and say this is what you should know. And this will only take several minutes or articulate what you should know. First, what's the definition? We have over some period of time now curated a concept that we define heart failure as patterns of left ventricular dysfunction measurable as the ejection fraction that are associated with certain clinical phenotypes. Phenotypes which then prompt specific therapies, therapies that have been explored and a host of randomized controlled trials. In 2013 the iteration of the guidelines we chaired came forward with a novel concept. We thought that there was more than just reduced ejection fraction and preserved ejection heart failure but that in fact in the group where the ejection fraction was preserved we felt as if there were two important components both within the space of an ejection fraction between 40 and 49. Specifically one group that has experienced recovery from a previous measurement of very low ejection fraction. I'll get to that in just a few minutes. Another group where the ejection fraction happens to be in this mid-range. We wanted to try to understand more of that process. What we did was something very different deliberately. We wanted to use the guidelines as a platform to incite more investigation so that we could understand more about these particular phenotypes. The next thing we did in 2013 was for the first time we bifurcated stage C. What you see before you is the template that really captures our best understanding. You can see that it marches from left to right through the stages of heart failure and then from top to bottom it goes through the prototypical patients and importantly identifies those evidence-based therapies that will modify the natural history. But for the first time we bifurcated saying that it is important to discriminate our thinking and our treatment decisions according to the best evidence guided by studies done with the very low ejection fraction less than 40 percent or the preserved ejection fraction. Note that I didn't say normal greater than 50 percent. We came up with this algorithm. This algorithm is necessarily complicated because we have more therapies that are effective. The algorithm states specifically this. Take a picture. That's obligatory. If the ejection fraction is reduced this algorithm applies. It is again obligatory that unless there is an absolute contraindication, ACE inhibitors, evidence-based beta blockers, diuretics is needed to control symptoms. After which we created this model that has six scenarios. These scenarios are not mutually exclusive. They all can be applicable at the same time. One goes through a thought calculus with each of the scenarios that prompts a therapy that is evidence-based. And once the model is constructed for a given patient that then becomes that patient's best iteration of guideline directed medical therapy. Only after we've been through that exercise do we progress to think about the other issues. We understood the complexity of this. And so when we reconvened in 2017 we realized we needed to make this easier. And so we came up with this app. This is from the American College of Cardiology and it's industry supported. It's intended to make the thought calculus easier. So this is treat HF. It's available in Google Play or the Apple Store. But it allows you to go through a series of interrogators. Those interrogators will query specific details about your patient and then prompt you to consider evidence-based therapies and give you a link to the evidence-based that says those therapies are most effective. So if you've not made a habit of looking at this particular app as a means to understand what constitutes evidence-based therapy for a given patient please avail yourself of that. More recently we've done a much better job now of thinking about who is it that really is at risk for having this condition. This is a contemporary art failure risk prediction score developed at our shop with the support of Don Lloyd-Jones but with one of our young investigators where you can input again relevant data that are known to be risk factors for heart failure identify those patients at risk. We have derived this score and validated it and now we have a funding request before the National Institutes of Health to test interventions to see if we can forestall the development of heart failure by applying a rigorous score. What about for HFPEF? Again for the fellows in the residence this is a brilliant score and I'd like to emphasize this score because it was created by Dr. Reddy. Dr. Reddy created the score the Mayo Clinic so as a fellow he was able to identify a scoring algorithm that helps you understand the pretest likelihood that a patient has heart failure with preservative. Imagine the benefit of having these risk prediction tools where you can anticipate who's likely to have heart failure or you can anticipate who's likely have heart failure with preservative ejection fraction. Whether for the purposes of research or therapy these are advantages that we didn't have before they're publicly and readily available for the house officers I would argue that you should make this part of your strategy when you approach a patient. Maybe it's because I'm now older or maybe it's because this is the right approach but no comment about heart failure is appropriate if we don't talk about prevention. I want to be emphatic and make this very clear. We can fundamentally prevent the majority of cases of heart failure in contemporary medicine and I'll show you three of the ways we can do that. First by the exquisite guideline directed control of blood pressure we now have incontrovertible evidence that controlling blood pressure in those patients at higher cardiovascular disease risk not everyone with hypertension but those patients with hypertension and increased cardiovascular disease risk profile when their blood pressure is exquisitely controlled we reduce the incidence of new onset heart failure sufficient to require admission to a hospital by 40 percent. The next thing we can do and I will emphasize this later is really embrace this newest science looking at the sodium glucose code transported to inhibitors and the first signals that now are strongly encased in evidence that we can fundamentally prevent heart failure particularly in the diabetic patient. That is remarkable and when you partner that with the fact that these drugs also reduce the incidence of CKD which has been the scourge of the diabetic patient for some time we all not just in chronologists we all should be facile with the science as we understand it behind these drugs and the best application and then the third way that we can prevent heart failure and maybe this is apropos for someone born in Louisiana who spent a lot of years in Texas lifestyle matters the lifestyle to which I was a culture rated is not a lifestyle that is friendly to the heart there is no mystery about why we see so much heart failure across the South but if you can incorporate a heart healthy lifestyle there is clear evidence not antidote evidence that we can reduce the incidence of heart failure so particularly for the house officers if you glean nothing else few minutes with me today walk away with the fact that we now have algorithms of care to help us treat and prevent heart failure particularly with reduced ejection fraction the unique statements that need to be made about women at risk for heart failure whether to do suggestion fraction particularly thinking about chemotherapeutics or preserve rejection fraction thinking about obesity we should be cognizant of what's necessary to prevent heart failure and women one of the efforts that I've been deeply engaged with has been trying to optimize the implementation of guideline directed medical therapy appropriate for reduced ejection fraction heart failure we've done all of this work but the evidence says from the discovery moment to the full implementation moment it's a 17-year time cycle that is too long to realize the benefits of these evidence-based therapies colleagues of ours went for it with the champ HF registry this really was a bellwether moment and heart failure because it demonstrated that in sophisticated practices where practitioners knew that a quality assessment was being made of the care they were providing for patients with a clear indication for guideline directed therapy without contraindications these were the findings only 25 percent of patients with a clear indication were on one drug in each of the three big categories for heart failure and only one percent one percent approximated the doses that were proven to be beneficial in clinical trials is very easy to sit back and hold fast that we know how to treat heart failure and that we're able to respond when queried about the best approach but it's another dynamic all together when we have to implement execute and really treat our patients in the best possible way so these champ HF data have been sobering but they've been important for us to promulgate so we can remember that as we are necessary for us to optimize therapy why is that these data from the proof HF dataset are very compelling let me outline this for you if you look at the response to the exposure to evidence-based medical therapy measured as the nadir of the interminable probe BMP biomarker survey what you see is something quite remarkable when the nadir is less than 1000 is seen here and here the two panels represent either death or hospitalization plus death it is remarkable how much discrimination there is and outputs between an effective change in the NT probe BMP signal and one that is absent that is further highlighted when you look at these data and see that particularly in those patients that go from a high biomarker profile to low biomarker profile seemingly in response to exposure to guideline directed medical therapy their response ultimately is if their biomarker profile was low to begin with point being is that there's not any secret here when we treat patients more effectively we now have a biology a biology that says they're reducing left ventricular wall stress and in turn we're seeing an improvement in cardiovascular disease events and so the substance of this is to be very assiduous in our deployment of evidence-based therapies because we recognize that markers have been trickle function whether rejection fraction and diastolic in systolic volume in the seas of markers of diastolic function all get better and so there is a science that argues that it is correct to optimize medical therapy not because we're trying to meet some arbitrary threshold from a trial but because the biology says we actually improve the substrate and that in turn leads to better outcomes. I've had the privilege over about 20 years of having a close collaborative relationship as investigators with Greg Fonerow who's now the chief at UCLA we talk no less frequently than once every other day about it seems like we speak to each other when we speak to our spouses but one of the things we've done over the years has been to try to understand what would be the benefit if we did all the right things for the patients with heart failure at the right time and we've now added the SGLT2 inhibitor to this list and you can see the remarkable change let me just have you look at one category look at two-year risk of death for heart failure for just on diuretics calcium channel blockers still the way some patients are treated a 35% chance of death at two years versus less than 10% that is remarkable that really changes the narrative for all the people that say there's not much you can do about heart failure it's a fail complete the patients will not thrive we argue stridently against that if you deploy evidence-based therapies correctly you see the outcomes so that is the first thing I wanted to convey particularly to the house officers so you can understand where the state of the art is want to take you through a couple of thought experiments now and say what are the unanswered questions and one of the really important unanswered questions is this heartfelt with preserved ejection fraction this picture is nearly ideal except it probably should be a woman the typical patient is now a woman who comes in older heavier dyspnea and has heart failure symptoms the key association here that is typified when you see the concomitant presence of visceral adiposity and an enlarged liver if you will non-alcoholic steatohapoptosis or fatty liver disease is a pro-inflammatory signal we believe quite substantially now that this pro-inflammatory signal generates a biology that largely intersects with the nitric oxide home your stasis pathways and that in turn leads to the vascular dysfunction seen in heart failure with preserved ejection fraction so when you look at the construct now thinking of it as a function of aging taken together all of these variables really lead to stiffness within the myocardium within the periphery loss of cardiac reserve and leads to the symptoms that we describe as heart failure with preserved ejection fraction now many of you know full well that we've exploited the use of the arne compound that is neprolysin plus an angiotens receptor antagonist specifically Velsartan that's in the setting of heart failure with reduced ejection fraction but we were enthused to see the initiation and completion of the trial in heart failure with preserved ejection fraction using the same model so paradigm HF was heartfelt with reduced df this is paragon the biology is as you've become familiar with we know that there's a duality of effect here blocking the effects of angiotensin to up regulating the many multiple effects of the appropriate presence of naturally peptides but does that work in heart failure with preserved ejection fraction what was the study design much like paradigm HF there was an open label run-in and a crossover then there was a double-blind randomized treatment period and those patients that could tolerate both the ARB and the combination therapy the primary endpoints heart failure hospitalizations in death a number of important secondary endpoints and the key inclusion criteria become uniquely important remember the definitions that I gave you heart failure with preserved ejection fraction EF greater than 50 but we had this category between 40 and 49 the investigators either deliberately or by committee assignment accepted an EF down to 45 for enrollment in this trial of heart failure with preserved ejection fraction that turns out to have served us quite well these were the results we all know the top line said that the study was not a positive trial but it was an incredibly informative trial and had there been six events that have gone a different direction this would have been declared a positive trial again for the house officers a p value of 0.059 is not statistically significant this uses a frequencies counting effect but it has been assessed that what this summer really tells us is not the strength of the effect but the certainty of the finding there's a difference between the effect size and certainty what this really says is that there are six chances out of 100 that this is due to a random play of chance meaning that there is curiosity that there's something to be learned here what might that be well first it shows that the signal was predominantly in hospitalizations not death but more importantly when we look at these subgroups and in this case it's not unreasonable to look at the subgroups because many were pre-specified I want you to see first of all the cluster of outcomes all line up in favor of a treatment effect so this really was a near miss if there is such a thing but more importantly and this is where things become very intriguing I've deconstructed that subgroup analysis to these important subgroups the first one is as a function of gender male or female and the second as a function of ejection fraction with the midpoint being greater than or less than 57 percent now why do we do this want to remind you that half of the patients in this particular trial were women so the usual critique that women were underrepresented in the clinical trial does not apply to this this is a relevant sample size from which we can make a reasonable set of observations so let's begin with the data thinking about women here the data are discriminated this is from John McMurray's presentation in November at the American Heart Association you see on the left the data for women and on the right the data for men now this is a continuous plot of the hazard ratio and the line of identity is the red horizontal line in each of the four plots the two top plots of the primary composite the two lower plots of total hospitalization I want your undivided attention to pay close attention to an important observation here for women the continuous plot of the hazard ratio these are the confidence animals doesn't cross the line of identity until the ejection fraction is at least 60 percent 60 percent meaning the potential of a treatment effect here for men it crosses the line of identity at about 50 percent if you now look at total hospitalizations it replicates the same thing so the question that I've placed parenthetically is simply this is this a statistical play of chance or could there be some truth in the idea that when we're thinking about heart failure ostensibly with preserved ejection fraction but particularly in women is there reason to believe there could be a difference so let's explore that further we believe that there might be reason to consider that there's a difference let me remind you that we already know full well that heart failure with preserved ejection fraction generates a muted response in the biomarker profile wall stress is distributed differently with a thicker ventricle and we know that there's an inverse relationship between obesity and the generation of anti-pro BMP we know from previous clinical trials that women enter those trials with a hard being in mind so the first premise is that half path may be a BMP deficient state and the second premise is that those that are obese have an even lower threshold of the naturally peptide it doesn't treat that intrigue goes deeper when we understand what pathways we're trying to excite when we give neprolysin we're trying to up regulate the naturally peptides in the activity of the naturally peptides is mediated through the soluble vinyl cyclase or receptor bound vinyl cyclase and what is receptor bound vinyl cyclase is the BMP receptors they actually generate a signal a cycle GMP the least of production of protein kinase G now it turns out that estrogen augments that cycle leads to an upregulated production nitric oxide and the pulse menopausal woman that cycle that signal is less robust the moment makes less enos has less vascular pliability and so now you have three issues one health path is a BMP deficient state two BMP is inversely related with obesity and women enter these trials at a heavier BMI than men and three particularly postmenopausal women they may have unique downregulation of nitric oxide arguing that if that particular phenotype received a therapeutic that especially upregulated the production of nitric oxide with that not be a benefit and then finally what about the measurement of ejection fraction when I was still at UT Southwestern we started the Dallas Heart Study a very appropriate longitudinal clinical clinical observational series not a trial that was intended to define the progression cardiovascular disease and a racially balanced cohort part of what was discovered is that regardless of any comorbidities women consistently have higher ejection fractions and so now you've got a much more intriguing model remember the subgroups of importance the EF response in Paragon up to an EF of nearly 60% particularly women and then uniquely the response to women you can see what the normals were the Dallas Heart Study so we would argue then that it is not just to play a chance it is not proven but it is possible the women may have amounted a response to augmentation of naturopathic peptides in this study now let's think more carefully about the ejection fraction since we've just thought about women this was a remarkable observation it really made all of us stop because if you look at the point estimate it's the truly normalize the F greater than 63 where we see nothing but in the group with ejection fraction between 50 to 57 we see a point estimate that looks very intriguing again is this a play a chance or is this real Scott Solomon did a brilliant job of bringing these data forward Scott combined the low EF study with the ironic compound paradigm and the higher EF study Paragon and now look at these point estimates starting with hospitalized heart for in cardiovascular death cardiovascular death etc. they all line up to suggest a treatment effect in both trials so what does that mean well again if you do the continuous function plot of the hazard ratio it really does argue that there is a signal from very low ejection fractions all the way through about 50 when the confidence intervals get broader but if you make this gender specific where women are in red and men are in blue once again you see this observation that looks like it's durable the women respond as if they have reduced EF heart failure all the way up to an ejection fraction of the mid 50s to 60 or so this really is disruptive because it says everything that we've tried to articulate in guidelines that limits the response of evidence-based therapy to a reduced EF characterized by something less than 40% may need to be totally reassess particularly from a gender-based basis so this is an area of really prominent research John McMurray and I share the same stage of the AHA to present these data to the community at large and what I meant to really point out was that even if you took a conservative point of view that's the purple art that I interjected on his graphic it would suggest that for women we have to consider ejection fractions up to 55 percent is being responsive to evidence-based therapy for reduced EF heart failure that is a wildly provocative hypothesis it's not a tenant that's proven but imagine how that changes the way we approach patients with heart failure if we now consider EFs up to 55 as the target for these evidence-based therapies part of what I enjoy doing in fact early this morning I was doing such serving as deputy editor for jamming cardiology and it's exciting to see ideas come to our desk and be considered for publication but when we saw these data in September we were really quite intrigued because maybe the time has come that ejection fraction alone is insufficient to describe and trickle performance particularly as a way to articulate what therapies patients should receive so let's go on to the next unanswered question I told you I would get back to the sodium glucose co-transform quarter to inhibitors as potential disruptive therapies and cardiovascular disease profiles we published these data some number of years ago and made the assessment that perhaps what's going on is that these compounds change myocardial metabolism that is still a work in progress still a theory we don't have the mechanism completely resolved but we know that there are renal effects we know that there are cardiac effects and we think that affects energetics but what really was interesting were these data these were the first clinical data for the sot2 inhibitors from the emperor trial because the FDA mandated that any new diabetic agent had to demonstrate neutrality on cardiovascular events these data were captured longitudinally and inexplicably was identified was this a striking difference and hospitalizations for heart failure was at a quirk or not turns out that's very real because when all three of these drug classes will look that in aggregate a colleague of mine Mark Savitin did this analysis and published it in january of 2019 in the lancid when you look at the data within pagliflozin the pagliflozin and canagliflozin all three major sot2 inhibitors the data are exactly congruent there is clear evidence either with pre-existing atherosclerotic disease or in the absence that there is an effective reduction in the incidence of heart failure and this qualifies as a preventive strategy what's happening here well the biology is simply elegant meaning that we really don't know but it's not just based on glucose law this is a very provocative model from a set of investigators in south america who have argued that the mechanism really does have to do with myocardial energetics they ascertain the following in the normal state the sglt2 receptor allows the entry of glucose into the myocardial cell but in the diabetic state not only is there more glucose in enters but it is concomitantly associated with the entrance of more sodium that overloads the cell and a high energy pump has to be effectuated to create homeostasis of electrolytes within the cell and concomitantly that stress of the high ATP consumption pump leads to a biotransformation of fibroblasts fibroblasts that ordinarily leads to the production of rithubcoitin now they become pro-inflammatory cells and that further augments stress reduces the rithubcoitin production we already know that when these drugs are given we see an increase in hematocrit we see an increase in rithubcoitin and now when these drugs are given we go back to steady state that is at least one theory that i think is calcium biology and is an operative therapy that again is independent of glucose lowering per se but what really made everybody think differently is when these data came out in august this is from the DAPA HF study with the paiglet flows in these data argued that not only was there a reduction in heart failure hospitalizations but look at what happened when one looked at the enrollment criteria that did not prespecify the necessity for diabetes whether with diabetes or without diabetes there was a remarkable signal and so now these drugs originally intended to affect glucose lowering and oh by the way we're associated with reduction in nuance at heart failure now are demonstrating a therapeutic efficacy for symptomatic heart failure absent the presence of diabetes this mechanism of action is completely unexplored but the signal cannot be dismissed it is such a strong signal that we are so tempted to begin implementation now even though it's a single trial it's one dose once a day no titration virtually zero side effect the original concerns about amputations were dismissed there were no episodes of diabetic ketoacidosis there's even data in patients older than 75 almost a perfect addendum to our armamentarium we're waiting for more evidence we have to be slow before we dramatically uptake this but this may be the next big thing this very intriguing editorial put in press by depot bot and dr brunwall really goes through the program development for these drugs but importantly this dr brunwall has suggested to all of us that we now have a new foundational pillow in the treatment of heart failure that would be significant change from what we've been doing and this is worth further discussion what about for heart failure with preserved ejection fraction is that an area that we can talk about well we know that there's some animal data this is an intriguing animal experiment taking a doka salt model feeding the animal salt and then doing a nefrectomy a union of rectumized animal that replicates the heff path phenotype and then coming in with empagliflosen you see the reversal of much of what we see in this phenotype but what's very interesting is adnecropsy in these animals what's important is that when the sglt2 inhibitors added to either the union of rectumized animal or the doka animal there's significant reverse remodeling of this heff phenotype smaller myocytes but it's not from a change in connective tissue because you see no change in connective tissue in the stains that are from e3h and so it intrigues us a not that there's yet another trial being done and this is the emperor preserve trying to exploit the possibility that this class may be beneficial and heff path when we look forward to seeing those data come forward there's a final unanswered question and this is about infiltrated diseases and this is something that i remember seeing full well when i was a resident at parkland with dr wilson when we would see amyloidosis and we would bring our hands because we knew what that meant it's remarkable thing that we now have therapies that can treat what usually had been an overtly fatal disease remember that etr amyloid starts with transthyretin made by the liver ostensibly to transport thyroid hormone and through a series of foldings from attachment to dimer it effectuates its functionality but occasionally misfolding occurs and when the misfolding occurs at least the deposits particularly for the house officers i want you to remember this there's an important distinction between al amyloid and ttr amyloid al amyloid is associated with a proliferation of plasma cells a plasma cell discreasure or flank frank multiple myeloma whereas ttr is akin to the process i've just described that is an important consideration i'll develop that further also recognize that this is not quite as random as it appears to be there's a genetic underpinning for amyloid and the cycle starts with those amyloid conditions that predispose the neurologic conditions versus those that predispose the cardiac conditions the v 122 i mutation is a substitute mutation is uniquely important in persons of african descent up to and including about four percent of the contemporary african american population but the v 30 is important as well for persons of italian descent so it's not just african americans that have this proclivity persons of italian descent and persons of japanese descent have a similar circumstance you see these images all the time this first image i'm sharing with you is what we see in heffa what we've talked about earlier in this presentation but we also know that there's another model that really is the prototype for amyloid vastly different we see this thickening of the septum that is pathologic we see thickening of the leaflets if we continue this process we have this new sign that has become quite important in contemporary echo laps where a mocardial strain is preserved here the apex the so-called bullseye sign but reduced elsewhere this really is one of the first steps that triggers us that there might be a amyloid person we know that looking at the late enhancement with cardiac MRI really does give us yet another tip that we might be dealing with an infiltrated process we know that if we look at t1 mapping times we can look uniquely at the extracellular volume and when we see that that's increased we know that too is consistent when i was a house officer at porclain we would facilitate the diagnosis of acute myocardial infarction with a pyp scan so i smiled quite broadly when i saw the reemergence of pyp scans because i thought well i'm familiar with those but in truth this is a very important diagnostic step it is 100 specific for ttr amyloid let me say that again 100 specific for ttr amyloid provided the diagnostic ratios are achieved here between bohem and myocardium this is of the utmost importance for house officers and fellows that are doing these evaluations you start with a clinical suspicion that amyloid might be present a number of potential clues carpal tunnel syndrome make a glossy or dematographia a number of things then look for evidence of light chains the light chains are positive you're committed to going on a pathway that leads to biopsy looking for the green biorefringence using a congo red stain if the light chains are negative and you have this clinical suspicion that's where a positive pyp scan can be so informative leading to the discovery of a ttr amyloid genotyping if necessary and then discrimination between a genetic variant versus wild type and so this is really the correct way clinically to reconcile this diagnosis and realize that depending on the point of action we have a number of therapies that are currently available and more that is soon to be available that are quite effective in the treatment of this condition there are three questions about amyloidosis that i want the house officers and the fellows to appreciate how best to make the diagnosis clinical red flags look for the monoclonal proteins do the pyp scan particularly if they're negative it's endocrinobob cell is required only when there's ambiguity if the monoclonal proteins are positive then the biopsy is obligatory what are the steps to need to institute therapy to feminists is available now we're using it on a regular basis in chicago it is incredibly expensive 650 a day a day so one has to work with insurers with the manufacturers to find these drugs and make them available and remember that the unique cohorts are those in italy northern ireland japan and of african descent so what i've tried to do for you today is to review what i've called heartfelt in 2020 the unanswered questions the first thing i wanted to do was remind you of where we are there's effective guideline directed medical therapy of giving you the app we believe that prevention is reality secondly i wanted to emphasize heartfelt with preserved ejection fraction using a trial that ostensibly was negative and showing you how informative that trial is how many in due directions we can pursue right now we have limited treatment options maybe the aldosterone antagonist of arb we don't know yet about the ionic compound we are intrigued with these gender sex-based differences they may inform other therapies that we have to consider we have to understand that up to about 15 percent of heffpeff may be due to an infiltrative cardiomyopathy the same for critical a s with small volumes and low flow and then finally the sglt2 inhibitors may be therapies for heffpeff i want to end with a thank you but importantly my thank you is based on this statement from sir isaac newton if i've had vision to do the things that i've done in my career it's because i've been able to stand on the shoulders of giants and this is the friendly giant that i know best