but thank you so much for having me here it is such an honor and pleasure to spend the next few minutes telling you a story and it's a story that spans more than two decades of a condition that continues to fascinate me to this day heart failure with preserved ejection fraction or have pen so well let's start in the 2000s what were you doing really think back a little between your munches well the younger me I suppose was grateful that the world didn't end with Y2K I love Destiny's Child so glad that hip-hop was in because I was listening to it and my cool iPod first introduced in by Apple in 2001 but at the same time I was packing that as well as the Blackberry ends up those who've also touched one of those and I was leaving my tropical island city of Singapore for the refrigerated state of Rochester Minnesota and that was to work with my first ever female Mentor Dr Margaret Redfield as you can see the strapping young man was also someone that I met in those early days and plays a huge role in why I really really got into heart failure as a sub-specialty but why leave a tropical island for this This truly cult State I mean I am actually standing on a frozen lake in that picture well that's because there was rumored to be a form of heart failure that encompassed at least the third and increasing to ha the heart theater population that we were seeing and that was even increasing relative to so-called systolic art failures now this was at least as reported in Olmsted County Minnesota whereas in Singapore and even in the current guidelines at that time there was widespread skepticism that this condition even existed you see look at the ESC guidelines in 2001 the definition of heart failure very simple there's no ejection fraction even mentioned there and under a little paragraph on heart failure due to diastolic dysfunction there was a lot of mention of debate uncertainty and a lack of evidence still why did we call it heart failure due to diastolic dysfunction or diastolic heart failure well it was because there were Landmark papers such as this from Dr Michael Zyle one of the first to really show that in this left ventricular pressure volume relationship compared to healthy young controls patients with so-called diastolic heart failure had an end diastolic pressure volume relationship that was shifted leftward and upward so that at any given filling volume feeling pressure was raised so that is diastolic dysfunction however please note that in this beautiful study the diastolic heart failure cases were majority men and middle-aged and that was quite unlikely epidemiologic studies we were hearing at the same time that this was a condition of hypertensive older women predominantly and so that gave me room to look at this in a population-based more unselected approach in Olmsted County and what we found was indeed the majority of patients in this study were elderly hypertensive women with heart failure but we also showed after age sex and body size correction that compared to controls in green patients with hypertensive heart disease but with no heart failure as well another control those with diastolic heart failure in red indeed had diastolic dysfunction leftward upward shifted and diastolic pressure volume relationship but there's more you see we also decided to characterize the end systolic pressure volume relationship and as you can see in red it is also steeper compared to both controls so there's systolic stiffening there's also enlargement of the left atrium increase in the end diastolic pressure nitrated peptides are increased and then if you go even more Upstream guess what even the pulmonary pressures are increased and in fact the prevalence of pulmonary hypertension in these patients is more than 80 percent so how does this all come into a picture well it's still pretty neat so far so what we have is by solid dysfunction there's increased left ventricular feeling pressure leading to lead natural hypertension the hypertension gets reflected backwards into the pulmonary circulation so there's primary venous followed by pulmonary arterial hypertension nice and neat but unfortunately there's a glitch and that's because in Olmsted County at the same time Dr Redfield showed that there is diastolic dysfunction even if you don't have heart failure and this is especially in elderly persons in the community and patients with cystolic heart failure have even more diastolic dysfunction so diastolic dysfunction is neither sufficient nor specific for diastolic heart failure and so that's why we decided okay maybe we should move away from this name of diastolic calculator implying that it's only because of diastolic dysfunction and why don't we name it something that focuses on its normal systolic function but the question is is systolic function normal so this entered many papers during that period you can co-look it up and it offered me a bit more room to do a bit more clinical research so we decided let's look at systolic function using knit wall fractional shortening by echo in these patients and we found that stress corrected midwell fractional shortening or a measure of contractility was actually reduced in half Nest compared to the other controls so despite a preservation of global ejection fraction at the myocardial level that is contractile dysfunction and you know what strain studies now show that and so on but what it says is I don't think we can use this term because this bullet function is not normal in at least some of these patients and hence came this term kind of non-committal really heart failure with preserved ejection fraction or have pet now this was originally coined in charm preserve it's almost an exclusionary name to refer to patients who did not have frankly reduced ejection fraction so it actually referred to Heart theater with anything more than 40 percent of an EF okay so I'm gonna go with that flow and use that term for now knowing that now it's got split even further but let's carry on because the nice thing is this prediction that half path would become the dominant form of heart failure as you can see that last year is 2020 turned out to be absolutely true and thank goodness because there's lots of skepticism from where I came from and so in the 2010s what were you doing all right I do confess I was into Gangnam Style and all those of you laughing were also obviously into it as well but I was also digging the new guidelines because look here now diagnosis of heart failure has half rep and half pet which to this days it looks a bit simplified because now as you you may know we've got more kinds than just these two but in the 2012 guidelines it still said no treatment has yet been shown convincingly to reduce morbidity and mortality in these patients now it was not for want of trying and what we did initially is apply all the therapies that had been proven in half breath and just try to extrapolate it to have pet and these were things like as you see I preserve pep CHF transfers of these were arbs seniors was beta blocker digitals of course digoxin and as you can see all the primary outcomes crossed the line of unity they were all neutral trials well how about a silver lining that we learned what not to do and that is to Target the nitric oxide cyclic GMP pathway at least in the ways we were doing so far now where did this idea come across well it was from really really classic papers and this is from Walter pollicis group mainly let me just explain it simply this paper is so beautiful because it actually takes human biopsy samples comparing half red have passed and then a pure obstructive model of aortic stenosis okay and as you can see myocardial Nitro tyrosine is an indicator of nitrosity stress so you can see nitrusted stress is highest in heav even higher than half ref and associated with very low cyclic GMP in The myocardium compared to the both other control comparator conditions and as a result the PKG protein kinase G activity which is Downstream of cyclic GMP was also reduced and this leads to fibrosis and different ways that Titan is phosphorylated which can then lead to stiffness of The myocardium so this was thought ah it's it's the access to Target so how did we do it okay well first why not give the patients lots of nitrates and inorganic nitrites because that's the stuff that causes um in the absence of wish means that one of these psyches cannot produce cyclic gmk so give the patients more of it enable more production of cyclic GMP why not directly stimulate soluble guanylate cyclase or prevent the breakdown of cyclic GMP by giving phosphodiesterase five inhibitors can you imagine what a great story that would be Viagra to counteract stiffness however none of these trials were positive why well I think we only really understood it recently and this is a very important paper I think it's from Joseph Hills group published in nature where finally there was a small animal model of have pef that more recapitulates the human situation so it is a multi-hit model um so that these patients really have a metabolic inflammatory type of rather than the transverse aortic constriction model which frankly is a hypertensive model of heart failure rather than this multi-system have pep model and I know that this is very consistent with large animal model work happening here at thi so this is really exciting but this showed us really convincingly that systemic inflammation and finals activation nitrogative stress and so on really are the drivers of hepath and so rather than nitric oxide inducing approaches we should be focusing on reducing the activation of inos and perhaps focusing on anti-inflammatory approaches and you know I I will be glad to elaborate but they are now very very interesting molecules in early phase testing of anti-inflammatory approaches one such is a myeloperoxidase inhibitor um that is being tested right now in a phase two trial and there are other very exciting ones coming up very similar to what is happening in the atherosclerotic world with the interleukin-6 inhibition for example with ziltovic command and so on so it's a very exciting area however in the meantime please let me catch you up on what I've been doing and so went back to Singapore started a observational study across 11 regions in Asia of patients with symptomatic heart failure and so in the next few slides can I please share how Asian patients were a little bit different from what I've been seeing so far in the U.S first of all Asian patients with manifest heart failure were strikingly younger and this really really pains me because we had patience with average age here would be much older in the 70s and 80s was in the 60s and in fact we had a very young heptath phenotype and when I say that I mean people less than 55 years old having again symptomatic have pef I'm not saying some kind of subclinical or pre-clinical no presenting already with decompensated symptomatic have pet and you know who they were interestingly they were obese male so very different from the hypertensive elderly women so that was interesting and in case you're thinking ah she must have made some kind of wrong diagnosis and this must be just decompensated deconditioned gentlemen well we compared their outcomes and their echocardiographic characteristics with age match controls in our community and the death rate in these patients was much higher and there was absolutely objective evidence of cardiac structural and functional abnormalities in these patients so it's real have pet but the younger patients tend to be obese just keep that in your mind now what else did we find now yes we did have some obese related Health path but in general guess what Asian patients were actually skinnier than the U.S counterparts oh okay no one's surprised but when we compare them even to the European counterparts from the Swedish heart failure registry it's really striking to me that if you compare regardless of or half rep and compare the amount of diabetes we have way more diabetes in our Asian cohorts of heart failure compared to the white patients and at any given BMI and you can see our strata go down to less than 20 and they go up to more than 30 we do not have any above 35. that's the range right look how much diabetes we have it's almost 60 so there is a correlation that with a higher BMI you get more but they are all rightly lean so we call this the lean diabetic phenotype of heart failure but what I'm getting is when we used machine learning so this is a technique called clustering to look for patterns of half path among our patients three emerge which I already described there's the elderly atrial fibrillation cohort and in our Asian HF these tended to be interestingly patients from Japan and Korea some of the oldest populations in the world then there was the obese metabolic and you can see Singapore is unfortunately well represented there and these really really were similar to what we'd seen described and increasingly more in Olmsted County here in the U.S and then there's the lean diabetic which really was quite unique and among all three the ones with the worst prognosis were the lean diabetics they had a lot of chronic kidney disease so just just an interesting another phenotype but the significance of all of it is it's really opening the door to phenotype specific treatment I mean it cannot be that an elderly hypertensive is treated the exact same way as an obese metabolic even though the symptoms and manifestation of the syndrome is the same and in fact this sort of phenotypic specific approach is an nhlbi research priority now and if you look at the trends of Trials it is heading that way we have trials now targeting obesity there's the summit trial the step petrol and these are with things like the glp-1 receptor Agonist or the combined glp-1 receptor administers appetite there's trials targeting have pet patients with inflammation so with a CRP level above something and so on so I think we're heading towards that okay but just one last word about the Asian phenotype now okay so in this lean diabetic and all this this stuff does the Obesity Paradox still exist in our Asian patients so let me first describe what the obese Paradox is it means that obesity is a risk factor to get heart failure we know that right but when you have heart failure obesity protects you from outcomes that's the Paradox and so when we looked at it in Asian HF we indeed found that obesity defined by body mass index on the x-axis if you look here on the x-axis with the probability here is adverse outcome cardiovascular death or heart failure hospitalization you can see that as body mass index increase the risk of adverse outcomes decreases that's the obese Peridot so guess what it still exists in Asian heart failure patients however if you now change the metric to waste height ratio have you ever seen anything so opposite the higher the waist height ratio the higher the risk of an adverse outcome so this immediately got us thinking okay it's it's got to be something about fat distribution right Central adiposity and currently there's a lot of work going on in that area we've got a review coming out in cardiovascular research focusing on this but to summarize it the thought process is first of all Asian patients may look skinny on the outside but we could be really fat on the inside and it's visceral adiposity that seems to matter and as you can see it is the patients with the lowest BMI but the largest waste that do the worst so it's the kind of lemon on sticks type of appearance if you can just think about that but it also made us think is it visceral adiposity rather than subcutaneous so is it the fat even close to the heart that could be playing a part and so we looked at it and we did this by Echo as well as by MRI and indeed found that epicardial fat thickness is increased in heppev compared controls but didn't in half ref compared to controls and again I'm sorry it's quite hard to see but just notice that in all the grass lines are crisscrossing totally different directions well each line one is and one is half ref and in each of the x-axis it's increasing epic cardio fat thickness all of it summarizes that there's very Divergent roles of these two things in half breath and have pet increasing epicardial fat is associated with more that ventricular dysfunction by Echo more fibrosis by MRI in her theft but a completely opposite um relationship in half ref Dr puglies at all took it further and looked at outcomes and here you can see with eat is epicardial adipose tissue please look carefully because you might pick these graphs look the same but they're actually the complete opposite right and have path patients who do worse are those with thick epicardial adipose thickness in half-ref the ones who do worse are the thing thin epicardial adipose so this is exactly what we've seen so there's a lot of people writing about this now but it it leads us to the hypothesis that excessive epicardial fat it's not just the quantity but the quality and we think that in hectare it's slightly dysfunctional secreting some pro-inflammatory factors whereas in have breath it might be playing a physiologic role maybe like a nutritional source for example and so the less you have of it the worse the the person with kefirm is doing so very intriguing obviously because it might open the door to therapeutic approaches which I will now try to elaborate a little bit on but the hypothesis is it's it's really it's been written about by luminaries Like Walter paulus Carson shoe Milton Packer the whole idea being a systemic systemic inflammatory in Hep have results in microvascular inflammation affecting throughout the body but also in the heart and the epicardial fat is also dysfunctional and inflammatory and may even be a transducer of that inflammatory Parts into the heart into the micro vessels and that in turn leads to Downstream increased fibrosis diasolic dysfunction and so on where is the evidence for that well here's where it's good to have good friends and so I'm really proud of this study because me sanjisha and Lars learned um we were all sort of fellow fellows at the same time and we decided hey let's get together and let's prospectively look at microvascular dysfunction in HEPA as U.S Europe and Asia and so we did this in the promise FPS study really interesting way of looking at coronary microvascular dysfunction if you don't mind me elaborating it's actually by Echo did you know that you hold the probe in a good enough way you can actually probe the left anterior descending artery by Echo so anyway we did this multi-center did it and found that the vast majority or prospectively identified patients with HEPA had coronary microvascular dye function but very importantly coronary microvascular dysfunction correlated with evidence of systemic microvascular dysfunction particularly involving the kidneys and so it is directly related to urinary albumin creatinine ratio and albuminuria now we just bear with me one more data slide because we said okay we've seen this but let's show it again with some fancy proteomics and so we did these old link panels and looked at 248 circulating proteins and on the simple story it's just that we found that circulating proteins indicated inflammation in these patients but we also showed that they mediated the effect of comorbidity burden and what we were seeing in Echoes the echocardiographic structure and functional abnormalities so what we're trying to sort of tie up the story in a human cohort that this is really evident supporting that inflammation leads to microvascular dysfunction and leads to the cardiac dysfunction that we see it's what we as good as we could in in a prospective study like this but the final thing is how does it impact treatment right and so if we identify that as potential treatment this is what Milton Packer also wrote about that these drugs might inhibit epicardial adipose tissue accumulation and inflammation and as you can see there are many of these medications that have or are currently even still being tested the mayoral corticoid receptor antagonists by the way are ones you should look out for and coming out very soon I I suspect in the next few years um the spirit Trials of spironolactone in pragmatic trials will read out soon and we now are looking at non-steroidal Mineral corticoid antagonist phenerenone is being tested in a trial called Fine Arts and if you if you're interested please write to me because there is also evidence that sglt2 Inhibitors directly reduce epicardial fat and epicardial fat inflammation uh in in hepat so it's it's a it's a nice story it's not the only way sglt2 Inhibitors act but it's enough for me to tell you a little bit more and Joe here's the here's the family picture of how I was productive in more ways than one in the 2010s 2015 that's that little booger my son Jordan that's also Jordan but his birth also meant that our second daughter became a middle child now it was um frankly at a bar uh in one of those meetings where the most productive conversations occur at the bar that's called Solomon and I decided hey you know what we should write a piece about the middle child of heart failure the ones with ejection fraction between 40 and 50 because at that time the oldest child have rev right heart failure with ejection fraction less than 40 percent got all the awards in terms of all the positive huge trials the youngest child then defining guidelines as ejection fraction of 50 or more was getting all the love and the middle child got nothing in fact in guidelines it was variously called the gray area the borderline the and well I'm just grateful that in 2016 that yes he guidelines in fact called in part failure with mid-range ejection fraction but notice these guidelines actually grouped treatment recommendations of health and heart failure with mid-range ejection fraction together saying that we don't know what to do but the guideline writers had a lot of foresight in saying as new data and analyzes become available it might be possible to make recommendations for each phenotype separately now what this guidelines did though it had inspired everyone to look at their databases that contained patients with ejection fraction between 40 and 50 so when we looked at this retrospectively in Trials we saw the same pattern now please get used to looking at this graph because I'll show another one later x-axis is ejection fraction across the entire spectrum of heart failure y-axis is treatment effect where if it's below one it means benefit of the drug compared to its comparator like a placebo so you can see here um what's highlighted are the 40 to 50 percent range and you can see the treatment effect shows benefit in the charm program across the ejection fractions from lower through 40 to 50 but do become attenuated at the higher ejection fraction Spectrum so we're seeing that in charm and Top Cat for spironolactone with a beta blocker meta-analysis that same pattern but it was really in the Paragon trial that this became most most obvious Paragon trial was a prospective randomized trial of Arne compared to Valsartan in patients with heftep we narrowly missed the primary endpoint however what was very clear was there was a striking significant heterogeneity by ejection fraction and sex where it was women and those with an ejection fraction below the median of 50 percent who appeared to benefit from Arnie foreign T led a lot of people to say hey maybe 57 or 60 is the new 40 in naming what is reduced and I'm not going to ask you to guess which one of us is the 60 versus 40. but we did look at a sex stratified results in paragon and again these are the same graphs of rejection fraction the x-axis and rate ratios on the Y you can see that there is benefit in women across the lower ejection fraction up to about 65 percent whereas in men it's about 55 percent so maybe even 65 is the new 40 in women but a bit lower and then I'm afraid in case you think it was a fluke in Paragon when we looked at this in charm in the MRA trials and of course that was um Paragon and paradigm what you see is the same pattern women in red benefit across a wider ejection fraction compared to men so in women it attenuates at a higher ejection fraction which led us to this if the patients with 40 to 50 or mid-range ejection fraction are benefiting like those with more reduced ejection fraction we should just call them heart failure with mildly reduced ejection fraction so you maintain that acronym of Mr but introduce the term reduce so that clinicians can give these patients a benefit about to treat these patients with the same neural hormonal agents that work in those with more reduced ejection fraction in this same paper though we also call for sex specific cutoffs which means in women do consider that your elderly patient with an ejection fraction of 55 who's a woman already has a reduced ejection fraction and it makes sense because if you look at community-based data and normal data of echo parameters in women and men you'll notice that ejection fraction increases with age in healthy populations and is always higher at any given age in women than men why because rejection fraction is just a fraction and women are honor so our denominator which is the end diastolic volume is smaller I hope we have the same stroke volume because if not I might be Keeling over if my stroke volume is also that low and so with the same stroke volume and a smaller denominator my ejection fraction is going to be higher than joules if we have the same ejection fraction there might be something wrong with me do you see so if if we don't use such specific cutoffs we might be depriving many more women from therapies that could potentially work I feel very strongly about this um so thank you for letting me elaborate for a while before we enter the 2020s boy we entered it with a bang we had the first FDA approved treatment for at least some patients with hepath in the army we finally welcomed a new guideline that indeed called it heart failure with mildly reduced ejection fraction and included as 2B considerations the same neural hormonal agents that we that we talk about in heart failures with reduced ejection fraction like to show that the American guidelines were perfectly consistent however you will note a very interesting difference is that the American guidelines included as a two-way recommendations the sglt2 Inhibitors and did this recommendation not only for Hartford with mildly reduced ejection fraction but also for heart failure with preserved ejection fraction and that's because the ESC guidelines were published before the emperor preserve results came out and the American guidelines were published right after notice that in half path there's an Asterix in the demarcation for RNA MRA or ARB where it says greater benefits in patients would be of closer to 50 so that is accounting for those splines that you keep seeing that you may get benefit up to 60 you know it doesn't say it it just says more benefit if it's lower and closer to 50. but I'm just thrilled to be standing here to now say this is like I've been waiting my entire career to say that we've got an actual treatment or heart data with preserved ejection fraction and now we have not just one but two robustly positive outcomes trials and they are both with the sglt2 Inhibitors one is Dr goodblosen and the delivery trial and one is emphagliflozin in the emperor preserved child and as you can see with the combined endpoints of cardiovascular death a heart failure hospitalization there's a 20 relative risk reduction if we look at cardiovascular death there appears to be a 12 Trend in that direction and it's I think beauty is the eye of the beholder whether a 0.052 you're going to take as evidence of benefit or not and we'll see how the evidence the guideline writers take that but for me I mean it's pretty consistent that there's at least a trend towards benefit and then of course a market reduction in heart failure hospitalizations this has led Scott and I to write this this other piece that my goodness have we reached a stage where we now have therapies that work across the entire range of ejection fraction and yes I believe so but maybe we should not be that surprised because we do also treat the fundamental congestive state of heart failure with diuretics for example or the fundamental states of skeletal muscle deconditioning with Rehabilitation so there are things that we do regardless of the ejection fraction and we believe the sjlt2 Inhibitors fall there and then for those with evidence of left ventricular remodeling mostly evidenced by A reduced ejection fraction below normal whatever normal is Which is higher for women then please consider the neural hormonal blockers and so just to end uh what will we be doing next well here are my five predictions I think first we will continue to Grapple with nomenclature you heard me already emphasize heart failure with normal ejection fraction I think we should just be going reduce to normal reduce could be mildly or frankly reduced and normal should be defined with six specific cutoffs please we will be looking for treatable mimickers so this is very important treatable mimickers cardiacomyloidosis pericardial constriction hypertrophic obstructive cardiomyopathies because there are specific treatments that could cure these patients we still will be trying to understand the patients with a higher ejection fraction the ones that seem to have attenuated response and everything else and well I think there's a lot of Hope with this multi-modality profiling I know that there are plans to do that here in thi I'm so excited that you will be looking at that at least in the cardiogenic shock or in the stage D heart failures but hopefully in time also have a database because I think this is very very powerful and the way to go where it's proteomics and image if I may call imogenomics to try to understand the different patterns now I I hate to geek out here but this is something that we have um submitted and and I thought for this audience you might want to see what I'm we've been thinking so this is imogenomics simplified that that we try to do in Asian HF we tried to look at patients with heart failure with normal ejection fraction and split them up and try to get machine learning to see if there are different patterns and we believe this is what we're seeing if this is the pressure volume relationship of a control this ship where everything shifts that steeper is that older hypertensive we think that this is what's happening with that younger obese that it's it's actually volume expansion in those patients and that's what we should be looking at now we will continue to test new therapies I've already mentioned some of the medical therapies but would also like to mention devices that I think are really cool I mean we're starting no we we've been testing creating an atrial shunt between the left and right atrium to actually offload the atrial hypertension in half pet and I think there's a lot of potential for split neck nerve uh modulation and this especially in the obese have pet where perhaps increasing the venous capacitance so that the volume distribution helps these patients and those with volume overload in other words I think that that holds a lot of promise and finally of course we will find ways to facilitate the diagnosis now that we have an effective treatment and this is one such example thank you Jordan for mentioning it a little bit earlier but this is using AI for example to help even um GPS for example make the diagnosis of where it's point of care Echo where you have ai to guide the acquisition and you have a full report immediately produced with telling you putting all those scores and guidelines together saying it's a high probability of have all of which is to identify the right patient at the right time for the right treatment so thank you very much for letting me share this story and I'm I'm just really really thrilled to be here and thank you very much for your attention