 It's always somewhat of a, I guess of a enigma of a diagnosis to make and hopefully, you know, can clarify a few things as far as the pathophysiology as well as phenotyping heart failure with preserved ejection fraction. So in general, heart failure is a epidemic, as you all know, and affects 8 million people in the United States by 2030. The healthcare costs are going to skyrocket for HFPEF, and currently in 2012 we're spending about $21 billion for heart failure, and by 2030 it will reach $53 billion. And HFPEF, or heart failure with preserved ejection fraction, accounts for 50% of heart failure in the population in the U.S., and it's growing by about 10% per decade. And the five-year survival, despite it being different than heart failure with reduced ejection fraction, is still poor up to 50%. So first of all, we have this diagnosis of HFPEF versus HFREF, and HFREF is heart failure with reduced ejection fraction. So what distinguishes these two entities? So what distinguishes these two entities? So first of all, HFREF is classically defined as heart failure with an EF less than about 40%. HFPEF, EF greater than 50%. In clinical studies, the area between 40% and 50% has been variable, and in some clinical trials they included 40% to 50% in those patients who had HFPEF as well. And one thing that I'll reemphasize is that diastolic dysfunction is not invariably present in all patients with HFPEF. So if you see a echocardiogram that diagnoses diastolic dysfunction, it doesn't necessarily mean this patient has HFPEF. So other characterizing, other differences with HFPEF versus HFREF, one is age. And these patients with HFPEF tend to be older, and as Dr. Coulter pointed out, these patients with HFPEF tend to be predominantly female. They also tend to be hypertensive and have high frequency of comorbid conditions, including obesity, metabolic syndrome, renal dysfunction, and anemia. And at this point, there is a lack of targeted therapies for HFPEF versus those patients with HFREF, where we've got 30, 40 years of clinical trials that guide our therapy. If you look at it from a macroscopic point of view, the patient above or the sample above is from HFREF. What you see is ventricular dilation. You have relatively lower wall thickness relative to chamber radius. So you've got a dilated LV. You've got higher filling pressures, and that subsequently leads to increased wall stress and higher BNP releases. HFPEF on the bottom tends to be characterized by concentric remodeling, as well as normal chamber size. And these patients tend to have lower BNP levels than HFREF, however, they tend to be elevated. So epidemiology, we kind of spoke about the rising sort of epidemic of heart failure as well as HFPEF. And we can see here, as with the slide here, heart failure projections into 2037 look like they're steadily increasing, mainly due to the aging of the population, as well as the increased prevalence of comorbid conditions such as obesity and hypertension. And if we look, the prevalence of heart failure increases with age, and elderly females will be more likely to develop heart failure. If we look at discharges for heart failure, they have been steadily increasing over time. And again, so far we have no trial that's demonstrated efficacy for HFPEF. And in this small cohort of patients who had heart failure, we see that those patients who had those patients with heart failure that were admitted, who were women, predominantly had HFPEF. So if we look at some of the temporal trends here, this is from the Mayo Clinic study. And this was sort of their initial, probably large, epidemiological look at HFPEF. And this was an article published in 2006, and that showed sort of the steady rise in heart failure with their dejection fraction over a six-year period in Olmstelle County. And on the slide over to the right, we can see that those patients, over that course of time, those patients in the black who had reduced dejection fraction had decreased mortality rates whereas those patients who had preserved dejection fraction had increased mortality rates. And the mortality with HFPEF versus HFREF tends to be very similar. And this shows that over time that these patients with HFPEF here really had no change in their overall mortality from 1987 to 2001. If we look at a more contemporary study here that looks at patients all the way into 2010, we see this ongoing increase in the amount of HFPEF. However, there may be a slight improvement in mortality, mainly due to a recognition of comorbid conditions. So what is the pathophysiology and phenotypic substrates that define HFPEF? And I think this is to emphasize that we see a lot of patients here with diastolic dysfunction characterized by impaired relaxation, increased LV filling pressures, decreased compliance. And then we see these patients who have heart failure or preserved dejection fraction. So again, diastolic dysfunction may be found in 70% of persons older than 70. However, those patients who have HFPEF about a third of those may not have actually distinct TTE abnormalities. So when we use the term diastolic heart failure, I think we have to be very specific about those patients that have HFPEF who also have echocardiographic abnormalities as well. I think one of the growing things that is being recognized is the importance of inflammation in HFPEF. And what you have is sort of some underlying condition, these comorbidities that include obesity, type 2 diabetes, hypertension and renal insufficiency. All of those lead to increased inflammation, including an upregulation of your cytokines marked by increased levels of CRP. And this inflammation or this system-wide inflammatory response causes various derangements across multiple organs. And depending on your degree of involvement of various organ systems, that can define a particular phenotype of heart failure with preserved dejection fraction. So one is the lungs. Those patients may have frank pulmonary hypertension that occurs with HFPEF. Skeletal muscle disorders tend to be very key to HFPEF as well as exercise intolerance, renal dysfunction we see a lot. And then on the cardiac level and coronary level we see significant endothelial dysfunction that ends up leading to myocardial damage. So we can phenotype these patients on the basis of what's really driving their HFPEF. And I think some of these patients you'll see who may be younger have type 2 diabetes and are obese. These patients may need a particular sort of treatment modality. Other patients may have arterial hypertension, perhaps you're elderly female who has very difficult to control and very labile hypertension. And then there are those patients who have renal dysfunction as well as coronary artery disease as well that may require a different mode of therapy. So I think by phenotyping these patients we can think about how to effectively treat these patients. So leading to HFPEF then are multiple derangements. You get diastolic dysfunction, you spoke about that, you get extracurriate causes of volume overload including obesity, arterial stiffness, pulmonary hypertension, endothelial dysfunction, chronochopin incompetence, as well as autonomic dysfunction. So on the myocardial level you can see extracellular matrix abnormalities including increasing amounts of collagen, collagen type 1 disorder crosslinking. At the cardiomyocyte level you may see crossbridge abnormalities. Titan is a key protein that's involved in relaxation, mutations in titans can lead to familiar restrictive cardiomyopathy, but this may also be involved in disordered relaxation. Along with that you get decreased nitric oxide availability as well that causes further derangements. These patients, subsequently those patients who have increased fibrosis and impaired relaxation act differently than those patients with normal hearts and for a given amount of volume you see higher degrees of LVEDP, so higher wedge pressures. And this is a key characteristic for HFPEF. The other thing you can do is characterize the amount of fibrosis and those patients who have HFPEF may have increased fibrosis here and this is an MRI study that showed that these patients had higher degrees of fibrosis, they had more echocardiographic diastolic abnormalities and likewise on pressure volume loops they had further derangements leading to the HFPEF syndrome. The other thing that you can see here and this is something that you may see in patients who are elderly is ventricular vascular coupling or discoupling actually and what you have is that generally you have to have your mycardium keeping up with your arterial system and if your arterial system has higher afterload due to aortic stiffness, decreased compliance and higher SVRs, it may pose a higher afterload to an already deranged heart that can lead to pulmonary vascular congestion and exercise intolerance. Obesity is central and in heart failure, this is sort of a general slide looking at obesity and heart failure showing how adipose accumulation can cause multiple derangements including sleep apnea, increased circulating blood loss, all of that can lead to various derangements that include pulmonary hypertension, RV failure as well as LV systolic and diastolic failure. Obesity has been shown to lead to LV remodeling as well and we can see an increase in mass with BMI and the other thing that it can lead to is multi-organ derangements due to inflammation so in the lung you get a restrictive physiology, pulmonary hypertension, sleep apnea in the heart you can get lipotoxicity, increased afterload as well as preload. You can have hepatic derangements, increased cytokine release through visceral adiposity increase, renal dysfunction as well as skeletal muscle dysfunction as well. All of that in the end leads to worsening neocardous association class and worsening quality of life and interestingly these patients who are significantly obese, these are the patients that we see all the time in our clinic, they weren't readily included in a lot of these heff path trials so there's not a lot of data for these patients. So diagnosis, one of the things to think about is what is your differential for these patients? Maybe it's not heff path, maybe they have significant pulmonary arterial hypertension, maybe they have constrictive perigarditis. One of the things to recognize is maybe the presence of infiltrative cardiomyopathy and I think this is something that's been under recognized quite a bit is amyloid and we typically think of AL amyloid which is your myeloma type of amyloid that affects the heart but what's really been under recognized is this transthoretin amyloid and that's a mutation that's seen more and more predominantly in the population and that can cause a restrictive cardiomyopathy, you can have a familiar mutation of TTR or you can have a wall type senile form of it and these patients, it's important to diagnose these patients because if you diagnose them early enough you can always think about transplant but there are a lot of interesting therapies that are being looked at to treat this disorder including RNA interference drugs as well as various NSAIDs and although you can use MRI to diagnose it, you can also use endomyocardial biopsy to diagnose these patients, it's all over the place and two biopsy samples can diagnose amyloid. Dr. Coulter is much better of a person to talk about echo criteria so I won't spend a lot of time talking about echo but it's obviously the essential first step in diagnosing a patient who you think has half-pef after seeing if they meet the clinical criteria. We obviously look at various parameters as far as the echo is concerned. I know our guidelines change quite a bit but for those people who aren't cardiology based here you can look at mitral inflow, we can look at tissue Doppler imaging and using that criteria we can look at whether a patient has diastolic dysfunction or not and then based on those criteria and these are from the 2016 updates we can determine whether these patients have increased left atrial filling pressures in advanced diastolic dysfunction. So using these parameters we can get a sonographic idea of these patients in diastole. One of the other things to think about is the importance of strain imaging and a lot of these patients who have half-pef actually have a subtle systolic dysfunction as well that can be detected by strain imaging. Biomarkers tend to be key as well as far as the diagnosis of heart failure with preserved ejection fraction. BMP levels tend to be lower in those patients who have half-pef and that's due to the lower wall stress. Other biomarkers that may be important that we don't routinely check include those that may be associated with myocardial hypertrophy, interstitial fibrosis. Galactin 3 has gotten a lot of sort of study press. We don't use that typically in our practice but it's a nice marker of myocardial fibrosis. Other things that can be checked include inflammatory markers as well as those patients who have suspected coronary disease, high sensitivity troponin and based on these biomarkers you can help guide a little bit of your therapy. One of the things that's interesting if you have the capability is invasive cardiopulmonary testing and this is probably an underutilized method of diagnosing a patient who has exercise intolerance and dyspnea. Basically you get patients either on a treadmill or on a bicycle and measure oxygen consumption as well as carbon dioxide production as well. In addition to getting a sense of what their respiratory capacity or incapacity is, there are some other centers out there and this is actually some slides from Massachusetts General that look at invasive cardiopulmonary testing where you can actually get a full assessment of their physiology by placing a swan. This is a patient here who had dyspnea and had relatively normal resting hemodynamics on his right heart cath. With exercise actually they had a significant increase in their pulmonary arterial pressures as well as their pulmonary capillary wedge pressure. So all that emphasizes not only the importance of maybe some degree of exercise testing but also the importance of catheterization for these patients when you really suspect heart failure with preserved ejection fraction. This can be very key. We can look at those patients who have high PA pressures. We look at transpulmonary gradients. That's a difference between your mean PA pressure and your wedge pressure and in most of our patients with heft-path they will have values less than 15 millimeters of mercury. Some patients however may have very high pulmonary vascular resistance and these may again form another phenotype of the heft-path population that have significant pulmonary hypertension. But I think without getting into too many details catheterization for these patients can be very helpful and I think it's important not to just do resting catheterization assessments but to think about volume loading those patients especially those patients have been fasting since midnight and then doing exercise testing to see if they've got increases in their wedge pressures and their PA pressures. The other thing to look at is again carefully looking at the relation of your wedge pressure to your diastolic to your PA pressures and this is something that the pH group that used to be here emphasize this is diastolic pressure gradient and that's the difference between your wedge and PA diastolic and these can identify those patients who have pulmonary hypertension. So what are some of our therapies that we have for heart failure with preserved ejection fraction and the answer is not many. So these were a couple of trials that looked at angiotensin receptor blockers. The first was Charm and that looked at Candisartin. This was a negative trial that demonstrated no improvements in their primary end points with the use of Candisartin. A few years later, Ibrisartin was also evaluated in a multi-center multi-national clinical trial and that showed no improvement in patients with heart failure with preserved ejection fraction and I think you know part of the main large fallacy with these trials was that there was such a phenotypic heterogeneity in the patients that were enrolled in these trials. So you had a lot of patients that had different reasons to have heft-peft and I'll get into that in a second with another trial. So if we look at some of our other phenotypes before getting into targeted therapy, maybe we should look at things that we can actually fix and some of the things that the Mayo Clinic and other areas in Chicago have emphasized is looking at risk factors. So one is CAD and AFib. In this study they showed an improvement in revascularization in those patients who had heft-peft. So again emphasizes the importance of looking for coronary disease in these patients because keeping in mind that relaxation is an active process. Also those patients who had AFib tended to have increased levels of various biomarkers and worsening outcomes and although there hasn't been a big trial looking at restoration of sinus rhythm in those patients exclusively that have heft-peft, there are smaller trials showing that these patients will have functional improvements. As far as lung congestion is concerned we can look at diuretic therapy. That tends to be one of these obvious things that we come to mind but I think some of the things also is that our diuretic therapies may need to be looked at further. They're actually looking in the heart failure research network at the differences with loop diuretics. One is torsomide versus furosomide and it's thought that torsomide may actually cause a decrease in inflammation and urinal angiotensin axis up regulation. The other thing to look at is maybe the importance of cardiopulmonary rehab in these patients. This was a study at a JAMA. This looked at caloric restriction as well as aerobic exercise training in patients who had heft-peft and it showed that the combination of both actually significantly improved symptoms versus placebo or versus control rather. Other things, statins may reduce inflammation in small studies. One of the things that's always came up until about 2015 was that maybe we should use nitrates in these patients and actually in this study from Mayo they showed that these patients actually did not benefit from the addition of isosorbide mononitrate and they actually did worse perhaps due to a reduction in their stroke volume from increased venous capacitance. Nitrates are not quite effective in all heft-peft patients so you may reserve them for those patients who have CAD. Then how do we treat the fibrosis? One of the big trials that looked at this was the Topcat trial. This was unfortunately a negative trial. This was a multi-center multinational clinical trial that looked at the efficacy of spironolactone for heart failure with preserved dejection fraction. Their composite endpoint spironolactone didn't show any improvements. One of the things that came out of this trial was that again getting back to the eye-preserved and the charm trials is that the patients that are enrolled there was a wide variability in the patients enrolled. In this trial they actually looked and they found that the patients in Russia and the country of Georgia actually they got in just because they were short of breath whereas in the United States and the Americas they were enrolled primarily due to BNP levels greater than about 400 or so. In those patients who were in the U.S. they actually did better with spironolactone than those patients in Russia who those patients actually had mortality rates that were equal to the general population. When they looked at the BNP levels they found that in the eye-preserve study here which was a 2008 study that those patients who had higher BNPs tended to do better with iber-sartan. I think it emphasized the importance of really looking at these patients and seeing if they have volume overload, high BNP levels and fit a particular phenotype and you may consider some of these therapies that were proved clinically ineffective. So one of the sort of interesting things I guess exciting things in heart failure with reduced ejection fraction is neprolysin inhibitor inhibition and neprolysin is an enzyme that breaks down various vasodilatory molecules including BNP and in a large trial for heart failure with reduced ejection fraction this is a paradigm HF trial they found that the combination of all sartan and succubitryl which is called intresto led to clinical benefits in heart failure so much so that a lot of us are changing our therapies and no longer using ACE inhibitors as a first line for these patients. So then the thought is that will intresto help in patients who have HF-PF and they're looking at this in the paragon HF trial so we'll see what that shows if there's an improvement in these patients. And I think part of the enrollment in this trial includes BNP levels so I think it'll be interesting to see what the results are. Rounding out some of our therapies heart rate and heart failure heart rate tends to be a key thing that we tend to focus on with heart failure with preserved ejection fraction. In general heart failure is we know in reduced ejection fraction is a bad thing it causes worsening heart failure outcomes through various modalities. In a large retrospective trial they actually found that beta blockers may show a signal to improve patients with HF-PF but again this is a large retrospective look and we need prospective trials looking at beta blockers. Evabridine was something that also was somewhat exciting not quite as exciting as intresto and evabridine is a specific inhibitor of the sinoatrial node and it's been shown to be effective in heart failure with reduced ejection fraction in those patients who are maximally beta blocked and have heart rates greater than 70. They looked at this in small trials and conflicting trials and haven't shown any major benefit of this drug as well. One of the things that I guess I'm more interested seeing pulmonary hypertension patients is PA pressures RV function functional class and the higher your PA pressures are the worst you do. So sildenafil has been looked at for HF-PF and PDE-5 expression is up-regulated and failing RV so it's thought that in those patients who have significant RV dysfunction sildenafil and todalafil may be effective because it up-regulates or acts on cyclic GNP and can serve as an inotropin these patients in addition to pulmonary vascular resistance reduction. However in a trial from 2013 they showed no improvements with the use of sildenafil but again I think it emphasizes the importance of trying to characterize these patients a little bit more clearly by cath. They actually have pulmonary hypertension in addition to their HF-PF leading to their symptoms and maybe these patients sub-selected will benefit. Another drug that's being looked at is Riaseguat. It bypasses nitric oxide and works directly on cyclic GNP and there are ongoing trials looking at this drug. So finally we'd like to intervene on patients so what are some of the interventional modalities for HF-PF that we have. Well one of the big things that we're doing for HF-RF is cardiomems. This is an implantable PA catheter. It takes like 10 minutes to put in. It's pretty simple and it basically gives you a readout of the PA pressure and we've done this quite a bit in patients who are frequent flyers to the hospital for decompensated heart failure. The basis for this is that elevations in volume PA pressure is actually preceded from like one to two weeks any sort of heart failure symptoms so you can actually preemptively reach out to these patients, increase their diuretics and guide their therapy using PA monitors. In the champion trial they showed interestingly an improvement in mortality rates with the use of PA monitors and it's important to note that in this trial they actually included both HF-PF and HF-RF so these patients who have HF-PF who keep on coming to the hospital with heart failure symptoms, something to think about in these patients is cardiomems. This is interesting, this was something that, no they were doing in Europe, but this is a device that actually creates a left atrial pop-off and you implant this via transeptal approach and it basically gives you a one-way left atrial, right atrial shunt that actually unloads the left atrium and this was looked at, this was a phase two study showing feasibility, efficacy and safety of this device and we'll see in phase three trials if this may help patients both with heart failure with preserved and reduced ejection fraction. So I think finally to finish off it's important to recognize comorbid conditions, one is sleep disorder breathing and the fact that OSA and CSA is very central to a lot of patients with HF-PF. And there are no clinical trials looking at these patients although ADAPTIS servo ventilation which actually gives you ventilation at the time of detected apnea episodes actually has been shown to maybe improve patients who have systolic heart failure. Other things to look at are treatment of other things such as anemia, diabetes, renal dysfunction as well as obesity. So in conclusion, HF-PF is a growing epidemic due to increased prevalence of comorbid conditions that contribute to the system especially obesity, aging, hypertension and diabetes. Phenotypic distinction of HF-PF can guide therapy and then central to HF-PF may be inflammation and systemic effects. Echocardiography can help diagnose HF-PF but diastolic dysfunction does not equate to HF-PF. And there are limited therapies for HF-PF and I think it's important though that we try to phenotype these patients, look for some of the zebras such as amyloid and treat their comorbid conditions.