Good morning, everyone. Thank you for being here so early. I really appreciate your presence here. My name is Hector Cajigas. I am the chair for this session. And I wanted to use the first four minutes before the actual conversation starts to introduce the speakers. And we can actually have in sequence so we don't have to wait in between so you can hear them all. So the first speaker is me. But then we're going to have Dr. Veronica Franco. She is a professor at Ohio State University. She is a heart failure specialist. So this is a particularly good topic for her to explain to us. She has been in chess with us before. So she's very dear to our conversations when it comes to heart failure. So she's coming second. And third, we have Dr. Vidu Anand. She works at the Mayo Clinic Health System with us. And she will be speaking about echocardiographic and imaging studies. She is an excellent speaker as well, a very knowledgeable person in the field. So her specialty is imaging in the area of cardiology. So it's perfect for these type of conversations that we're going to have. And last but not least is Dr. Adriano Tonelli. He is a cardiologist who then trained in pulmonary medicine. So who is practically the ideal person who can treat or see pulmonary hypertension because he has the two specialties in this field. And he works at the Cleveland Clinic. So he'll come at the end to speak more about invasive procedures in the diagnosis of heart failure with preserved ejection fraction and pulmonary hypertension, which is a topic that we all have difficulties handling. So we have a stellar group of people to explain to you some of the aspects of this difficult condition. So I thought I was going to need more time to introduce them. So you guys need to do more things or tell more good things about you all. So no, but they are very accomplished people. So it's 6.58. So I think I'm going to start my conversation. So my topic is Locating the Problem in Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension. And we're going to do a quick review on what we already know. So what are we trying to learn today? So we're going to see some of the definitions, epidemiology, and the nature of this disease. The audience will try to learn or attempt to learn pathophysiology of the right heart dysfunction in heart failure with preserved ejection fraction and pulmonary hypertension. And we'll introduce some diagnostic techniques and monitoring options in this disease process. So let's start with the definition. Based on the latest guidelines that were published in 2022, pulmonary hypertension associated to group 2 disease or heart failure or left heart failure includes those who have a mean pulmonary artery pressure by cardiac catheterization of more than 20 millimeters of mercury and a pulmonary capillary waste pressure of more than 15 measured by invasive procedure. So now we divide them into isolated pulmonary or post-capillary pulmonary hypertension, which is the one that we see most commonly, which is the above measurements and the PVR less than 2 with units, meaning that we have direct transmission of the left-sided pressures into pulmonary vascular system. And we have the combined post-capillary and pre-capillary pulmonary hypertension, which is when we have the above. But our pulmonary vascular resistance is definitely higher or more than what we expect to see as normal individuals. So how common is this? So prevalence is a difficult thing to assess. So in the TopCat, which is the study that studied aldosterone antagonists in patients with heart failure with preserved ejection fraction was 36%. And then in Mayo Clinic follow-up study of three years found that the prevalence was 80%. So, and most recently data shows that it's actually more than 50% for sure. So in a retrospective database of 455 patients, when they met criteria for heart failure with preserved ejection fraction and pH, these patients, they were like the ones that we see in our clinic all the time. They were older, obese, diabetic, had COPD, atrial arrhythmias and their complaint was dyspnea on exertion. Who doesn't see those cases? So very common. IPC-PH or the one that is the direct transmission from the left side is more common than the one that has an elevated PVR, 60 to 70% versus 25 to 35%. But that also varies, depends on the study that you read, but definitely is more common than the actually who has an elevated PVR. Those ones who do have an elevated PVR more than two woods units and they have a high wedge, they have worse RV function, TR is more prevalent, they have more atrial fibrillation, they have worse hemodynamics and rest and with exertion. And obviously survival is compromised. Those patients with heart failure with preserved ejection fraction who do have pulmonary hypertension, they do have a worse survival. And this is a prospective follow-up three-year study that is older now, 2009, but it continues to be quoted over and over because this is the only one that has actually told us the survival just by echo measurements. So let's talk a little bit about what the problems are here. So the first screen of the first picture up there shows the transmitted or the normal circulation. So normally we're able to accommodate very high levels of volume in our pulmonary circulation. But then when we have problems in the left side, as we see in the middle graphic, we start having changes in the walls of the vessels and we start having some degree of abnormalities in the pulmonary circulation that causes some stress failure of the alveolar capillary junction. We start having pulmonary edema. We start having these patients with decreased diffusion capacity when we try to measure the pulmonary function testing. We see inflammatory mediator changes. It's well demonstrated that we have increase in endothelin-1. We have a decrease in nitric oxide. We start having more fibroblasts. So we have a continuous, continuous pressure into the areas that normally are not affected. And we start having this growth of organization of areas in the interstitium that creates also neurohormonal activation, thickens the alveolar septal. The decrease in the left atrial compliance is gonna lower your pulmonary artery compliance and increase your pulmonary pulse pressure, which is never welcomed by the right ventricle, and increasing the pulmonary vascular resistance. Your lymphatics are gonna engorge and then you're gonna start having the actual backup system pressure when you start having that remodeling. And why remodeling is important. Everything that I'm telling you about the fibroblast proliferation, thickening, and so on has been proven. And we have this study that showed that lung specimens of patients in autopsy or biopsy who has heart failure with preserved ejection fraction with pulmonary hypertension, they were compared to those ones with reduced ejection fraction and those ones with pulmonary venal occlusive disease. You know, pulmonary venal occlusive disease became a little fashionable since it's understood a little better, but it's a bad disease to have. So in the first two pictures on top, those are a normal artery and a normal vein. And then following, we have a patient with heart failure with preserved ejection fraction and pulmonary hypertension, artery and vein. And on the bottom, we have those patients with PVOD. So what it was found in this study done by Maggie Redfield at Mayo Clinic that vein remodeling is more prominent in heart failure with preserved ejection fraction and more severe than what we see in arteries. So we start seeing that the severity of pH correlated more strongly with venous remodeling. And it's understandable because it's the first line of defense. It's where the pressure ends up first and it causes more damage. So it's called almost like a functional PVOD. So you don't get to have the same degree of severity that we have in PVOD, but actually has a lot of pulmonary vein involvement. Now, the pathophysiological cascade for heart failure with preserved ejection fraction and pH is very logical. So we have a high pressure system and that VLV diastolic dysfunction with left atrial hypertension starts to increase the pressures to the point that we end up with the postcapillary pulmonary hypertension. So this is really not a lot that we don't know already from this perspective and the changes that I explained to you. But what happens with exercise? And we talked about this all the time about we always test our patients in baseline resting state. And often we don't find actually this diagnosis. And I think it's very important to understand that with exercise, we have serious changes in the vasculature. So if we start with somebody who has an increase in left atrial pressure because they have heart failure with preserved ejection fraction, and those patients have already some chronic backward transmission if we look on the left side. So you're gonna increase your pulmonary vascular remodeling, pulmonary vasoconstriction. Then you are actually gonna decrease your pulmonary vascular reserve. You're gonna increase your pulmonary pressures. And when you exercise, you're gonna try to increase your venous return, but you're gonna have difficulties getting that worked into the circulation. So if we look down in the three arrows down there, so when you have left atrial hypertension, you're gonna increase your LV feeling pressures. You're gonna decrease your preload to the LV. You're gonna decrease your LV stroke volume. And then when we look into the left side or right side of this slide, when you go into the development of right heart remodeling and dysfunction with exercise, you're gonna increase your congestion. You're gonna decrease your RV systolic reserve. And then you're gonna decrease your RV stroke volume during the exertion. That without counting for the increase in ventricular interdependence. And that's a term that cardiologists use a lot, and I will try to explain a little bit more as well. But all that actually turns out at the end that we have this exercise intolerance with a decrease in VO2 or oxygen consumption. So it's a multifaceted abnormality that we have in these patients with this type of disease. So now what is this pericardial constraint concept or this concept of increased ventricular interdependence on LV transmural feeling pressure? So now let's think of this chart and this is a study that was done very nicely by Barry Borlaug there at Mayo Clinic. So there is a moment that our right atrial pressure can increase so much, even though we can have a pulmonary capillary waste pressure that is very high, that it almost equalize. And as you understand, the pericardium is not a very flexible structure. So there is gonna have some restraint. And the upper right shows the relationship of pericardial pressure with right atrial pressure. So it has been considered that measurements of right atrial pressure correlate very well with what we call pericardial pressure. So when we actually calculate our LV transmural pressure, which is the difference between your capillary waste pressure and your right atrial pressure, in the two pictures in the bottom shows when the RV is very bloated, it's gonna push into the LV. And that is definitely gonna decrease your transmural pressure. And that is gonna decrease your LV stroke volume. So that's why even if you see in graphic C, when they are very high, the right atrial pressure approximates your pulmonary capillary waste pressure, even small reductions with diuresis of right atrial pressure is gonna decrease your waste pressure as well, improving your transmural pressure. That's one of the principles why diuresis is so important in these patients, because you are gonna find that your transmural pressure for the LV will significantly increase. So it's gonna be able to have a better LV stroke volume. So that's one of the things or one of the rationales where we have to always think about when we have these very high right atrial pressures, how could this be affecting adversely these patients too? So what about those patients who have latent disease? This is a relatively newer concept or has been entertained more about what about those patients who have a normal PVR or relatively normal PVR, but then you exercise them. And these are all heart failure with preserved ejection fraction. So it was noted in this Italian study of not many patients, but they found that about 21% of patients who actually had a diagnosis of HF-PEF, you put them to exercise and they increase their PVR more than 1.74, which by another study was noted to be significant to change survival. So even increasing a PVR of more than 1.74, it was found that those actually have a worse outcome. So those patients are common. So they could have a normal wedge pressure at rest and PVR at rest, I'm sorry, a high wedge pressure and normal PVR at rest, but you put them to exercise, their PVR goes high. So what happened with those patients? They do worse. These patients actually do have a worse cardiac output when they exercise. These patients, PVR tends to increase over time. And more importantly, these patients actually do have a significant decrease in stroke volume and cardiac performance. They have also higher dead space ventilation as well. So even though, again, they may have a high wedge and they have a normal PVR at rest, you exercise them, they increase their PVR, and these patients, and it doesn't have to be much. It has to be just 1.74 when they have all these abnormalities and this study did demonstrate the survival of those patients is definitely lower than those patients who don't have this latent pulmonary vascular disease. So it's important to recognize them. So at the end, how do we get to have right heart failure when you have actually heart failure with preserved ejection fraction? So there are many reasons, but again, preload, afterload, and contractility. We always talk about that when we talk about heart failure. So preload-related mechanisms, often atrial fibrillation that actually makes a change in your preload mechanism, the degree of tricuspid regurgitation, we underestimate what TR means for these patients. It's very significant as well, and many of these patients should be looked at into tricuspid repair system if it's possible as well, if they are candidates. So they do have a dysfunctional preload. They have a dysfunctional splaconic vessel accommodation of fluid. Majority of us were able to move our splaconic volume easily to accommodate for needs of increased cardiac output. These patients actually have abnormalities in that as well, and they have dysfunctional preload. And then we have the afterload-related mechanisms that we're talking about, the increased pulsatile load that actually is from the left atrial hypertension. You do have the remodeling with increased PVR, and then at the end, you end up decreasing pulmonary artery compliance that ends up affecting the RV. But who has this? And we talked about this, that most of these patients with heart failure with preserved ejection fraction, they have absolutely different biological phenotypes. They do have significant disease processes, and heart failure itself is not known yet to be a reason or the cause, or end up being the effect of having many other conditions. So they do end up with a skeletal muscle dysfunction, peripheral vascular dysfunction, they're obese. They have other abnormalities that you know very well because you see this in your daily practice. And we know that many of those comorbidities by this BC slide shows that overweight, obesity, hypertension, diabetes, and so on, increased inflammatory mediators, increases reactive oxygen species, decreases nitric oxide, and ends up causing a lot of the endothelial abnormalities that we see in PAH. You don't get to have PAH because it's a completely different disease from that perspective, but all these abnormalities in the milieu of patients with heart failure with preserved ejection fraction are present. Now, how we diagnose? I think in the 2019 guidelines, they just tell us who can have a high probability of heart failure with preserved ejection fraction and pulmonary hypertension. And I think this seems quite obvious for all of us. Older people has a high probability, obesity, hypertension, hyperlipidemia, diabetes. If they have a prior intervention, atrial fibrillation, if they have a structural heart disease, again, we're gonna hear about echocardiography, exercise studies, and even cardiac MRI. So you can have a collection of tests that can put you in a very high probability for that. And if you have a high probability, then you're gonna manage the left heart disease. Still, we are gonna hear about treatments, how to manage this with Dr. Franco in a few minutes. But if you don't, if you have intermediate pre-test probability, you are supposed to move on into the right heart cath, and Dr. Tonelli will tell us much more what to do with those cases. I will not speak about what to do with the right heart cath because that would be his thing. Now, therapy for heart failure with preserved ejection fraction, and that is a blank slide, and I would stay blank. And I don't have anything to tell you there because it continues to be that way. It's sad because it's such a pandemic to have this condition, and we don't have anything to offer. But we have ways that we could use, things that we don't do on a regular basis that we should be doing more in your programs, in your facilities, if they have the ability to use cardiomems, which is the implantation of the pulmonary artery monitoring. This has actually demonstrated in studies prospectively that actually reduce hospitalization up to 46% of patients with heart failure in general, and including those ones with heart failure with preserved ejection fraction. And when you study the pH subgroup of the champion trial, which is the figure on the right, it still does show that the hospitalizations related to heart failure decrease. So I don't know why we don't use this more. Then after a year, they noticed that in 2,000 patients, they did notice that actually this continues to be present in those patients who use the pH monitoring. So push your institutions. This requires resources, but it's actually a good tool to use, particularly to try to decrease those wedge pressures in those cases. Because, for example, we can have the option of this small study that was relatively recently studied, like Entresto in heart failure with preserved ejection fraction and pH. And they use in this case, for example, if you can see in that graph right here, when they use pre-medication with cardiomems, that's what they use, the same monitor I told you, they saw a decrement in pulmonary pressures in weeks of using the medication, and then going up in weeks that they didn't. So we may actually use this tool also to understand if any treatment could be a little helpful. So we can say the heart failure with preserved ejection fraction and pH is a morbid state, high mortality, high cost, epidemiological concern, but the physiology is still evolving, lags behind other areas of study in cardiology, I have to tell you that. The number of failed trials frustrate the outlook of this disease, and particularly when we try to use other pH drugs. But it's important to get the phenotypes or genotypes figured out. Thank you. Well, thank you very much. I want to thank the organizers for inviting me to discuss this very important and concerning public health problem. Currently, heart failure represents the number one cause of hospital readmissions in the US, and the number one cause of admissions in those above 65. 50% of those patients admitted have a normal ejection fraction, therefore, meet that definition of HF-PEF. And so this is really important in likelihood. You've seen these patients on your practice regularly. I'm going to start with a case, a 78-year-old female with a past medical history of hypertension and diabetes. She has had progressive shortness of breath to the point that it's difficult to do some of her activities at home, and has been admitted twice already in the last six months. She's been treated with a calcium channel blocker, a diuretic, and metformin. Her testing is really unremarkable, other than the presence of left ventricular hypertrophy and left atrium enlargement, both hallmarks of HF-PEF. We did an exercise study, and she was very limited, only able to exercise for three minutes because of significant shortness of breath, and no ischemia was noted. She also had no coronary artery disease. So as Hector mentioned, our next step was to do a catheterization, particularly because of her advanced symptoms and two recent admissions, which was very concerning. As he mentioned as well, her hemodynamics and feeling pressures were normal at rest, and the cardiac index was just slightly reduced. But when we exercised her, we noticed a significant increase in the pulmonary pressures, as well as the wedge, which are both hallmarks of HF-PEF. These patients are very difficult to diagnose, and I do encourage you to use cardiomyems or write her cath, because most of the time when we check hemodynamics at rest, they're really unremarkable. I do have to say, we have several treatments, really good treatments for patients that have reduced ejection fraction, including medications, surgeries, transplants, LVADs, but unfortunately, all those therapies have shown no benefit in patients with normal ejection fraction. We have study patients with ACE inhibitors with no significant improvement in mortality as well as heart failure hospitalizations. An improvement in heart failure hospitalizations is one of the main things we look for just because, as I mentioned, this is the number one reason for readmissions. Similar resource were found with angiotensin receptor blockers in two studies. Now this study over here is very important that we notice. There was a sub analysis of the CHARM preserved study because they noticed a trend to improve outcomes. So they did a sub analysis and they found it that candesartan improve mainly heart failure hospitalizations. And the p-value that they found in this adjusted hazard ratio was 0.051. So definitely a trend into the reduction of heart failure hospitalizations but not clinically significantly. So I'll come back to that in the next few slides but I just want to point that out there that there was some trend to improvement. We also evaluated mineralocorticoid receptor antagonist in the Topcat study and again no significant improvement in the primary outcome of mortality or heart failure hospitalizations. Initial studies with beta blockers show improvement in terms of mortality but it's important to know that these patients had all coronary disease. So probably some of that improvement that we saw in mortality was due to the coronary disease more than the HFPEF because when we did subsequent studies on beta blockers the studies were negative with no significant changes. So when the guidelines came up in 2013, the only medication that had a class 1 indication was really just diuretics. Very, very important. I agree with Hector to have the patients at uvulemia. And this is very, very hard to treat because there are normal arrests but then they increase their wedge when they're exercising. So how do we treat that without causing hypotension? That's why it says here if there is volume overload. These patients have very narrow diuretic window where they can easily develop renal failure. So it's a thing that we constantly evaluate in clinic and we probably need to check them frequently because diuretics are very important but they also can go to the other side very easy. Very important as well to control comorbidities, particularly blood pressure with a goal systolic blood pressure we say now around one less than 130 as well as obviously revascularization, control of ischemia, and atrial fibrillation with restoration of sinus rhythm. The beta blockers, ACE inhibitors, and ARBs were mainly recommended for patients with hypertension. So the guidelines recommend that if you have somebody with hypertension and HFPEF, if you're going to decide what diuretic to use, use one of those. They were not really recommended per se for HFPEF. Out of desperation because we really didn't have any other medications, the guidelines had a class 2b recommendation for ARBs, mainly because of that study I show you on the chart preserved that show a trend to improve admissions. Subsequent analysis of the TAPCA study showed that there was a four-fold difference in outcomes between the Americans and those patients enrolled in Russia and Georgia. So they did a postdoc analysis to analyze those two groups separate, and actually they found significant improvement in the outcomes of cardiovascular mortality and heart failure hospitalizations for those patients treated with spironolactone. So that was very promising. Again, this is a postdoc analysis. We were looking for anything to help at this point, so we also evaluated PDE5 inhibitor. Sildenafil has been evaluated in multiple studies for the treatment of HFPEF, and this was the first, kind of the first, randomized placebo-controlled trial, which unfortunately was negative. It didn't show improvement in functional capacity or any of the secondary endpoints, including quality of life. There have been, as I mentioned, several studies with PDE5 in HFPEF. There were smaller studies, they were using higher pulmonary pressures, but they were not really randomized placebo control. So this is the study that the guidelines have looked at when they look at that and the update in 2017. So at that time, diuretics remain a class 1 indication. The addition of mineralocorticoid antagonists to maybe reduce hospitalizations with a 2B, and the recommendation of not using nitrates or phosphodiesterase inhibitors had a class 3 indication. There's a study I didn't show that also included nitrates similar to sildenafil, no improvement at all. So we are still really kind of, at this point, not with really good medicines. The new kid in the blog is Entresto, and Entresto has been shown to be very promising with incredible outcomes on patients with reduced ejection fraction. So we tested in normal ejection fraction patients, and unfortunately, like the other ones, it was also negative, negative results. Now if you can see in the top two graphs, there is a trend, again, for improvement in outcomes. And when they are not subsequently analyzed where those outcomes were coming from, it was mainly reduction in heart failure hospitalizations. So even though it didn't meet that endpoint and that criteria, like ARBs and mineralocorticoid antagonists, there was a trend on reduction of hospitalizations with these medications. The other new kid in the blog is the SGLT2 inhibitors. And finally, we were very excited to have a positive trial with reduction in cardiovascular mortality or heart failure hospitalizations with these medications. So the 2022 updated ACC recommendations included SGLT2s with a 2A recommendation because he had, you know, very good results, and also included ARNIs, again, with a 2B recommendation similar to MRAs and ARBs. The guidelines from Europe from 2021 has very similar recommendations to these. Now some more studies have been done with SGLT2 inhibitors, and they have shown very consistently on different studies to have improvements in outcomes of cardiovascular mortality as well as heart failure hospitalizations. So this class of medication was updated to a class 1 indication for that 2023, so this year, ESD guidelines. Now if you don't know this medicine, we are using it like in the water in heart failure. This was a medicine that was initially studied for diabetes, but the FDA has a mandate to evaluate all cardiovascular outcomes on diabetes medications. So we recorded all cardiovascular outcomes, and we noticed that there was significant improvement even in patients without diabetes. So that's where they have been multiple, multiple studies in the last few years studying SGLT2, and very consistently have shown improvement in cardiovascular events, not just on diabetics, but as well in non-diabetics. So this is the updated guidelines from the European guidelines from 2023, so heart of the press, and SGLT2 got a class 1 recommendation. Diuretics is still there, and the other ones that we have mentioned is still recommended, mainly for reduction in hospitalizations with a 2B indication. Very, very important to not forget the comorbidities. Treatment of blood pressure, coronary artery disease, and atrial fibrillation are always important and beneficial in these patients. In addition, there was addition recommendations for prevention, particularly weight loss and exercise activities. Now, as you probably heard, if you're in the U.S., semaglutin is everywhere, and so we have a study on semaglutinin heart failure as well within just published and presented at the ESC meeting that show improvement in symptoms as well as 6-minute walk test distance, so stay tuned for updated recommendations from the guidelines. As I mentioned, comorbidities are really important, and I'm not going to touch base that much on this busy slide, but it's important for the pulmonologists in the group that the ACC statement from 2023 have recommendations into treatment of sleep apnea as well as obesity here. These medications don't come without problems, so it's very important if we're going to use them to be aware of the side effects, particularly the risk of recurring urinary tract infection or fungal, vaginal, and genital infections with SGLT2s. Obviously, we are all aware of the problems with creatinine and potassium with the other ones. So for our case, in our patient, we will change Norvast for ARNI or ARB. She has failed hydrochlorothiazide with a recurring admission, so that will change for a thiazide diuretic, which is the recommended diuretic for HEF-PEF, and the metformin will change for SGLT2. Now, the other part of the topic. Unfortunately, I don't have a lot to say, but different medications for pulmonary hypertension have been studied in HEF-PEF and out of proportion, with really not really positive results. This is the study on Rio Ciguar at DEMPAS, and there was a really nice study that took care, a few years ago, with Orenitram, evaluating patients with very high PBR out of proportion to the wedge, and that study actually was terminated early for lack of improvement. We have a very nice new modicle, Sodatorcep, that have very promising effects in pulmonary arterial hypertension. It's a different type of medication. It's a different class that blocks acting and growth factors, and there is an ongoing study on patients with a very elevated PBR, but HEF-PEF, called cadence, which will evaluate this medicine there as well. So, in summary, heart failure with preserved ejection fraction is associated with high mortality and morbidity. It's a very complex disease. The only medications that we really have are diuretics and HGLT2, so I encourage everybody that can be on an HGLT2 should be on it for reduction of, for improvement of outcomes. Very, very important to treat comorbidities. Thank you. Aloha, everyone. Thank you for the kind introduction. All right, so we are going to jump into the imaging for HEF- PEF now. I have no relevant disclosures, and my learning objectives are to review the echocardiographic characteristics of patients with HEF-PEF, to review the different grades of diastolic dysfunction and assessment of filling pressures, and apply the ASC, American Society of Echo, guidelines to a case example. We'll also appreciate the emerging role of novel echocardiographic and cardiac MRI measures of HEF-PEF. So, as we have studied so far, dyspnea is a common complaint, and majority of the patients are seen in pulmonary clinic, and out of those patients, HEF-PEF constitutes about two-third of the cardiac causes of dyspnea. The burden of HEF-PEF is rising, and the prevalence in patients over 60 years is around 5 to 8 percent. It's a clinical syndrome of heart failure associated with preserved ejection fraction more than 50 percent. The prevalence is increasing as our population is aging, and with the epidemics of diabetes, obesity, hypertension. Now, we have seen the different comorbidities and risk factors associated with HEF-PEF, and the pathophysiology as well, so I'll be brief here. There are abnormalities in myocardial relaxation. There is systolic dysfunction, even though EF is preserved. Atrial dysfunction, vascular stiffening, impaired vasodilatation with stress, diminished stroke volume response to exercise, and chronotropic incompetence. I want to highlight that diastolic dysfunction that you see on echocardiogram does not equal HEF-PEF. Diastolic dysfunction does not equal HEF-PEF, because HEF-PEF is a clinical diagnosis, and asymptomatic diastolic dysfunction is much more common than HEF-PEF. So, do not think diastolic dysfunction is equal to HEF-PEF. We need to look at the patient, and if there are no heart failure symptoms, it is not HEF-PEF, but we'll look at some nuances in the next couple of slides. The clinical diagnosis, as highlighted by the previous presenters, is challenging because of the high frequency of comorbidities that mimic the symptoms of dyspnea most commonly, and there is lack of single objective marker, and BMP is often normal or mildly elevated in HEF-PEF. Now, there are some diagnostic scores that have developed that can help us in making this diagnosis, or at least assess the probability which can lead to further diagnosis to confirm, further testing to confirm the diagnosis, and there are two risk scores. The more commonly used is H2F-PEF score, developed by my colleagues at Mayo Clinic, and the different parameters that go into the score include BMI, history of hypertension, atrial fibrillation, pulmonary hypertension, age, and filling pressures as assessed on echocardiogram. And the other score is HFA-PEFF that includes some other measures that are not commonly performed in echocardiogram. Now, there are four basic echocardiographic elements that help in assessment of diastolic function. Left atrial size or left atrial volume index, mitral annular tissue doppler, mitral inflow doppler, and right ventricular systolic pressure. Left atrial volume index, as the name suggests, is the left atrial volume. If the left atrial size or volume is normal, it means there has been no long-term stress or pressure elevation, which means LA pressures are normal. But if the left atrial size is increased, this is a nice diagram that shows that the pressures were increased at some point, but we cannot disown the current filling pressure. So if you look at the two balloons that are same size, the one on the right, it depicts high filling pressures at the current time, but the one on the left, although the size is similar, shows the filling pressures are normal at the current time. And so when we do the left atrial volume estimation, it's important not to include the appendage and the pulmonary veins, and these are the different cutoffs for the size estimation, normal, mild, moderate, and severely enlarged. All right, so tissue doppler. Now, the tissue doppler, what we look at is the velocity of myocardial relaxation at the level of mitral annulus, and the normal values for the medial E prime, and that's E prime is the early diastolic velocity, A prime is the late diastolic velocity, which is associated with the atrial contraction, and S prime is the systolic velocity. So the normal medial E prime is more than 7 centimeter per second, lateral is more than 10. Now, this is the most sensitive marker, one of the earliest to become abnormal in patients with diastolic dysfunction, and if the relaxation is normal, diastolic function is mostly normal. Now, mitral inflow provides us an insight into the pressure gradient between left atrium and left ventricle. This is a hemodynamic catheterization tracing, and this is the corresponding echocardiographic mitral inflow. This is a nice video that I'm going to play here. Now, with grade 1 diastolic dysfunction, there is impaired relaxation, so the A wave, the filling of the ventricle associated with the atrial contraction becomes more prominent, and as the diastolic function grade increases, now the left atrial pressures are elevated, that pushes the blood into the ventricle, and again, the E wave becomes prominent. Now, if you notice, the E wave is prominent more in the normal individuals, because normally about 75-80% of filling of the ventricle is passive, but it's also increased in grade 2, 3, and 4, and the difference between the normal grades and the elevated filling pressures in the normal individuals, there's suction of the ventricle, which kind of sucks the blood into it, whereas in diastolic dysfunction grade 2 or higher, there are elevated left atrial pressure that pushes the blood into the ventricle. So now, this is a summary of the different grades of diastolic dysfunction. So in a normal individual, E wave is prominent, A wave is small, LA size would be normal, because filling pressures are normal, E prime, the velocity of myocardial relaxation would be normal, and EE prime, which is a surrogate of filling pressures on echocardiogram, would be normal. And we're going to talk about the EE prime in next couple slides. Now, in grade 1, there is impaired relaxation, so A wave becomes prominent. There's more contribution of atrial contraction in filling of the ventricle. Left atrial size may be normal or enlarged, E prime would be reduced, and E over E prime ratio would be normal, because the filling pressures are normal in grade 1, but when you go on to grade 2 and 3, now the left atrial pressures have increased, that pushes the blood into the ventricle, E velocity again increases, the left atrium is enlarged, E prime is reduced, and E over E prime ratio would be high. All right, so EE prime ratio is an echocirrugate for filling pressures, and a value over 14 is associated with higher pulmonary capillary wedge pressure, but there is data from many studies that show that the absolute number of EE prime does not correlate with absolute left atrial pressures or pulmonary capillary wedge pressure. So it's quite specific, but not sensitive. So EE prime correlates with wedge pressure, but in a binary fashion rather than linear. So the absolute numbers may not necessarily mean higher wedge pressure or left atrial pressure, but the value over 15 would mean elevated, would suggest elevated pulmonary capillary wedge or left ventricular filling pressures, and less than 8 is highly likely to have normal pulmonary capillary wedge pressure. Now important to note, as has been shown previously by Dr. Kahigas, that resting filling pressures in HFPEF are also frequently normal. Now that creates a confusion, right, of how do we really make the diagnosis on imaging, and we're gonna look at some nice case example in just a bit. Now the next parameter, if you remember, is the pulmonary artery pressures. And as has been shown previously, that 2 3rds of the patients with high left atrial pressures have pulmonary hypertension. And in patients with HFPEF, about 80% patients may have elevated pulmonary pressures on echocardiogram. And most of the times, about 60%, it's isolated post-capillary. PVR is only mildly elevated, but about 20% or so, they have combined pre and post-capillary because of longstanding remodeling, even including the pulmonary arterioles. Now, there are two algorithms in American Society of Echocardiogram Guidelines that help us in evaluation of a diastolic dysfunction grade. Now, we're gonna only look at the algorithm one, which includes patients with normal LVEF, because that's the patients with HFPEF. So the four features included are the ones we just talked about. EE prime ratio, more than 14. E prime velocity, less than seven for diastolic dysfunction, and lateral, less than 10. TR velocity, more than 2.8 meter per second. And LA volume index, more than 34 in large left atrium. Now, if more than 50% of these are present, it means there's diastolic dysfunction. If less than 50% positive, it means normal. And if it's 50-50, it's indeterminate. And that's where there is role of some other echo features. It's important to not apply the guidelines in cases of mitral or aortic valve prosthesis, in cases of mitral annular calcification if there is significant mitral stenosis or regurgitation, because these can affect both mitral inflow and the tissue Doppler velocities. In left bundle branch block, because the medial E prime may be reduced because of that, in tachycardia, and atrial fibrillation, where E and A waves may be fused. And in patients with pre-capillary pH, if you suspect that. Now, the hemodynamic hallmark of HEF-PEF is that about 50% patients have normal filling pressures at rest. And this is work by Dr. Borlaug and colleagues at Mayo Clinic, which shows that with exercise, there is a significant increase in pulmonary capillary wedge pressure and pulmonary artery pressure, which is a significant increase more than the usual mild increase in the controls of normal individuals. And so if you combine some kind of exercise testing, either exercise hemodynamic catheterization, and we are gonna learn about that in just a bit, or exercise echocardiogram, the sensitivity and specificity of diagnosing HEF-PEF increases significantly. Now, this slide just shows how it's done at our lab. This is the echo lab, and this is our cath lab. And so we have the patient exercise and measure these parameters both at rest and with exercise. And in patients with HEF-PEF, the E velocity, the early filling velocity increases significantly with exercise, but the E prime, the tissue Doppler relaxation velocity either remains same or increases mildly. And as a result, the E E prime ratio, the echo surrogate of filling pressure would increase with exercise, whereas it remains stable or even decreases sometimes in normal individuals. And now this is a work from our group, which will be published soon. Thousands of patients who underwent a diastolic stress test, the exercise testing for evaluation of diastolic function added on to the ischemia evaluation. And in patients presenting with dyspnea, we were able to make the diagnosis of HEF-PEF and even exercise-induced pH, even if there was no ischemia. So we were able to help with the diagnosis of this condition when patients were predominantly referred for coronary artery disease evaluation. Now let's look at a case, 70-year-old female with six months of progressive dyspnea. The EF is normal, there are no regionals, no valve disease to explain her symptoms. The left atrial volume size is normal. EA ratio is reduced, so suggesting grade one, right? E prime velocity is reduced. This is the first marker to becoming abnormal or most sensitive one. So some degree of diastolic dysfunction perhaps, right? EE prime ratio though is normal, less than 15, and TR velocity is less than 2.8. And this is the grade one looking pattern. But if you follow the algorithm, now only less than 50% of the parameters is abnormal in this case, right? Really only E prime velocity. So you would call this normal diastolic function, right? But we called it normal filling pressures at rest because this is all resting data. And the patient had symptoms and so we did a stress cycle. Exercise capacity was poor, only did four meds. And with exercise, the EE prime ratio increased significantly from eight to 16. And so we were able to make the diagnosis of HF-PEF. They had some other risk factors as well that when put together helped in making the diagnosis and ischemia was ruled out. There were no regional wall motion abnormalities. So there are some limitations in the guideline and an alternative algorithm has been proposed by my colleagues at Mayo Clinic where they say, if more than 50% normal or three or more normal, then you just say it's normal filling pressure. It may be normal diastolic function, but it may be grade one at rest, right? Because 50% patients may have normal filling pressures at rest. And in those patients, we can exercise or perform diastolic stress test, either echo or right heart catheterization. And if more than three are abnormal, three or more, then it's easy. It's diastolic dysfunction, elevated filling pressures. And if they're two and two, then we can look at some other echocardiographic parameters such as pulmonary veins, IVRT, left atrial strain, or we could exercise them. So the additional variables are pulmonary veins. We can look at the profile, systolic Doppler, diastolic Doppler flow velocities that can help in assessment of filling pressures. We can look at the A-wave duration difference between pulmonary veins and the mitral inflow that can help again in estimation of left ventricular filling pressures. And L-wave, which shows mid-diastolic flow between E and A-wave also suggests increased filling pressure because the pressure in left atrium is high even in mid-diastole, the diastasis period that there is flow going into the ventricle. Some of the novel markers include left atrial strain because studies have shown that left atrial volume index is insensitive in early disease and does not typically reverse. Left atrial strain can help in diagnosis and grading of diastolic dysfunction and has been shown to be incremental and superior to left atrial volume index and predictive of filling pressures with exercise and symptoms and diagnosis of HEF-PEF and was also associated with outcomes in a sub-study of TOPCAT trial. Now even though EF is preserved in HEF-PEF, there is still systolic dysfunction because the global longitudinal strain may be abnormal. And it has been again shown to have prognostic importance in TOPCAT study. We can assess the extravascular lung water by looking at the B lines which you're all familiar with and in our lab, it is a part of a protocol when we do the diastolic stress test, we evaluate four focused lung zones. So the summary of echo findings, we have looked at this low E prime velocity, elevated E over E prime, dilated left atrium, elevated PA pressures, there may be left ventricular hypertrophy because of hypertension, reduced global longitudinal left ventricular strain, LA strain, B lines on lung ultrasound. It's important to keep in mind the mimickers of HEF-PEF which of course includes low EF, valve disease, constriction, and restrictive cardiomyopathies such as amyloid. There is some role still under research though for cardiac MRI for HEF-PEF diagnosis through 4D flow analysis here, we can look at the flow vortices which can help us in getting curves similar to echocardiogram of mitral inflow and tissue Doppler. But more importantly, there is established role of cardiac MRI and evaluation of HEF-PEF mimickers, in this case, concentric left ventricular hypertrophy and diffuse late gadolinium enhancement suggesting cardiac amyloid. So my take home points are, echocardiography has a key role in assessing diastolic function and filling pressures and identifying mimickers of HEF-PEF. If resting echocardiogram is normal or shows indeterminate filling pressures, consider exercise stress echo. Key features of HEF-PEF on echo includes dilated left atrium, reduced LA strain, low E-prime velocity, elevated E over E-prime, and elevated PA pressures. E over E-prime correlates with pericapillary wedge pressure but in a binary than linear fashion. Value more than 15, highly likely to have elevated wedge pressure, less than eight, highly likely to have normal pericapillary wedge pressure. And important to keep in mind that resting filling pressures in HEF-PEF are frequently normal, so there is role of exercise testing. And there is prognostic significance of subclinical systolic dysfunction that can be evaluated by strain. There is role of novel markers such as LA strain, lung ultrasound, and an upcoming role of cardiac MRI, and established role in ruling out the mimickers. Mahalo. Thank you. Thank you, Hector, for the invitation and the wonderful presentation and also for the other speakers that gave this wonderful talks. Just going to be moving on more towards the invasive assessment of patients with heart failure with preserved ejection fractures. Have no conflicts of interest in relation to this talk. My objectives are going to be simple, discuss when to consider Raja catheterization in patients with heart failure with preserved ejection fraction, common errors in the measurement of wedge, because wedge pressure, as you saw in prior speakers, is essential for the diagnosis. Both do it in rest and also exercise. And then there are different tests that you can use to challenge the pulmonary vascular circulation, the cardiopulmonary system, if you will, that we will be describing. So when to consider Raja catheterization in patients with heart failure with preserved ejection fraction. I have to put some thought on it, but it will depend on the institution. In my institution, since it's a referral center, the Cleveland Clinic, we do, based on catheterization, most of the patients that get referred for heart failure with preserved ejection fraction, so you have an initial baseline, and also then you can compare with future assessments if the patient gets worse. But you could potentially say, you know, hey, I think it'd probably be better to do in patient with heart failure with preserved ejection fraction who have worsening of symptoms, they're not getting better with the treatments that they were described before, that patients have RV dysfunction where you want to check whether they have pre-capillary pH. If they have worsening right ventricular systolic pressure, RV function on the echo, and you want to assess whether this is related to the development of pre-capillary pH. And some patients with what we think is group 1 pH, pulmonary arterial hypertension, they're not getting better with treatments, and that they have pulmonary wedge pressure between 13 and 15 that you think they may have an occult group 2 pH that could be heart failure with preserved ejection fraction. So when we do the RAHA catheterization, we get the essential measurements, the radiator pressure, I mean pressure wedge, the cardiac index, and the stroke, and the mixed venous O2. Calculate the PVR, and then we do, depending on the case, different advanced cardiopulmonary interrogations. So as we discussed, the pulmonary wedge pressure is essential since it will allow us to determine the presence of post-capillary pulmonary hypertension and also an elevated wedge for heart failure with preserved ejection fraction. In order to do that, we need to be really good at getting this measurement. Sometimes we see reports where the wedge is elevated, and it doesn't make sense with the clinical scenario. And it's because it was not obtained in different places with different type of balloon inflation. With this study where we show that approximately 10% of the patients will require a wedge on the left lung and will require it with the smaller balloon inflation. There are five criterias for pulmonary wedge pressure that need to be followed. The wedge should be lowered under the diastolic pulmonary artery pressure. The tracing should be compatible with an A and a B waveform. If you have fluoroscopy, the catheter should be stable, should not be moving in the pulmonary artery. And if you do a square test, you will see the typical parameter of the catheter. It's open into the vessel. And if you get blood out of the wedge position, the blood will be oxygenated with a SATS above 90%. So this was a study that we did where we saw that, for example, in this case, it's an incomplete wedge. On the right side, this also is an incomplete wedge. You see that the SATS are low. And then as you advance and reduce the volume inflation, you get a better fit into the vessel and a better, more reliable wedge. The guidelines have changed, as Hector showed in the first talk. The mean pressure dropped from 25 to 20, and the PVR from 3 to 2. But the wedge, the normal value, is 12. And hasn't dropped yet on the guidelines, maybe in the next ones. We used a cutoff of 15, which is above normal. So the group of patients with 13 to 15 is a very special group. Because as you saw, there's a substudy of the ambition study, where those patients, when they initially include these patients with a wedge of 13 to 15, they didn't do as well as others with a lower wedge. So these patients may have a component of occult heart failure with preserved ejection fraction. And they may even have a lower wedge, or a normal wedge, when you get a catheterization because of negative fluid balance. Obviously, they would be paying more attention to the diet and taking all the medications before the assessment. One thing we have, and we're putting a lot of effort in diagnosing, is when you have obesity, the intrathoracic pressure goes up. And we see that in the ICU, where we put esophageal balloons to adjust the PEEP. Well, the same happens when you do a catheterization. If you are a very large person, and with the high intrathoracic pressure, that will also translate into the pulmonary vascular measurement. So for example here, you see in the dotted line, in the gray one up top, this will be the pulmonary pressure measured in the patient. The intrathoracic pressure measured by an esophageal balloon is down here in orange. And when you adjust for that, you have a lower pulmonary artery pressure. But the same happens with the wedge. The first one, where you see the A and the B, here is the conventionally measured pressure. This is the esophageal pressure. And when you adjust, this patient ends up having a normal wedge pressure at 12. So let's say you believe that this patient, this obese patient, had a wedge of 30, and you start giving diuretics. Suddenly, the renal function will get worse, the bicarb will go up, the patient will not get better. And it's because the wedge, it was not related to volume overload, but just to inflated value by high intrathoracic pressure. So we saw that in a paper that we published at CHESS, where the number of this obese individuals that had post-capillary pH, or combined pre- and post-capillary, dropped significantly when you adjust the wedge by the esophageal pressure measurement. So when we see the patient in a catheterization, we assess whether we need to do an exercise for her cath, or we need to give fluids, or we need to challenge them with nitric oxide. And you can say, hey, nitric oxide is for group 1 pH, why are you guys doing it in this patient? And I'll show you why when we study that. So you could do exercise. The exercise you can do in different ways, and there is a lot of protocols. We have a paper in the review where we compare a sitting bike with a supine bike, and the values are strikingly different. As you probably know, when the patient is in flat position, there's more, obviously, preload, and the wedge tends to be higher. As you sit the patient up, the wedge will lower, and then you may reduce the sensitivity for the diagnosis, but you also improve the specificity. So if you were to have a high wedge in this position during exercise, it's very specific. Not in this case, since the wedge may be started at 15, when you exercise, it will rapidly go up to 20. What we are doing now, and following Louie's paper, is the slope, where you see the wedge over cardiac output slope. And if the slope is above 2, like in this dotted line, the slope is 2.5, the higher the increase in the pulmonary wedge pressure for the increase in cardiac output, if it is above 2, then that would be abnormal and supportive of post-capillary component of pH. We did, recently, a study where we compared three maneuvers during rheumatoid catheterization. The passive leg raising, a submaximal exercise, and a fluid challenge. One would think, wait, why do you need a maximal exercise if you already get enough information submaximally? Why would you have to take the patient to extreme tests? That would be a different protocol that people may have. But in this case, we did submaximal to 60 watts, and then we did a fluid challenge, and also PLR. So, as you can see here, the exercise was able to increase the wedge more than fluids and PLR. And it was able to diagnose post-capillary pH significantly more than all the other tests. So, exercise, I believe, is the way to go. We also published this paper where we did fluid challenge in 174 patients, and you have, by guidelines, a positive response when the wedge increases more than 18. We compared that with all the other parameters that were already shown here of the pre-test probability of pH, and there was not a good correlation, was not strong, like low Pearson correlation coefficients. And what we noted that was very interesting is that pretty much every patient with a wedge of 13 to 15, which is this higher than normal one, not yet 15, as the guidelines said, they all have, on the majority, had a positive fluid challenge. It was easy for them to go from, let's say, 13, 14, to more than 18. And then you question the challenge, because if everyone is positive here, why would you really need to do the test? And also supports changing the cutoff to 12 instead of 15 that's kind of on the guidelines. We also did this study that I thought it was really interesting, but the reviewers didn't, where we had 104 patients with combined pre- and post-capillary pH, and we provided inhaled nitric oxide, with the idea that if you decrease the pulmonary vascular resistance, you will increase the preload to the left ventricle, and if you were to have heart failure with preserved ejection fraction more severe, then the wedge will go up significantly, and then you would say, hey, that's not a patient that we want to give pH therapy, because obviously you have higher wedge and more increase in pulmonary edema, more shortness of breath. So as you can see here, in this patient, for example, when nitric oxide was given, the wedge significantly went up. So the cardiac output increased, and the PVR dropped, and the wedge went up. And this one didn't. So the hypothesis was like, hey, you know, this would be a good tool to differentiate those patients with the heart failure preserved ejection fraction of FPH, disproportionate pulmonary hypertension, that you may want to treat with vasodilators. But we couldn't really prove that. We found that there was no relationship between these changes in wedge with nitric oxide and the tolerance to pH medications. Also there was no association within this response in heart failure hospitalizations or mortality. So unfortunately, we cannot really support the use of inhaled nitric oxide, and we're not doing any more. So in summary, an adequate wedge determination is essential to manage these patients. Because if you don't have the right wedge, then it's hard to really adjust diuretics or all these treatments. Maybe you misdiagnose the patient, such as in a case of severe obesity. And then there are different methodologies to challenge the pulmonary circulation, and exercise, I think, is the best one, as other presenters mentioned. And it's essential to get the most precise diagnosis and also guide treatment decisions. And with that, we're finished. Thank you.

heart failure with preserved ejection fraction

HFpEF

pulmonary hypertension

diagnostic challenges

echocardiography

right heart catheterization

filling pressures

pulmonary artery pressures

exercise stress testing

cardiac MRI

PH