Time Stamps

  • 01:59 Pearl 1 – What is HFpEF?
  • 11:22 Pearl 2 – Echo findings and diastolic dysfunction
  • 19:21 Pearl 3 – BNP
  • 25:06 Pearl 4 – Advanced Testing
  • 32:03 Pearl 5 – Treatments for HFpEF



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Show Notes

Pearl 1: What is Heart Failure with Preserved Ejection Fraction (HFpEF)?

  • Definition
    • Clinical syndrome of volume overload and elevated left filling pressures at rest OR exercise in a patient EF of 50% or higher
    • Poorly understood systemic syndrome that is likely an umbrella term for multiple conditions
    • Symptoms: dyspnea on exertion, PND, orthopnea, fatigue, exercise intolerance
    • Physical exam findings: JVD, pulmonary rales, LE edema
  • Pathogenesis for “Garden Variety” HFpEF or Cardiometabolic HFpEF
    • Originally thought of as a result of long-standing hypertension leading to LV remodeling and stiffness
    • Now, thought to be a result of obesity and cardiometabolic disease leading to systemic low grade inflammation, but still with evolving understanding
    • Coronary microvascular dysfunction, endothelial dysfunction, and altered myocardial energetics are thought to be central to pathogenesis
  • Risk Factors
    • Age
    • Cardiometabolic risk factors: obesity, hypertension, diabetes, CAD,  sedentary lifestyle
      • Over 80% of HFpEF patients are overweight or obese
    • Female specific risk factors include hypertensive disorders of pregnancy, specifically preeclampsia
  • Increased risk factors lead to increased prevalence of “garden variety” HFpEF
    • HFpEF makes up about 50% of HF cases, though the proportion is increasing due to an increase in cardiometabolic risk factors
  • HFpEF masqueraders
    • Based on history and physical examination, “masqueraders” of HFpEF must be ruled out
    • Clues towards possible HFpEF masqueraders
      • Suspected HFpEF but with low H2FPEF score
      • Kussmaul’s sign (increased JVP with inspiration)
      • Low voltage ECG relative to increased wall thickness
      • Intolerance of standard GDMT/neurohormonal blockade
      • Risk factors present for infiltrative/restrictive HFpEF in a young patient
    • Non-cardiac masqueraders: Pulmonary disease, kidney disease or nephrotic syndrome, cirrhosis, anemia, chronic venous insufficiency 
    • Cardiac masqueraders: Hypertrophic cardiomyopathy, restrictive cardiomyopathy, cardiac amyloidosis, cardiac sarcoidosis, hemochromatosis, valvular disease (severe stenosis, regurgitation, or mixed), myocarditis, pericardial disease

Pearl 2: Echo Findings and Diastolic Dysfunction

  • Echo findings alone cannot make or exclude a diagnosis of HFpEF
  • Diastolic dysfunction = inability to fill ventricle with adequate preload volume (end diastolic volume) at acceptably low pressures
    • Diastolic dysfunction and HFpEF are NOT synonymous terms
      • Diastolic dysfunction is an abnormality in relaxation/filling, separate from LVEF or symptoms
    • Diastolic dysfunction can be a part of human aging
    • Diastolic dysfunction is a risk factor for development of HFpEF
    • Diastolic dysfunction cannot be observed on resting echocardiograms of of HFpEF patients
    • Diagnosed by echo with the following parameters, where 2 parameters is indeterminate and 3 or more is diastolic dysfunction
      • LA volume index > 34 mL/m2
      • E/e’ > 12-14
      • e’ velocity
        • Septal e’ velocity < 7 cm/s
        • Lateral e’ velocity < 10 cm/s
      • TR velocity > 2.8 m/s
  • Other echo findings
    • Elevated LV filling pressure, either at rest or with exertion
      • Usually assessed with E/e’ (early  diastolic transmitral inflow velocity to mitral annular tissue velocity)
    • LA pressure increases -> progressive LA dilation
    • Increased LV mass index
    • Pulmonary hypertension in 70-80% of HFpEF patients
      • PA pressure estimated using TR jet velocity and RA pressure
    • RV dysfunction in 20-35% of HFpEF patients (marker of increased morbidity and mortality)

Pearl 3: BNP

  • Natriuretic peptides are produced/released due to increased myocardial wall stress and cardiac stretch
    • May be normal in HFpEF
      • HFpEF does not necessarily elevate end diastolic wall stress (when concentric remodeling with LV hypertrophy occurs)
    • BNP is just one clue in diagnosing HFpEF, but must be combined with the entire clinical picture and echocardiogram
  • NT-pro-BNP is influenced by key features of HFpEF (AF, obesity, renal impairment, age)
    • Obesity is associated with lower BNP levels 
    • AF and chronic kidney disease are associated with higher BNP levels
  • Natriuretic peptide deficiency, which is strongly correlated with obesity, may leave individuals more susceptible to pressure/volume overload 
    • “Natriuretic” means sodium in the urine
      • Since BNP makes an individual urinate out sodium, one can understand why BNP might be elevated in volume overload and why lower than expected levels might be problematic.

Pearl 4: Advanced Testing

  • HFpEF probability scores
    • H2FPEF score
      • Use only with clinical suspicion of HFpEF
      • More useful in outpatient setting
      • Estimates probability of HFpEF vs non-cardiac causes of dyspnea 
      • Heavy, Hypertensive, Atrial fibrillation, Pulmonary Hypertension, Elder, Filling Pressures
    • HFA-PEFF Score
      • Calculated using functional/morphological criteria (based on echo) and biomarker criteria (BNP) levels to estimate probability of HFpEF
  • If diagnosis remains uncertain, consider RHC, including provocative maneuvers
  • Exercise RHC/stress echo to eval for elevated filling pressures that develop during exercise
  • Cardiac MRI and other advanced testing (e.g. cardiac PET) not required for a diagnosis of HFpEF, but can be used to investigate HFpEF masqueraders (e.g., hypertrophic cardiomyopathies, cardiac amyloidosis, or cardiac sarcoidosis)

Pearl 5: Treatments for HFpEF

  • Control risk factors
    • Manage hypertension, coronary artery disease, diabetes, and obesity
  • Medications
    • SGTL2i is the first line choice for HFpEF (class IIa in AHA/ACC guidelines, class I in ESC guidelines)
    • MRA (class IIb in AHA/ACC guidelines)
    • ACE/ARB/ARNI (class IIb in AHA/ACC guidelines)
    • Add on loop diuretics to decrease congestion
  • Outcomes and trial data:
    • EMPEROR-Preserved: Empagliflozin in HFmrEF and HFpEF
      • Empagliflozin decreased risk of HF hospitalization and CV mortality in patients with HFmrEF or HFpEF (EF > 40%)
      • 13.8% event rate in the empagliflozin group vs. 17.1% in placebo group (HR 0.79, 95% CI 0.69-0.90)
    • DELIVER: Dapagliflozin in HFmrEF and HFpEF
      • Dapagliflozin reduced HF hospitalizations and CV mortality in patients with HFmrEF or HFpEF (EF > 40%)
      • 16.4% event rate in dapaglifozin group vs. 19.5% in placebo group (HR 0.82, 95% CI 0.73-0.92)
    • TOPCAT: Spironolactone for HFpEF
      • Spironolactone is associated with a small reduction in HF hospitalization, but does not reduce CV mortality in HFpEF
      • Heterogeneous results across regions of enrollment in the trial have raised controversy about the trial results
      • Post-hoc analysis showed statistically significant benefit in the Americas for the primary composite outcome of CV death, aborted cardiac arrest, or heart failure hospitalization  (HR 0.82, 95% CI 0.69-0.98)
    • CHARM-Preserved: ARBs in HFpEF
      • Candesartan had no effect on CV mortality but prevented admissions for HF hospitalization for those with EF > 40%
    • PARAGON-HF: ARNI in symptomatic HFpEF
      • Compared to valsartan alone, sacubitril-valsartan did not lower HF hospitalizations or CV mortality, however, there was improvement in NYHA class and less decline in renal function in the sacubitril-valsartan group
      • Possible benefit in those with EF in lower range of eligibility 
      • Sacubitril/valsartan was associated with reduction in HF hospitalization/CV mortality in women, but not men
    • Future of GLP-1 agonists
      • The STEP-HFpEF trial showed treatment with semaglutide 2.4 mg weekly led to greater reductions in weight loss, symptoms, and physical limitations compared to placebo
      • Ongoing trials are assessing effects on CV events and mortality


Dr. Emily Lau: this is a really confusing condition. So if you’re confused, it’s not because there’s something wrong with your diagnostic abilities. It’s that it’s a very confusing condition.

Dr. Shreya Trivedi: That is Dr. Emily Lau, cardiologist at MGH. Welcome to the Core IM 5 Pearls Podcast, bringing you high-yield evidence-based pearls.   This is Dr. Shreya Trivedi

Dr. Rati Vani: An Dr. Rati Vani, an internal medicine resident at Beth Israel Deaconess Medical Center. And today we will be focusing on heart failure with preserved ejection fraction aka HFpEF. 

Dr. Shreya Trivedi: And hopefully we will make this topic a little less confusing about what we do and don’t know about HFpEF. Let’s get right into those pearls we’ll be covering in this episode. Be sure to test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains.

Dr. Rati Vani: Pearl 1 – What is HFpEF?

Dr. Shreya Trivedi: What causes HFpEF? And what are the biggest risk factors?

Dr. Rati Vani: Pearl 2 – Echo findings and diastolic dysfunction

Dr. Shreya Trivedi: Does diastolic dysfunction imply HFpEF? And what are typical echo findings in patients with HFpEF?

Dr. Rati Vani: Pearl 3 – BNP

Dr. Shreya Trivedi: What are BNP levels influenced by? And is BNP a level helpful in HFpEF?

Dr. Rati Vani: Pearl 4 – Advanced Testing

Dr. Shreya Trivedi: What scoring systems can be helpful in ruling in HFpEF? And What other testing and imaging can be helpful when the diagnosis of HFpEF is unclear?

Dr. Rati Vani: Pearl 5 – Treatments for HFpEF

Dr. Shreya Trivedi: What’s the 1st and 2nd line treatment for HFpEF?

Pearl 1 – What is HFpEF?

Dr. Shreya Trivedi: I was so surprised when we started this episode, a lot of my cardiology friends were like HFpEF is probably the hardest topic and I was like really? HFpEF? The thing that is in almost all our patients one-liners?

Dr. Rati Vani: Yeah so it turns out that HFpEF is such a heterogeneous disease that we actually just don’t know a lot about. So a lot of prepping for this episode has been unlearning what I had associated with HFpEF. 

Dr. Shreya Trivedi: Needless to say we were ready for this challenge. To clarify the murkiness around HFpEF and are so excited to share what we have learned and, as Rati just mentioned, a lot of what we’ve unlearned also!

Dr. Rati Vani: So to start off, in the simplest terms, HFpEF is the clinical syndrome of heart failure with an EF of 50% or higher

Dr. Ravi Patel: Heart failure in and of itself is a syndrome, and in cardiology we have few syndrome. So broadly in its broadest sense, heart failure with preserved ejection fraction is defined as a clinical syndrome most commonly, which presents with dyspnea either at rest or with exertion that is due to a rise typically in left ventricular filling pressures at rest or with exercise.

Dr. Shreya Trivedi: That is Dr. Ravi Patel, a cardiologist and Director of HFpEF program at Northwestern. These definitions make HFpEF seem so straightforward. Right?! But now that I know more, I need to put a huge highlighter, double underline the word “syndrome” with HFpEF syndrome. 

Dr. Emily Lau: I do think in general, when we’re talking about HFpEF, we’re not talking about conditions with known etiologies. We’re really talking about this kind of umbrella term, poorly understood systemic disorder condition. And this is why this is one of the hot topics in the cardiovascular community today because we simply don’t understand this condition at all. We don’t yet have a consensus on how to diagnose this condition. It’s probably multiple conditions all under an umbrella term of HFpEF and understanding and sort of respecting the ambiguity I think is actually an important principle.

Dr. Rati Vani: And to clarify why this HFpEF syndrome is poorly understood and a systemic disorder, we have to understand how HFpEF even develops. Dr. Jen Ho, an advanced heart failure and transplant cardiologist at BIDMC did a great job explaining so succinctly just that.

Dr. Jen Ho: So the pathogenesis of HFpEF is really complex. I’m not sure anybody fully understands what happens. We used to think of HFpEF really as a disease related to hypertension and hypertensive LV remodeling that leads to LV stiffness. And I think this has really shifted more recently to this idea that it happens in multi morbid patients with central contributions from obesity and cardiometabolic disease. We think that those predisposing factors probably incite systemic inflammation that then leads to endothelial dysfunction and altered myocardial energetics and abnormalities in skeletal muscle. And so it’s a lot more complicated, I think, than we initially appreciated. 

Dr. Shreya Trivedi: Okay! So unlearning point #1, HFpEF is NOT classic high blood pressure causing stiff ventricles. HFpEF is so much more. And what really stood out to me is that it’s not the heart that is the initial culprit in the “classic” garden variety HFpEF. 

Dr. Emily Lau: Where as in garden variety, HFpEF talking about sort of a culmination of one’s risk profile that then seems to activate inflammation, that then leads to all these downstream sequelae that then kind of lead to structural changes and functional changes to the heart that can then contribute to the syndrome of signs and symptoms of heart failure and preserve ejection fraction. 

Dr. Ravi Patel: As we think of HFpEF as a syndrome from the outside in that’s affecting the heart as opposed to HFrEF, which is an intrinsic myocardial process, then exhibits negative effects to all other organ systems.

Dr. Rati Vani: I love that comparison of HFpEF to HFrEF. 

Dr. Shreya Trivedi: Also for those not in the know, HFrEF is HF with reduced ejection fraction.

Dr. Rati Vani: Yeah thanks clarifying, Shreya! I hope its mostly the cool kids listening to us. We can think of HFrEF as a central cardiac disorder where after the EF takes a hit it has all these downstream effects on other organ systems. But HFpEF starts as a systemic disorder with all these outside cardiometabolic risk factors like obesity, pre-diabetes, hypertension. And all of those come together and lead to pathogenesis that no one really understands but has to do with inflammation that then affects the heart. 

Dr. Shreya Trivedi: Yeah, now that I think about it that classic one-liner for most of our patients are like “A 72 year old woman with hypertension, hyperlipidemia, type 2 diabetes, and HFpEF presents with x, y, z”

Dr. Rati Vani: So, your one liner highlights another big risk factor – an older person.

Dr. Ravi Patel: HFpEF is outstripping HFrEF as the most common type of heart failure. And as we get older, our immune systems change. There is more adverse inflammation that may occur, and there is an accrual of comorbidities as well that can ultimately lead more likely to HFpEF than HFrEF. 

Dr. Shreya Trivedi: Wow. So interesting to think about as people are getting older the immune system changes and how we may be more prone inflammation with just natural aging and that contributes to this syndrome.

Dr. Rati Vani: I know! There’s actually one other demographic risk factor to bring up that surprised me and was actually one of the reasons why I chose this topic.  

Dr. Shreya Trivedi: Oh yeah which one is that Rati?

Dr. Rati Vani: So HFpEF affects a higher proportion of women than men. Dr. Lau actually has a clinical interest in this, so I was really excited pick her brain on what she’s thinking about this trend.

Dr. Emily Lau: We’re increasingly also beginning to recognize that there are other female specific risk factors like history of preeclampsia, which may also be related to HFpEF. And so it really underscores this idea that HFpEF is really a systemic condition. 

Dr. Shreya Trivedi: Oh man. I’m trying to wrap my head around how certain aspects of pregnancy, like hypertensive disorders of pregnancy, like preeclampsia, may make someone different in terms of inflammation and what that means later on for these increasing proportion of women developing HFpEF. 

Dr. Rati Vani: Yeah, so if we think back to the pathogenesis of preeclampsia, we can remember it involves systemic inflammation and endothelial dysfunction. So when you see it like that it does kind of make sense that we’re seeing this connection. The caveat we should say is, there’s still a lot left to be uncovered about these female-specific risk factors.

Dr. Shreya Trivedi: Yeah, caveats aside, inflammation is all over and rears its head again. I think it re-iterates to me that my biggest takeaway here is to change my one-liner to say HFpEF syndrome to really do it justice.

Dr. Rati Vani: To summarize what i’ve learned about HFpEF syndrome

Dr. Shreya Trivedi: I see what you did there!

Dr. Rati Vani: It is a systemic disorder that is the culmination of a patient’s cardiometabolic risk factors and even things we don’t fully understand related to pregnancy. All that activates inflammation and endothelial dysfunction, which then alters the structure of the heart. And then these structural changes in the heart lead to rise in LV pressures at rest or exercise. 

Dr. Shreya Trivedi: Before we close out this pearl of what HFpEF is, we should caveat that there are also tons of HFpEF “masqueraders.” its not all the classic garden variety HFpEF in the typical patient we see with obesity, hypertension, diabetes.  

Dr. Rati Vani: Yeah! And HFpEF has a broad definition and its hard not to label everyone with it because almost everyone we see comes in to the hospital with some dyspnea and EF >50% 

Dr. Jen Ho: Now, something that comes up a lot in terms of diagnostic workup is that there are things that can look like HFpEF that we call HFpEF masqueraders that can cause heart failure with normal ejection fraction. And so it’s really important to try to identify and differentiate HFpEF masqueraders from what I call garden variety HFpEF, because the management is often really different. 

Dr. Ravi Patel: Cirrhosis, nephrotic syndrome, are things that you’d be surprised but sometimes come into my clinic and are billed as potentially HFpEF.

Dr. Rati Vani: It’s kind of crazy to think through a list of things that can cause a little dyspnea. I wouldn’t even know where to even begin…

Dr. Shreya Trivedi: One place to separate this is into cardiac HFpEF masqueraders and non-cardiac HFpEF masqueraders. Cardiac masqueraders are things like amyloidosis, sarcoidosis or  valvular disease. Non-cardiac masqueraders are the ones that Dr. Patel just mentioned like nephrotic syndrome, cirrhosis, anemia, of course, anything with the lungs.

Dr. Rati Vani: Our actaully reviewers pointed out how we need on masqueraders and we honestly we just weren’t able to cover it all in this episode, so just look out for a bonus episode on HFpEF masqueraders.

Pearl 2 – Echo findings and diastolic dysfunction

Dr. Rati Vani: So since this syndrome is so heterogeneous let’s dig into the objective data that can make us more confident when we’re trying to find out does someone have HFpEF or do they not have HFpEF.

Dr. Shreya Trivedi: Yes, let’s get into all things echos.

Dr. Rati Vani: Finally!

Dr. Shreya Trivedi: I bet that will makes your cardiology heart very happy, Rati!

Dr. Rati Vani: So with the echo, we can look at diastole. And diastole is the ability of the heart to relax to fill with blood. 

Dr. Shreya Trivedi: And the term we always hear associated with HFpEF is diastolic dysfunction. But the big money question is does diastolic dysfunction mean slam-dunk HFpEF?

Dr. Jen Ho: I always go back to the very classic physiologic definition of heart failure, which is the inability of the heart to meet the metabolic demands of the body or to do so at the expense of elevated filling pressures. And so it’s a clinical syndrome at the heart of it. So if you just have an imaging finding of diastolic dysfunction, but the person doesn’t have any symptoms of heart failure, can exercise, run five miles. That is not HFpEF by definition. You have to have the clinical syndrome.

Dr. Shreya Trivedi: Okay unlearning point #2! And I think i have to repeat this to myself a bunch. HFpEF and diastolic dysfunction are not synonymous terms. Diastolic dysfunction is an abnormality with relaxation or filling that is separate from HFpEF syndrome, which requires clinical symptoms.

Dr. Jen Ho: Now invariably diastolic dysfunction is an important component. We know patients with heart failure with preserved ejection fraction have LV stiffness as a big problem that really makes them exercise intolerant. And so this is a really complex issue. I would look at them as sort of slightly overlapping Venn diagrams. There are people that have both, but having diastolic dysfunction does not mean you have HFpEF automatically in the absence of the clinical syndrome.

Dr. Shreya Trivedi: This brings up unlearning point #3. I used to look echos and if I did NOT see diastolic dysfunction in the impression, I kind of rule out HFpEF for their symptoms but that’s not the right way to think about it.

Dr. Ravi Patel: So you can have HFpEF without diastolic dysfunction, and it is quite common. We see it more and more. Diastology and the assessment of diastology is one aspect of understanding if an individual has HFpEF, but it’s not the whole story. What we’ve come to realize is that while diastolic dysfunction is prevalent in many patients with HFpEF, there are also many patients who do not have that same delayed relaxation of the heart, that true diastolic dysfunction as you would measure it on an echocardiogram, but still have a syndrome of heart failure, which is a rise in left ventricular filling pressures at rest or with exercise. 

Dr. Rati Vani: That’s so interesting. I started reading into that and was surprised to learn that  ⅓ of HFpEF patients don’t have diastolic dysfunction on their resting echocardiograms. 

Dr. Shreya Trivedi: Yeah and this may be getting too into the weeds, but  there are basically 4 specific things you look at on the echo to determine diastolic dysfunction. We will link more specific these in the show notes. But big picture, what are the 4 things? 1) LA enlargement or LA volume index, 2) The E/e Prime ratio >12-14. Which just means hard did that left side have to work to pump blood, 3) Looking at tissue doppler velocities (which the septal and lateral e prime velocity), and lastly 4) TR velocity. If 3 or more present on echo are abnormal on echo, that is diastolic dysfunction, and if 2 are present it’s “indeterminate.” 

Dr. Jen Ho: The other point to keep in mind with echo is it can be helpful when it’s abnormal. However, some people with HFpEF can actually have normal echoes as well. So that’s what makes it really, really tricky. 

Dr. Shreya Trivedi: Wait wait wait…we went over that patients with HFpEF do not necessarily have diastolic dysfunction, but now you’re telling me some patients with HFpEF have no abnormal finding on echo?

Dr. Rati Vani: That is exactly what we mean! And this  blew my mind, too!

Dr. Jen Ho: There was a trial called PARAGON-HG, which looked at a ARNI versus ARB in patients with HFpEF and the echocardiographic sub-study looked at a bunch of patients who were enrolled with known HFpEF and up to a third had normal echoes, meaning they didn’t have evidence of left atrial enlargement or left ventricular hypertrophy. And so you can see that again, echo is not a gold standard diagnostic test for HFpEF. Some people, for all intensive purposes can have normal looking echoes and still have the clinical syndrome of HFpEF. So that’s I think another challenge in this field. 

Dr. Rati Vani: Yet another wrench to throw into the diagnostic challenge. And I really like cardiology because I really like when things make sense and so I loved how Dr. Patel explained how particularly patients with obesity might have normal echos. 

Dr. Ravi Patel: Essentially there’s a syndrome that we are beginning to see where patients’ hearts are, especially in obese patients, are just essentially mismatched in terms of size. So their LV size is just not big enough to handle the amount of circulating blood volume that they have. As a result, they might not have elevations in filling pressures at rest, but when they exercise and more circulating blood volume is required, they will have elevations in their wedge pressure and symptoms of dyspnea.

Dr. Rati Vani: So another way to frame this is that the heart can’t supply the metabolic demands of the body in obesity, and this can lead to high output heart failure which can be considered a subset of HFpEF. 

Dr. Shreya Trivedi: Oh yeah, so I guess you’re saying that in patients with obesity, there are more cells, creating more demand, and that can lead to the symptoms of heart failure.

Dr. Rati Vani: That’s a great way to put it. So often patients with obesity will have normal echos at rest but then its really on exertion that their LV cant compensate for these higher circulating volume and that leads to the higher pressures we see.

Dr. Shreya Trivedi: I used to think that someone could not have heart failure unless they have a large atrium and stiff ventricles meaning e/e’ ratio >12-14 but I realized that is not the case.

Dr. Rati Vani: I’m totally with you, Shreya, I’m used to being on heart failure rounds and looking at echos and pointing out how dilated the atria. Let’s take a minute to talk a little more about the left atrium. 

Dr. Ravi Patel: We assume that diastolic dysfunction is also resulting in certain aspects we see on an echocardiogram like left atrial enlargement. Left atrial enlargement in and of itself does not measure anything with regard to diastology, but it’s felt to be a surrogate for chronically elevated left ventricular filling pressures. And the same goes for pulmonary artery or right ventricular systolic pressures on echo, which we use as a surrogate for diastolic dysfunction. 

Dr. Rati Vani: It looks like all of these echo findings tie together, and none of them in particular give us a clear picture on their own. So patients with HFpEF can have a clear combination of these findings, but they could also have none of these findings at all.

Dr. Shreya Trivedi: Ah, it is a hard topic. So let’s summarize what were taking away, we learned that having diastolic dysfunction doesn’t label someone as HFpEF. And on the flip side, we learned that NOT having diastolic dysfunction on the echo doesn’t NOT mean HFpEF. A patient needs to have the the clinical syndrome of volume overload and elevated left filling pressures at rest or exercise (which we talked about in obesity) and they can have a completely normal echo meaning normal LA size and all those  e’ velocities.  

Pearl 3 – BNP

Dr. Shreya Trivedi: So that was all echos! What about brain natriuretic peptides? BNPs? Can they help us out with something a bit more objective when it come to HFpEF?

Dr. Ravi Patel: So BNP, it’s a very unique hormone. It’s obviously one that’s secreted by the heart and its secretion is stimulated by wall stress. Okay, so wall stress of the LV wall, stress of the LA and potentially the RV will contribute to elevation in BNP. So if one is potentially congested, BNP will go up as a result of wall stress.

Dr. Rati Vani: So that all makes sense in theory. But wall stress means BNP should be elevated. So technically it should be able to help us out with the diagnosis of HFpEF.

Dr. Jen Ho: There are various different reasons why you can have an elevated natriuretic peptide level. The most typical reason is with cardiac stretch. And so that’s what makes it such a good marker of heart failure. So we know that of course in patients presenting with dyspnea and suspected heart failure, natriuretic peptides are sort of the central test that we send to try to verify whether or not they have heart failure. I think certainly in the setting of chronic kidney disease in the setting of atrial fibrillation, your natriuretic peptide levels can often be more elevated than what we would typically see in just volume overload states. Women typically have higher natriuretic peptide levels compared with men in general. So I think that’s so fascinating. We don’t really know why. And then I guess, the flip side, similar to echo, a normal peptide level unfortunately is not awesome at ruling out HFpEF. 

Dr. Shreya Trivedi: Oh, bummer! It sounds like BNP by itself is another test that can be helpful, but is just one more piece of the puzzle. Rati, can you help us make it all make sense! Why would the BNP be normal in some patients with HFpEF?

Dr. Rati Vani: So what I learned from talking to our experts is that NT-pro-BNP is influenced by all like of factors like age, obesity, or as Dr. Ho mentioned,  atrial fibrillation and kidney disease.  

Dr. Shreya Trivedi: So sounds like most of these confounders are related to our garden variety patient with HFpEF, especially with metabolic syndrome and all, so I see how this things add up to be a bit tricky.

Dr. Rati Vani: Yeah and it gets even trickier because one surprising confounder that I learned about is in our patients with hypertension who over time develop LV hypertrophy and that actually ends up lowering the BNP.

Dr. Ravi Patel: Hypertrophy of the LV will actually create less wall stress. So a condition that is very common in HFpEF can actually paradoxically result in lower BNP. So the stimulus for BNP going up, which is increased wall stress goes down in the setting of LVH. So that’s one reason why it’s not as helpful or it might not rise as much. The second is the clearance of BNP, which we think is due to adipose tissue. We think adipose tissue clears natriuretic peptides out of the circulation. So in patients who are obese, they may have lower BNP because that BNP is being cleared more quickly.

Dr. Shreya Trivedi: Ah! This is such interesting physiology, when there is left ventricular hypertrophy, that decreases wall stress and less BNP is leaked out and adipose tissue, on top of that, clears the BNP. 

Dr. Rati Vani: And then I also learned a new term that was pretty interesting – BNP deficiency.

Dr. Ravi Patel: There’s thought that potentially there are patients who are BNP deficient, BNP is a marker, but as a hormone in its function, it’s a B type natriuretic peptide. It results in natriuresis, it’s a vasodilatory hormone that is a beneficial hormone. We’ve studied natriuretic peptide analogs as therapies for heart failure. And so there’s a thought that there are some patients who don’t secrete enough BNP and their BNP is low, and that might actually drive some of their heart failure, that they don’t have this beneficial hormone. And so that’s why we don’t see it in the circulation.

Dr. Rati Vani: Thats such a new way of thinking about BNP, as a helpful hormone in heart failure. I’m just so used to seeing an elevated BNP and thinking “oh no” but maybe I should be more concerned when I look at a patient and they’re clearly volumed overloaded to me and I turn and look at the computer and see the BNP is really surprisingly low.

Dr. Jen Ho: We know there are patients who have natriuretic peptide deficiency we call it. They can often have very low natriuretic peptide levels despite being very volume overloaded. In some studies we think this is tied to having obesity. Some of it might be related to insulin resistance as well. And we know there are natriuretic peptide gene variants that can often affect your natural levels of natriuretic peptides and cause some variation between individuals even in healthy states. So all of those reasons are potential etiologies for natriuretic peptide deficiency. And so when you see a normal BNP in someone presenting with true clinical heart failure, they still have true clinical heart failure.

Dr. Shreya Trivedi: Okay so to to recap, BNPs are normally produced and released because of increased myocardial wall stress, but the BNP level can be normal in HFpEF especially when there is left ventricular hypertrophy going on for a while or obesity. Last interesting thought to end is that there is actually BNP deficiency which can actually leave some of our patients even more susceptible to volume and pressure overload.

Pearl 4 – Advanced Testing

Dr. Rati Vani: Before we get into advanced testing for HFpEF, it may be helpful to recap the big picture where we are.

Dr. Ravi Patel: I think that HFpEF is a very unique syndrome in cardiology. Again, we don’t have one diagnostic test. I am very, very reticent to rule out the diagnosis of HFpEF based off of a single test, whether it be a BNP, an echocardiogram, specifically those two criteria. And I would say that that’s one of the things that I’ve learned a lot is, is that there’s no one test to rule in, but there should be no one test to rule out either. So if there is a patient that you see in clinic that is complaining of shortness of breath and things don’t smell cardiac based off of laboratory testing or echocardiographic testing, just be mindful that there is a possibility that it is still HFpEF lurking.

Dr. Shreya Trivedi: So there’s a lot of clinical gestalt and factors you are weighting when we’re talking about HFpEF. And it just makes me wonder if there are any HFpEF risk calculators to have something to help guide us one way or the other?

Dr. Jen Ho: I do think the risk scores may be helpful when the diagnosis isn’t clear based on your first tier testing. So your first tier testing I would say is your clinical exam, your history, natriuretic peptides, and echo. If after that the diagnosis is still not clear, I think potentially getting some sense from these diagnostic scores of risk stratification can be helpful.

Dr. Rati Vani: We asked Dr. Ho to tell us a little more about these risk calculators and how to use them, when to use them, if we should even be using them.

Dr. Jen Ho: There are two diagnostic scoring algorithms that have been developed in recent years. One is called the H2FPEF score and the second is called the HFA-PEFF score. The idea of both of these scores is that they incorporate comorbid conditions plus natriuretic peptides plus a echo findings to kind of risk stratify people. And if you have a low risk score, you effectively rule out HFpEF. If you have a high risk score, you effectively rule it in. And if you’re intermediate, those are the people where we may want to consider pursuing advanced testing. So those are the two scores. I would say that there’s some potential for misclassification with these scores, and so we just have to be cautious. For example, the H2FPEF score was developed in the Mayo Clinic where people get referred if there’s a question for HFpEF. And so the pre-test probability walking in the door of somebody having HFpEF was something like 60% or greater.

Dr. Shreya Trivedi: Okay. So we have to think carefully about who we invoke these risk calculators. So I am curious then, who is it useful for? 

Dr. Ravi Patel: There are people who do walk around with HFpEF who may not be hospitalized frequently, if at all, and this score can be extremely useful for them. So I use it in the outpatient setting a lot among patients who have never been hospitalized and who are having dyspnea related syndromes and have seen pulmonary or seeing me and have not had a diagnosis made. I’ll use this as a screening tool to say, well, what’s the probability of having HFpEF?

Dr. Rati Vani: And in some cases where it’s really hard to tease out if it’s HFpEF, is it not,  and particularly if the patient’s exam is tough to tell if they are volume overload and their symptoms are vague, then it is helpful to reach for some more advanced testing like right heart cath or cardiac MRIs. 

Dr. Jen Ho: There are cases that are challenging where the diagnosis is still not clear, you’re not really sure where the JVP is. It’s hard to see. And in that setting, if the diagnosis is still not clear, I do think I sometimes turn to what I call advanced testing, and that can involve invasive hemodynamic testing. So we can do, for example, a right heart catheterization to assure that what we think is the JVP on exam is actually evidence of elevated filling pressures in somebody. And so that might be really helpful to confirm your diagnosis in cases when you’re still not sure and the exam maybe is not so clear. 

Dr. Shreya Trivedi: Man, can I just say how validated I feel when cardiology sees one of my patients, also feels like the exam is hard and recommends a right heart cath! And I am like, yes, please, thank you!

Dr. Rati Vani: I know exactly how you feel! Especially when you have a patient who only has symptoms on exertion. 

Dr. Ravi Patel: So patients are often, they often feel fine at rest, but with exercise they get short of breath and it’s often not diagnostic when all of our diagnostic tests are when the patient is lying down in the left lateral decubitus position that we’re going to be able to identify the syndrome. It’s a syndrome that is exertional. It’s a syndrome that is exercise induced. And so a lot of times we have to bring a patient to the cath lab, put a right heart catheter procedure and get that done, understand what their physiology is when we perturb the system, when we exercise them, to really understand what’s going on. And that’s not easy to tell in clinic.

Dr. Shreya Trivedi: Wow, I’ve never heard of someone exercising  during the right heart cath. And though Dr. Ho did agree exercising is good provocative maneuver, but she also shared some other options if that isn’t possible…

Dr. Jen Ho: The other provocative maneuvers that have been studied in that setting are either passive leg raise. So it turns out that even with passive leg raise and increasing your venous return, sometimes you can sort of provoke an abnormal response. And then the other potential maneuver to consider is volume challenge. So you can give them some IV fluid and sort of see do they have, again, it’s like very exorbitant rise in LV filling pressures that indicates LV stiffness. 

Dr. Shreya Trivedi: Okay so that’s the right heart cath. What about cardiac MRIs? When can that be helpful?

Dr. Rati Vani: So cardiac MRI or other advanced testing is not required for a diagnosis of HFpEF, but cardiac MRI can really be helpful to investigate those HFpEF masqueraders, we talked about way in the beginning, like amyloidosis.

Dr. Shreya Trivedi: Okay so it sounds like MRI wont necessarily give us any more information about the typical, garden variety HFpEF but is more helpful in investigating HFpEF masqueraders, which definitely kind of changes management. To wrap this up this pearl, we talked about risk calculators for HFpEF which are typically used for more ambiguous cases in the outpatient setting where you’re suspicious of possible HFpEF. These particularly tricky cases can be further worked up with right heart cath, especially when you want to provoke symptoms during exercise.

Pearl 5 – Treatments for HFpEF

Dr. Shreya Trivedi: Now that we have unlearned a ton of about the diagnosis of HFpEF. I’ve lost count on the things I’ve unlearned. Let’s round things out with management of HFpEF.

Dr. Jen Ho: HFpEF is a disease of multimorbidity and so often it’s really hard to completely attribute someone’s symptoms to one single cause alone. Right? Often we see patients who have obesity plus HFpEF plus C OPD plus diabetes and hypertension, and maybe some valvular component to this as well. And I think it’s really challenging and often impossible to kind of pinpoint your finger as to one etiology that’s going to fix all of their symptoms. Because often they’re presenting with multimorbid conditions, and so really making sure we’re treating their hypertension, their coronary disease, we’ve optimized their diabetes treatment, we’re thinking about obesity. So all of those things are really important. 

Dr. Rati Vani: I really appreciate how Dr. Ho talks about treating the risk factors as a part of the management explicitly. I know when I look at notes and under the #HFpEF problem, I rarely see focusing on the risk factors for HFpEF 

Dr. Shreya Trivedi: Yeah same! I’m glad we went over that. I think something I can change, in addition to HFpEF syndrome, is adding a risk factor point in there. With that being said, let’s move on to medications for the true clinical HFpEF. I know with HFrEF, it seems straightforward with the GDMT we have, but I’m curious with HFpEF, what’s the treatment we have on deck here?

Dr. Jen Ho: In terms of a general approach, I would say I typically consider SGLT2 inhibitors broadly in everyone with HFpEF. When there’s congestion present, I actually really like potentially considering upfront mineralocorticoid receptor antagonist because they can treat some of the congestion and may minimize your use of the loop diuretic. But if people still have congestion, then of course we’re using loop diuretics. And then in the setting of persistent symptoms with blood pressure room, I would consider ARNI.

Dr. Rati Vani: Okay so the key players in HFpEF are SGLT2 inhibitors and mineralocorticoid receptor antagonist aka MRAs. We can also think about ARNIs especially if blood pressure is still an issue. And then we cannot leave out the huge utility of loop diuretics for symptom management.

Dr. Shreya Trivedi: With all that laid out, let’s take a closer look into the 1st line treatment in HFpEF, SGLT2 inhibitors.

Dr. Jen Ho: There have been two pivotal trials that have really put SGLT2 inhibitors on the map as first line for anybody with HFpEF. Those two trials were EMPEROR-Preserved and DELIVER, and they looked at treatment with either empagloflozin or dapagliflozin. 

Dr. Shreya Trivedi: So these studies showed that Empagliflozin decreased risk of HF hospitalization and CV mortality (we love that) in patients with  HFpEF as well as heart failure with mid ejection range, which has a cutoff of EF >40%. I think the cool kids say HFmrEF for that?! Rati, am I correct?

Dr. Rati Vani: As a cool kid myself, I would say HFmrEF.

Dr. Shreya Trivedi: You’re definitely more in the know than most of us!

Dr. Rati Vani: Thanks, Shreya, and to build off of that, the second line treatments after an SGLT2i is added include both MRA and ARNI.

Dr. Shreya Trivedi: So with MRA, we have the TOPCAT trial showed that spironolactone is associated with a small reduction in cardiovascular hospitalizations.

Dr. Rati Vani: Yeah but spironolactone didn’t reduce cardiovascular deaths in HFpEF in that trial.

Dr. Shreya Trivedi: Okay, that’s all good to know. And then what about ARNIs? When are we reaching for that? What’s the story behind why ARNIs made it into second line.

Dr. Jen Ho: Angiotensin receptor-neprylisin inhibitors or ARNI. The trial that looked at the use of these agents is called PARAGON-HF. The overall trial was neutral, but subgroup analysis showed some potential benefit in people with what they called the low normal EF, and interestingly also benefit among women compared with men. So currently ARNI use deserves a class IIB indication in the US guidelines. And I would say that we’re using them mostly in people who have persistent symptoms on an SGLT2 inhibitor who also have evidence of hypertension, and in particular in people with below normal EF or in this awkward category of heart failure with mid-range EF. 

Dr. Shreya Trivedi: So ARNIs for HFpEF aka  acubitril-valsartan or Entresto did not lower heart failure admissions or cardiovascular mortality more than valsartan alone. But the good thing was that the ARNI group did have an improvement in symptoms.

Dr. Rati Vani: I do have to take a moment here, Shreya, it’s fascinating what Dr. Ho mentioned, that PARAGON-HF showed how ARNIs led to a reduction in HF hospitalizations and cardiovascular mortality in women, but it did not do the same thing in men.

Dr. Shreya Trivedi: Yeah! That is really interesting to say, and it’s all subgroup analyses, but maybe this is a good point to recap treatment of HFpEF. It goes without saying that we have to address the risk factors of HFpEF and not just throw on meds. And then when it comes to meds, our 1st line treatment in HFpEF is SGLT2 inhibitors. And then after that, I can add either an MRA if there is congestion or ARNI when patients have a slightly lower EF or maybe in women (and again, this is all subgroup analysis rather than a hard recommendation). 

Dr. Rati Vani:And as we learn more about HFpEF there’s going to be even more to consider. We hear about GLP-1 agonists all the time.

Dr. Shreya Trivedi: All the time!

Dr. Rati Vani: So it’s not surprising that they have a role here as well.

Dr. Jen Ho: There’s a lot of excitement around an evolving role of GLP-1 receptor agonists. There were some promising data recently published and presented with a trial called STEP HFpEF that showed that GLP-1 receptor agonists in patients with HFpEF resulted in a sustained weight loss, but also really remarkable improvements in quality of life and also 6-minute walk distance. We don’t have trials powered on outcomes just yet, but I think this will be a quickly evolving landscape.

Dr. Shreya Trivedi: And like all things cardiology where there is so much research, and I’m sure the landscape will evolve rapidly and we will have data on GLP-1s when it comes to hospitalizations and mortality and things we care about pretty soon!

Dr. Rati Vani: And on that note, that’s a wrap for today’s episode!

Dr. Shreya Trivedi: Please share this with colleagues or anyone who may find this helpful. Please check out our Youtube channel for some behind the scenes interview content that did not make it on air, but is still so good!

Dr. Rati Vani: And thank you to our reviewers Dr. Greg Katz, Dr. Snehal Bhatt, and Dr. Randy Goldberg. This episode was made in part from the Digital Education track at BIDMC. Thank you to all the mentors involved in the work!

Dr. Shreya Trivedi: Thank you to Daksh Bhatia for the audio editing. As well as Dr. Michelle Lo for the accompanying graphic. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.


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