Heart Failure Podcast

HFpEF Mimickers, GDMT and Treatment-Tailoring Strategies

Michelle M. Kittleson, MD, PhD; Jennifer E. Ho, MD


April 06, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Michelle M. Kittleson, MD, PhD: Welcome to Medscape InDiscussion on heart failure. I'm your host, Dr Michelle Kittleson. This is episode five of our 12-part series, in which we first explore the six core challenges and issues affecting patient care, and then turn our attention to tackling special concerns in the final six episodes. Today we'll discuss the management of heart failure with preserved ejection fraction, or HFpEF. Why is HFpEF difficult to diagnose and treat? What do busy clinicians need to know to efficiently diagnose this heterogeneous and increasingly prevalent condition? What are the must-use tools to support decision-making and optimal care? For expert guidance on these questions, we've invited advanced heart failure specialist Dr Jennifer Ho. Dr Ho is associate professor of medicine at Harvard Medical School, and she directs research in the Division of Cardiovascular Medicine at Beth Israel Deaconess Medical Center in Boston, Massachusetts. Dr Ho's research focuses on the mechanisms driving heart failure, with a specific focus on HFpEF. Welcome, Jen. I'm delighted to have you.

Jennifer E. Ho, MD: Thank you so much, Michelle. It's such a pleasure to be here.

Kittleson: You're known for your expertise in HFpEF. Can you tell us what it was that made you want to specialize in heart failure? What do you do to stay engaged today?

Ho: There are really two aspects of why I'm passionate about heart failure. First, clinically, I've always loved the fact that if you can understand underlying pathophysiology with your exam or with your hemodynamic evaluation, it can directly help guide what you do from a therapeutic perspective at the bedside. Second, what we get to do every day is special. We get to know our patients, to walk alongside them through both the ups and the downs of their disease trajectory. I think that's unique.

Kittleson: I couldn't have said it better myself. You get emotional fulfillment and intellectual fulfillment. Why isn't everyone a heart failure cardiologist? Amazing. Our focus today is on HFpEF. We're going to cover challenges in diagnosis and management.

So, your patient has shortness of breath. The echo shows an EF of 50%. How do you know it's HFpEF? What do you need to exclude? What treatment strategies are beneficial? Let's talk about that patient with shortness of breath and an echo showing an EF of 50%. What's your approach to make the diagnosis? Do you use scores like the H2FPEF and HFA-PEFF in clinical practice, or is it more of a clinical gestalt?

Ho: First, I think an important point to make is that HFpEF is largely a clinical diagnosis. We can really rely on the fundamentals of a good history and physical exam. If there's evidence of congestion based on the typical features of heart failure, such as orthopnea, PND [paroxysmal nocturnal dyspnea], and elevated jugular venous pressure, then a diagnosis of HFpEF can be made. We, of course, use natriuretic peptide levels and evidence of cardiac remodeling on echo to help confirm the diagnosis here.

Where I think the diagnosis of HFpEF is much more challenging is among patients who present primarily with dyspnea on exertion or exercise intolerance. These patients may have no evidence of rest congestion. It's really with exercise that we unmask very abnormal left ventricular filling pressures. In the latter case, I usually start with an echo and check natriuretic peptides, but it's important to remember what we've learned from multiple studies: that both the echo and the natriuretic peptide levels may be normal in patients who have HFpEF. This is where I think some of the diagnostic scores you mentioned, such as the H2FPEF score or the ESC's [European Society of Cardiology's] HFA-PEFF score, can be useful. We think that low-risk scores effectively rule out the diagnosis and high-risk scores rule it in. In the intermediate-risk group is where we can consider advanced testing, such as provocative maneuvers or exercise hemodynamic evaluation. You've previously shown that there can be some misclassification that happens with these scores, particularly among the low-risk category. I don't typically use them as definitive evidence but rather in the context of the whole clinical presentation.

Kittleson: It's really a snapshot of medicine in general — the importance of the history and physical exam to start your wide differential, then you narrow down successively with ancillary testing and the lesson that no test is 100% perfect. You must incorporate it into your clinical gestalt. I love that framework you gave us: Start with the history, move on to the physical, and use these scores to help you, but don't blindly follow them. Trust your judgment and how the patient in front of you looks. Super-helpful.

Now, the other issue is the mimickers or the masqueraders. Which ones do you routinely consider? For example, we know that in observational series of patients admitted with decompensated heart failure and preserved EF, about 15% of them can have cardiac amyloidosis — a diagnosis you don't want to miss. How do you reassure yourself when you encounter a patient who is short of breath with preserved EF that it's a garden-variety HFpEF vs another condition for which there might be disease-directed therapy?

Ho: That's a really important point. There are many etiologies that can lead to the diagnosis of HFpEF on echo. It's really critical to distinguish other primary causes that lead to secondary HFpEF or mimickers of garden-variety HFpEF, which is typically what we think of as somebody with HFpEF in the context of typical comorbid conditions, such as obesity or metabolic disease. The most important mimickers that I routinely consider are infiltrative cardiomyopathies, such as cardiac amyloidosis (as you mentioned), coronary artery disease, valvular disease, sarcoid and hereditary or genetic cardiomyopathies, such as hypertrophic cardiomyopathy, or pericardial disease. The reason that this is important is that these conditions would prompt a specific management strategy that differs from the routine management of HFpEF.

How do we approach this evaluation? I think it's easy for all of us to get anchored on a single diagnosis, and this is the one case in which we want to be actively thinking about it across the broad differential of mimickers. I typically again start with the basics — a good history, physical exam, ECG and echo, and natriuretic peptides. I think easy clues to look for are anything that makes me think there's significant right ventricular involvement. For example, a Kussmaul sign on exam or right ventricular hypertrophy on echo should prompt you to think that there's potentially a more global process, including a global cardiomyopathy. Left ventricular hypertrophy that's out of proportion to the degree of hypertension or aortic stenosis, for example, should prompt you to think that there may be an infiltrative component or hypertrophic component. Biatrial enlargement suggests an infiltrative process that's not typical of garden-variety HFpEF. With findings such as conduction block on ECG, it's important to have a low threshold for further diagnostic testing. Then there are other clues on medical history that suggest systemic disease, and family history that we can gather. I think this is a situation in which we need to be detectives and constantly be vigilant about these mimickers to prompt comprehensive diagnostic evaluation.

Kittleson: I love that approach as well. I think it becomes so overwhelming sometimes for the busy clinician. You're faced with a patient in whom you don't want to miss anything, but some of it is pattern recognition — that is, the pattern recognition you get from the history, the physical exam, and the basic initial testing. You would never recommend that all patients who present with heart failure and an EF above 50% need an MRI, that they all need a technetium scan, that they all need a monoclonal protein screen — absolutely not. But there are things that don't sit right. They're not your typical older woman with hypertension, diabetes, obesity; there's something not quite right. There's a family history. There's musculoskeletal neurologic-type or autonomic dysfunction. There's something heading you in a different direction. Listen to your gut. Do the pattern recognition before you decide on other tests — the perfect approach.

The other thing that's interesting to me about HFpEF is that heart failure is a scary term for patients. We know that HFpEF and HFrEF — heart failure with reduced ejection fraction — have comparable prognoses, so patients with HFpEF often succumb to comorbidities rather than to advanced heart failure. We know that patients with HFpEF are generally older and often don't have options, such as heart transplantation, available to them. How do you counsel patients with HFpEF on their diagnosis and prognosis, offering that appropriate balance of tempered optimism? Realistic expectations? I'd love to hear your approach.

Ho: Keeping the patient perspective at the center of this discussion is such an important point. Coming off the heels of our first positive HFpEF trials with SGLT2 [sodium glucose cotransporter 2] inhibitors, we're all excited to finally have something to offer with respect to therapies. But at the same time, I think it's crucial to recognize that the residual risk remains incredibly high among patients with HFpEF. For example, across about 13 CPET [cardiopulmonary exercise test] studies, the average peak VO2 [oxygen consumption] among patients with HFpEF is somewhere on the order of 15 milliliters of [O2] per kilogram per minute. This is really low and means that many of our patients with HFpEF are limited even in their activities of daily living. I think some encouraging results from trials such as PRESERVED-HF and other smaller trials of SGLT2 inhibitors do suggest that these medications significantly improve quality of life, as well as exercise capacity. I think that this is important to share with our patients, and it may have a major impact on what matters most to them from a day-to-day standpoint. On the other hand, a lot of work remains to be done. I hope this motivates us as an HFpEF community to keep going and to really encourage our patients to participate in some of the many ongoing clinical trials focused on HFpEF, which are looking at evolving medical therapies as well as devices. So, I remain hopeful that we can continue to make strides in the future.

Kittleson: That's such a good point. It's hard when patients perhaps go to Dr Google and look up HFpEF, and maybe read things out of context and look at survival curves. It's hard to apply the general statistic to the individual patient. I tell patients, "Listen, let's not stress about what we cannot control. No one can predict or control the future, but we control what we can, which is giving you, number one, the right diagnosis; that's empowering. And number two, the best therapy we can give you, so you have peace of mind. You've done everything you can to feel as good as possible." I love that point you made about the clinical trials. It's such a ripe area for clinical trials, where there's much we need to know and so much that patients can't receive with routine care.

You touched a bit on treatment. We have guideline-directed medical therapy [GDMT] for HFpEF. We have the 2022 Heart Failure Guidelines, which have some class 2a and class 2b recommendations. For you, is it a one-size-fits-all? If so, what medications do you give, or do you tailor pharmacotherapy based on sex or based on the EF? Tell us your approach to GDMT.

Ho: I think of GDMT and a tailored approach as treatment strategies we really should be considering in parallel so we can maximize what we can do for our patients with HFpEF — again, going back to the previous point you made: Can we really do everything possible to help our patients feel as good as they can? Certainly, in terms of treatment, the primary goal is to treat volume overload if present. We know that diuretics are the only class 1 indicated medication in HFpEF. With respect to GDMT, we now know this consists of three classes of medications: SGLT2 inhibitors, mineralocorticoid receptor antagonists [MRAs], and angiotensin receptor neprilysin inhibitors, or ARNIs. My approach is to consider all these classes of medication in everyone with HFpEF. If we choose not to start one of them, make sure we understand why that is. We really should be thinking about it almost as an opt-out, rather than an opt-in, approach. We know that there's some interaction in left ventricular EF with ARNIs and with mineralocorticoid receptor antagonists, where most of the benefit is in patients with lower EFs. That's an important consideration.

In parallel, we need to be thinking about tailored strategies. I think the most important consideration is to treat underlying comorbidities. We know that treatment of hypertension, atrial fibrillation, and coronary artery disease is central to what we can offer. One big area that's really evolving is obesity, and related metabolic dysfunction has really become a key contributor to HFpEF. How we address this is central. We know that diet and exercise training can be beneficial. There is an evolving role of newer medical therapies to treat obesity. I'm excited to watch ongoing trials that are looking at GLP-1 [glucagon-like peptide 1] receptor agonists in patients with HFpEF. This is an evolving space that's exciting. Then last, in the right setting, we should be thinking about device therapies as well. We know from the CHAMPION trial that implantable hemodynamic monitors are useful in patients with HFpEF who have persistent symptoms or who are in and out of the hospital.

Kittleson: There was so much richness in there. We're going to dive deep now because I've got questions. So, the SGLT2 inhibitor, the MRA, and the ARNI are your go-to agents. I love how you said "opt out." This is the standard of care — triple therapy for HFpEF. But tell me, does it matter to you if they're a man or a woman? Do you stratify by EF, or do you say, "You know what, if I check three echo's 3 days in a row, they'll probably be a little bit different. Everyone gets everything."

Ho: Those are such great questions. I have not begun to treat women and men with HFpEF differently, although there are some data suggesting that the benefit of ARNIs may extend to higher left ventricular EF ranges among women. We do have some active work trying to figure out: Are we using EF cut points the same way in men and in women? Is that really the right approach in patients with HFpEF? I think there's more to come there. In general, I do consider all three agents for everybody. I do think that with ARNIs in particular, because they have the greater blood pressure effect, I feel more strongly about trying them in patients who have the lower end and normal EFs, rather than super-normal EFs. We know from a physiology standpoint that patients with small, stiff hearts tend to be less vasodilator responsive. That's sort of the thought process that we typically go through in considering that class of medications.

Kittleson: I love this approach you've given. I love it because the one thing we all get drilled into our skulls during medical school — not literally; there's no trepanation involved — is that subgroup analyses are hypothesis-generating. While wonderful, amazing researchers like you are going to ultimately tell us someday what we're supposed to do about EF gradations and sex differences. Right now, based on the best evidence we have, it's "Give your SGLT2 inhibitor; give your MRA; consider that ARNI." If we go by the Heart Failure 2022 Guidelines, we know that SGLT2 inhibitors have a class 2a rating because of meeting their composite endpoint. We know that the MRA and the ARNI have a class 2b rating, but maybe there's more to come. The strength of the recommendation may change. Triple therapy for HFpEF — opt-out. Make sure everyone is on them if there are no contraindications.

Ho: The other point to think about is we know that treatment of volume overload is central to treating HFpEF. While we use loop diuretics as the mainstay of therapy, we know that SGLT2 inhibitors and MRAs also have diuretic effects. So, I would say that in the presence of volume overload, we also should have a very low threshold for considering these other two classes of medications.

Kittleson: You also mentioned the lifestyle changes of obesity, the impact of exercise, the impact of weight loss. We know that cardiac rehab is not yet covered for HFpEF, so how do you counsel your patients when you know that exercise, calorie restriction, and weight loss can be beneficial?

Ho: I agree. I think the fact that cardiac rehab is not yet covered by CMS [Centers for Medicare & Medicaid Services] for patients with HFpEF is a challenge. In patients with severe obesity, I've benefited from consulting with my colleagues in the weight management center and nutrition department, and I often engage them early to have a multidisciplinary approach to the treatment of obesity in these individuals. One trial I'm excited about and to be aware of is REHAB-HFpEF. This is being led by investigators at Wake Forest and is actively enrolling. It is the first trial to look at a physical rehab strategy that's powered to examine clinical outcomes in HFpEF. Hopefully, with this in our armamentarium soon, we will be able to make moves on cardiac rehab reimbursement with respect to patients with HFpEF.

Kittleson: It's really what you mentioned — reaching out to your colleagues. Medicine is a team sport, and it's no more a team sport than with HFpEF, in which there are so many comorbidities in so many different organ systems.

So, what's the one thing you want listeners to do differently after hearing this podcast?

Ho: Maybe I'll ask for some leeway. There are two things I want listeners to take away: First, from a diagnostic perspective, I would say that going back to the basics again, including history and careful physical exam, is really important in making the diagnosis and also can provide clues to potential HFpEF mimickers, with natriuretic peptides and echo to help guide diagnosis and differential. The second point is that we're at an exciting time in the HFpEF space, in that we have therapies that work. We really ought to be thinking about GDMT in all of our patients with HFpEF, considering the three classes of medications that we mentioned — SGLT2 inhibitors, MRAs, and ARNIs — that are really the foundation, in parallel with targeting comorbid conditions such as hypertension and obesity.

Kittleson: That's amazing. I'd like to underscore a few takeaways from our conversation. One: Don't forget your history and physical. Two: Be reassured, based on your history, physical, and ancillary testing, that you have ruled out conditions that are masquerading as HFpEF. Three: Remember triple therapy for HFpEF. If patients are not on it, why are they not on it? Can they benefit from a blood pressure and volume management standpoint?

Dr Ho, it's been such a pleasure. Thank you for being here.

Ho: Thank you for having me.

Kittleson: Thanks for joining our discussion with Dr Jennifer Ho. There's much more ahead in the coming episodes, so be sure to check out the Medscape app and share, save, and subscribe if you enjoyed this episode. I'm Dr Michelle Kittleson for Medscape InDiscussion.


How to Diagnose Heart Failure With Preserved Ejection Fraction: The HFA-PEFF Diagnostic Algorithm: A Consensus Recommendation From the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

Prognosis of Adults With Borderline Left Ventricular Ejection Fraction

The H2FPEF and HFA-PEFF Algorithms for Predicting Exercise Intolerance and Abnormal Hemodynamics on Heart Failure With Preserved Ejection Fraction

Dyspnea, Orthopnea, and Paroxysmal Nocturnal Dyspnea

Natriuretic Peptides for the Detection of Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction—A Systematic Review and Meta-analysis

Invasive Hemodynamic and Metabolic Evaluation of HFpEF

Heart Failure Resulting From Age-Related Cardiac Amyloid Disease Associated With Wild-Type Transthyretin: A Prospective, Observational Cohort Study

Cardiomyopathies: An Overview

Kussmaul's Sign for the Diagnosis of Right Ventricular Myocardial Infarction: A Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies

Echocardiographic Evaluation of the Right Heart

MGUS Predicts Worse Prognosis in Patients With Coronary Artery Disease

Effect of Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Cardiopulmonary Exercise Test: Background, Applicability and Interpretation

Peak Oxygen Consumption and Prognosis in Heart Failure

The Prevalence of Activities of Daily Living Impairment in Patients With Heart Failure: A Systematic Review and Meta-analysis

The SGLT2 Inhibitor Dapagliflozin in Heart Failure With Preserved Ejection Fraction: A Multicenter Randomized Trial

2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines

Heart Failure With Preserved Ejection Fraction: A Kidney Disorder?

Optimal Pharmacologic Treatment of Heart Failure With Preserved and Mildly Reduced Ejection Fraction: A Meta-analysis

The Role of Sacubitril/Valsartan in the Treatment of Chronic Heart Failure With Reduced Ejection Fraction in Hypertensive Patients With Comorbidities: From Clinical Trials to Real-World Settings

Effects of Mineralocorticoid Receptor Antagonists on Left Ventricular Diastolic Function, Exercise Capacity, and Quality of Life in Heart Failure With Preserved Ejection Fraction: A Meta-analysis of Randomized Controlled Trials

Glucagon-like Peptide 1 Receptor Agonists and Heart Failure: The Need for Further Evidence Generation and Practice Guidelines Optimization

Wireless Pulmonary Artery Pressure Monitoring Guides Management to Reduce Decompensation in Heart Failure With Preserved Ejection Fraction

Narrative Review in the Current Role of Angiotensin Receptor-Neprilysin Inhibitors

Medicare Coverage Database: Cardiac Rehabilitation Programs

Beth Israel Deaconess Medical Center Weight Loss Program

Physical Rehabilitation for Older Patients With Acute Heart Failure With Preserved Ejection Fraction (REHAB-HFpEF)

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