HFpEF: 5 Pearls Segment

Core IM

On this episode of Core IM, the team discusses the diagnostic uncertainty around HFpEF, especially as this systemic condition becomes more prevalent with each passing year. In terms of diagnostics the episode will review echo findings, BNP nuances, and utility of advanced testing. It will also review evidence-based treatments for HFpEF. 

Learners will better understand the systemic pathogenesis of HFpEF as it relates to known risk factors, how to work up and interpret diagnostic studies in a patient with suspected HFpEF and the pharmacologic management of HFpEF.   

You’re invited to join Dr. Shreya Trivedi and her guests as they examine these points and more in HFpEF: 5 Pearls Segment.

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Welcome to Core IM, a virtual medical community! Core IM strives to empower its colleagues of all levels and backgrounds with clinically applicable information as well as inspire curiosity and critical thinking. Core IM promotes its mission through podcasts and other multimodal dialogues. ACP has teamed up with Core IM to offer continuing medical education, available exclusively to ACP members by completing the CME/MOC quiz.

Pearl 1: What is 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 (especially for predominant metabolic 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 

      • E/e’ > 14 

      • Septal e’ velocity < 7 cm/s, lateral e’ velocity < 10 cm/s 

      • TR velocity > 2.8 m/s 

      • LA volume index > 34 mL/m2 

  • 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 

    • 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 



Shreya Trivedi, MD, ACP Member – Host, Editor
Rati Vani, MD – Host, Editor, MOC questions
Abhi Gami, MD - Editor
Jennifer Ho, MD - Guest
Emily Lau, MD – Guest*
Ravi Patel, MD - Guest


Randy Goldberg, MD
Snehal Bhatt, MD *
Gregory Katz, MD

*Snehal Bhatt, MD – Consultant: Janssen Pharmaceuticals 

*Emily Lau, MD – Consultant: Astellas Pharmaceuticals; Travel: Roche Diagnostics Corp

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  June 5, 2024 

Expiration Date: June 3, 2027 

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