HFpEF: 5 Pearls Segment

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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 ⅓ 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 

Contributors

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

Reviewers

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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