What is heart failure with preserved ejection fraction (HFpEF)?

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

HFpEF is a clinical syndrome characterized by symptoms and signs of heart failure (dyspnea, fatigue, edema) with a left ventricular ejection fraction ≥50%, elevated natriuretic peptides, and objective evidence of cardiac structural or functional abnormalities causing elevated filling pressures—not simply "diastolic heart failure." 1

Core Definition and Diagnostic Criteria

HFpEF requires three mandatory components to establish the diagnosis: 1

• Clinical symptoms/signs of heart failure: Including dyspnea on exertion, orthopnea, fatigue, jugular venous distension, pulmonary rales, peripheral edema, or S3 gallop 1
• LVEF ≥50% on echocardiography or other imaging modality 1
• At least one of the following objective findings: 1
  • Elevated natriuretic peptides (BNP >35 pg/mL or NT-proBNP >125 pg/mL in ambulatory patients; BNP >100 pg/mL or NT-proBNP >300 pg/mL in hospitalized patients) 1
  • Objective evidence of cardiogenic pulmonary or systemic congestion on imaging or invasive hemodynamics 1

Critical distinction: HFpEF is not synonymous with "diastolic heart failure"—this outdated terminology should be abandoned because most HFpEF patients exhibit both systolic and diastolic dysfunction. 2

Epidemiology and Clinical Impact

• HFpEF accounts for >50% of all heart failure cases in the United States, affecting more than 3 million Americans 1
• Incidence is rising while HFrEF incidence remains stable or declining, driven by population aging and increasing comorbidity burden 1
• Women are disproportionately affected compared to men, with higher prevalence and distinct clinical phenotypes 1
• Mortality is substantial: Annual mortality approximately 8% (lower than HFrEF at 19%), but morbidity remains comparable with frequent hospitalizations and severe functional impairment 2, 1

Pathophysiology and Clinical Manifestations

The primary clinical manifestation is severe exercise intolerance with exertional dyspnea and early-onset fatigue, even with mild physical activity. 1 This occurs because:

• Impaired ventricular relaxation and reduced compliance elevate left ventricular filling pressures, causing pulmonary congestion despite preserved systolic function 2
• Stroke volume and cardiac output remain normal at rest due to compensatory elevated filling pressures, but become severely compromised during exercise 2
• Reduced arteriovenous O₂ difference accounts for >50% of the reduction in peak VO₂ and is a stronger predictor of outcomes than exercise cardiac output 3

Common Comorbidities and Phenotypes

HFpEF is driven by systemic comorbidities that create distinct clinical phenotypes: 1

• Obesity/metabolic phenotype: Present in >80% of patients, with excess intra-abdominal fat playing a pivotal pathophysiological role 1
• Hypertension: Highly prevalent and a major risk factor for HFpEF development 1
• Diabetes mellitus: Present in 25-50% of patients, associated with worse outcomes 1
• Coronary artery disease: Common and associated with greater deterioration in LV function 1
• Pulmonary hypertension: Occurs in 52-83% of HFpEF patients, contributing significantly to right ventricular dysfunction and worse prognosis 3, 4
• Chronic kidney disease: Bidirectional heart-kidney dysfunction mediates volume overload and poor outcomes 1
• Sarcopenia and frailty: High burden associated with worse quality of life and increased clinical events 1

Diagnostic Challenges and Pitfalls

Common pitfall: Natriuretic peptide levels are lower in HFpEF than HFrEF for a given elevation in left ventricular end-diastolic pressure, and higher BMI (prevalent in HFpEF) further suppresses natriuretic peptide levels. 1 Do not rule out HFpEF based solely on "normal" natriuretic peptides in obese patients.

HFpEF mimics must be excluded: 1

• Infiltrative cardiomyopathy (amyloidosis, sarcoidosis)
• Hypertrophic cardiomyopathy
• Significant valvular disease (especially aortic stenosis, mitral regurgitation)
• Pericardial disease (constrictive pericarditis, tamponade)
• High-output heart failure
• Primary noncardiac causes (advanced kidney or liver disease)

Distinction from HFmrEF and HFrEF

The current classification system defines: 1, 2

• HFrEF: LVEF ≤40% 1
• HFmrEF (heart failure with mildly reduced EF): LVEF 41-49%, representing a heterogeneous group including patients with improving HFrEF or worsening HFpEF 1, 5
• HFpEF: LVEF ≥50% 1

This separation is clinically important because therapeutic strategies differ substantially—medications proven to reduce mortality in HFrEF (ACE inhibitors, beta-blockers) have not shown similar mortality benefit in HFpEF. 2

Treatment Implications

Management focuses on: 1

• Symptom control with diuretics for volume overload (started at low doses to avoid hypotension) 2
• Aggressive comorbidity optimization (hypertension, diabetes, obesity, atrial fibrillation) 1
• Guideline-directed medical therapy including SGLT2 inhibitors and selected use of mineralocorticoid receptor antagonists and angiotensin receptor-neprilysin inhibitors 6
• Supervised exercise training to improve exercise capacity and quality of life 1

Unlike HFrEF, positive inotropic agents are not useful in HFpEF since systolic function is preserved. 2