Heart failure with preserved ejection fraction (HFpEF)

Heart failure with preserved ejection fraction (HFpEF): diagnosis and management

A comprehensive, guideline-oriented clinical review

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Definition and epidemiology

Heart failure with preserved ejection fraction (HFpEF) is defined as clinical heart failure with a left ventricular ejection fraction (LVEF) ≥50%, evidence of cardiac structural and/or functional abnormalities, and elevated filling pressures at rest or during stress.

HFpEF accounts for ~50% of all heart failure cases and its prevalence continues to rise due to population aging and increasing burden of hypertension, obesity, diabetes, and chronic kidney disease. Mortality remains comparable to HFrEF, with frequent hospitalizations and poor quality of life.

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Pathophysiology: why HFpEF is complex

HFpEF is not a single disease but a syndrome driven by systemic inflammation and multiorgan dysfunction.

Key mechanisms include:

• Left ventricular diastolic dysfunction (impaired relaxation + increased stiffness)

• Concentric remodeling and hypertrophy

• Left atrial dysfunction and elevated filling pressures

• Coronary microvascular dysfunction

• Pulmonary hypertension (post-capillary ± pre-capillary)

• Chronotropic incompetence

• Skeletal muscle and peripheral oxygen utilization abnormalities

Comorbidities such as obesity, diabetes, hypertension, atrial fibrillation, CKD, anemia, and sleep apnea play a central pathogenic role rather than being mere associations.

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Clinical presentation

Symptoms are often nonspecific and exercise-related:

• Exertional dyspnea

• Fatigue and reduced exercise tolerance

• Orthopnea or paroxysmal nocturnal dyspnea

• Peripheral edema (less prominent than HFrEF)

• Palpitations (often due to atrial fibrillation)

Elderly women with long-standing hypertension and obesity represent the classic phenotype, but HFpEF is increasingly recognized across all demographics.

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Diagnostic approach to HFpEF

HFpEF diagnosis requires integration of clinical, imaging, and biomarker data.

Step 1: Confirm heart failure syndrome

• Typical symptoms/signs of HF

• Exclude non-cardiac causes of dyspnea

Step 2: Document preserved EF

• LVEF ≥50% on echocardiography

Step 3: Demonstrate elevated filling pressures

This is the cornerstone and most challenging step.

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Echocardiography in HFpEF

Transthoracic echocardiography is the first-line test.

Key parameters:

Structural criteria

• Left atrial enlargement (LAVI >34 mL/m²)

• LV concentric remodeling or hypertrophy

Functional criteria

• E/e′ ratio (septal ≥15, average ≥13)

• Reduced e′ velocity (septal <7 cm/s, lateral <10 cm/s)

• TR velocity >2.8 m/s

• Pulmonary artery systolic pressure elevation

Diastolic dysfunction grade II or III strongly supports HFpEF.

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Natriuretic peptides

• BNP ≥35 pg/mL or NT-proBNP ≥125 pg/mL supports diagnosis

• Levels may be falsely low in obesity

• Atrial fibrillation markedly elevates values

Normal natriuretic peptides do not fully exclude HFpEF, especially in obese patients.

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Scoring systems for diagnosis

H2FPEF score

Components: • Heavy (BMI >30)

• Hypertensive (≥2 antihypertensives)

• Atrial fibrillation

• Pulmonary hypertension

• Elder (age >60)

• Filling pressure (E/e′ >9)

Score ≥6 → high probability of HFpEF

HFA-PEFF algorithm

Developed by the Heart Failure Association of the European Society of Cardiology.

Domains: • Functional

• Morphological

• Biomarkers

Score ≥5 → definite HFpEF

Score 2–4 → indeterminate (requires diastolic stress testing or invasive hemodynamics)

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Advanced diagnostic testing

Diastolic stress echocardiography

• Exercise E/e′ and TR velocity

• Useful when resting studies are inconclusive

Invasive hemodynamics (gold standard)

• PCWP ≥15 mmHg at rest or ≥25 mmHg with exercise

• Reserved for complex or uncertain cases

Cardiac MRI

• Detects infiltrative diseases (amyloidosis, Fabry)

• Tissue characterization and fibrosis assessment

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Differential diagnosis to exclude

• Constrictive pericarditis

• Restrictive cardiomyopathy

• High-output heart failure

• Primary pulmonary hypertension

• Valvular heart disease (especially MR and AS)

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Management of HFpEF: principles

HFpEF management is multifaceted and phenotype-driven.

Core goals: • Reduce congestion

• Improve symptoms and quality of life

• Reduce hospitalizations

• Treat comorbidities aggressively

Unlike HFrEF, no single therapy dramatically reduces mortality; benefit comes from combination and personalization.

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Disease-modifying pharmacologic therapy

SGLT2 inhibitors (cornerstone therapy)

Empagliflozin and dapagliflozin are recommended for all eligible HFpEF patients regardless of diabetes status.

Benefits: • Reduced HF hospitalizations

• Improved quality of life

• Renal protection

This is the strongest evidence-based therapy in HFpEF.

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RAAS modulation

• ARBs (candesartan, valsartan): modest reduction in hospitalizations

• ARNI (sacubitril/valsartan): benefit particularly in LVEF 40–57%, women, and recent hospitalization

Blood pressure control remains a key indication.

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Mineralocorticoid receptor antagonists

• Spironolactone may reduce HF hospitalizations

• Careful monitoring of potassium and renal function required

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Diuretics

• Mainstay for symptom relief

• Loop diuretics for congestion

• No proven mortality benefit, but essential for quality of life

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Management of comorbidities (critical in HFpEF)

Hypertension

• Strict BP control (<130/80 mmHg)

Atrial fibrillation

• Rhythm control often preferred

• Catheter ablation may improve symptoms

• Anticoagulation per guidelines

Obesity

• Weight loss improves exercise capacity

• GLP-1 receptor agonists show promising data

Diabetes

• SGLT2 inhibitors first-line

• Avoid thiazolidinediones

CKD

• Nephroprotective strategies

• Avoid volume depletion

Sleep apnea

• Screen and treat (CPAP)

Coronary artery disease

• Revascularize when indicated

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Non-pharmacologic management

• Regular aerobic and resistance exercise

• Sodium restriction (individualized)

• Fluid management education

• Vaccinations

• Multidisciplinary HF programs

Exercise training has one of the strongest effects on functional capacity in HFpEF.

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Special HFpEF phenotypes

• HFpEF with pulmonary hypertension

• HFpEF with atrial functional MR

• Amyloidosis-related HFpEF

• Elderly frail HFpEF

• Obese-metabolic HFpEF

Future management is moving toward phenotype-specific therapy rather than a single umbrella approach.

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Prognosis

• Mortality similar to HFrEF

• High rehospitalization rates

• Prognosis driven by comorbidities rather than EF alone

Early diagnosis and comprehensive management significantly improve outcomes.

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Key take-home points

• HFpEF is a systemic, heterogeneous syndrome

• Diagnosis requires symptoms + preserved EF + elevated filling pressures

• Echocardiography and natriuretic peptides are central tools

• SGLT2 inhibitors are foundational therapy

• Comorbidity management is as important as HF drugs

• Personalized, phenotype-based care is the future

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