What is the diagnostic approach for Heart Failure with preserved Ejection Fraction (HFpEF)?

Diagnosis of Heart Failure with Preserved Ejection Fraction (HFpEF)

HFpEF diagnosis requires three mandatory components: symptoms/signs of heart failure, preserved left ventricular ejection fraction ≥50%, and either elevated natriuretic peptides OR objective evidence of cardiac structural/functional abnormalities, followed by systematic exclusion of cardiac and non-cardiac mimics. 1

Step 1: Establish Clinical Suspicion

Assess for cardinal symptoms and signs using specific criteria:

• Major criteria: orthopnea, jugular venous distension, hepatojugular reflux, pulmonary rales, S3 gallop, acute pulmonary edema, cardiomegaly 1
• Minor criteria: dyspnea on exertion, nocturnal cough, ankle edema, tachycardia (>120 bpm), hepatomegaly, pleural effusion 1

Identify high-risk demographics and comorbidities:

• Hypertension, obesity, diabetes mellitus, advanced age (>65 years), atrial fibrillation 1, 2
• These comorbidities are not just risk factors but often contribute directly to the pathophysiology 3

Step 2: Confirm Preserved Ejection Fraction and Measure Natriuretic Peptides

Obtain echocardiography to document LVEF ≥50% 1, 4

Measure natriuretic peptides with specific thresholds:

• Ambulatory patients: BNP >35 pg/mL or NT-proBNP >125 pg/mL 1
• Hospitalized patients: BNP >100 pg/mL or NT-proBNP >300 pg/mL 1

Critical caveat: Normal natriuretic peptide levels do NOT exclude HFpEF, particularly in obese patients who may have falsely low values despite elevated filling pressures 1, 5. If clinical suspicion remains high with normal peptides, proceed to advanced testing 5.

Step 3: Comprehensive Echocardiographic Assessment (HFA-PEFF Scoring)

Perform detailed echocardiography evaluating specific parameters with a scoring system:

Major criteria (2 points each):

• Septal e' <7 cm/s or lateral e' <10 cm/s 2
• Average E/e' ratio >15 2
• Left atrial volume index >34 mL/m² 2
• Tricuspid regurgitation velocity >2.8 m/s 2

Minor criteria (1 point each):

• LV mass index ≥115 g/m² (men) or ≥95 g/m² (women) 2
• LV relative wall thickness >0.42 2
• LV global longitudinal strain worse than -16% 2
• Average E/e' ratio 9-14 2

Interpretation:

• Score ≥5 points: Definite HFpEF 2
• Score 2-4 points: Indeterminate—proceed to functional testing 2
• Score ≤1 point: HFpEF unlikely 2

Step 4: Exclude HFpEF Mimics (Critical Step)

HFpEF is fundamentally a diagnosis of exclusion. 3 You must systematically rule out conditions that present identically but require different treatment.

Non-Cardiac Mimics:

• Kidney failure, liver failure with ascites, chronic venous insufficiency 3, 1

Cardiac Mimics Requiring Specific Testing:

Cardiac amyloidosis—test if:

• Increased LV wall thickness with "sparkling" appearance, musculoskeletal issues (carpal tunnel, lumbar stenosis), neuropathy 3
• Testing: Serum/urine immunofixation electrophoresis, serum free light chains, technetium pyrophosphate scan 3

Hypertrophic cardiomyopathy—test if:

• Unexplained LV hypertrophy, LV outflow tract obstruction, family history 3
• Testing: Cardiac MRI if echocardiogram uncertain 3

Cardiac sarcoidosis—test if:

• Extracardiac disease (pulmonary, ocular, dermatologic), high-degree AV block in patients <60 years, ventricular arrhythmias 3
• Testing: Cardiac MRI, FDG-PET scan, tissue biopsy 3

Hemochromatosis—test if:

• Family history, frequent blood transfusions, diabetes, erectile dysfunction 3
• Testing: Ferritin, transferrin saturation, HFE genetic testing, cardiac MRI with T2* imaging 3

Fabry disease—test if:

• Angiokeratomas, sensory neuropathy, proteinuria 3
• Testing: Serum alpha-galactosidase level (men), GLA genetic testing 3

High-output heart failure—test if:

• Four-chamber enlargement on echo, increased LV outflow tract velocity-time integral 3
• Testing: Investigate anemia, arteriovenous malformations, cirrhosis, fistulas, thiamine deficiency 3

Valvular heart disease, pericardial disease, restrictive cardiomyopathy:

• Usually evident on initial echocardiography but may require cardiac MRI for confirmation 3, 1

Step 5: Functional Testing (If Diagnosis Remains Uncertain After Step 3)

When intermediate HFA-PEFF score (2-4 points) or high clinical suspicion despite negative resting studies:

Exercise stress echocardiography:

• Measure E/e' ratio during exercise; elevation >15 confirms elevated filling pressures 1, 2

Invasive hemodynamic exercise testing (gold standard):

• Measure pulmonary capillary wedge pressure at rest and with exercise 1, 6
• Elevated wedge pressure ≥15 mmHg at rest or ≥25 mmHg with exercise confirms HFpEF 6

Step 6: Identify Contributing Comorbidities

Once HFpEF diagnosis is established, systematically document all contributing conditions that require treatment:

• Hypertension, diabetes, atrial fibrillation, obesity, coronary artery disease, renal dysfunction, sleep apnea 3
• These are not merely associated conditions but active contributors to the HFpEF syndrome requiring aggressive management 3

Common Diagnostic Pitfalls

Do not over-rely on single parameters: HFpEF diagnosis requires integration of clinical presentation, natriuretic peptides, and comprehensive imaging findings 1

Not all dyspneic patients with preserved EF and comorbidities have HFpEF: Exhaustive exclusion of mimics is mandatory before labeling a patient with HFpEF 3, 1

ECG abnormalities support but do not confirm diagnosis: Look for LV hypertrophy, atrial fibrillation, repolarization abnormalities as supportive findings 1

Avoid exhaustive testing in every patient: Tailor mimic evaluation based on clinical clues from history, physical examination, and initial echocardiography 3

Chest radiography has limited diagnostic value: It may show cardiomegaly or pulmonary venous congestion but cannot establish or exclude HFpEF 3