What is the diagnosis for a patient with elevated N-terminal pro b-type natriuretic peptide (NT-proBNP) levels and a normal ejection fraction (EF)?

Diagnosis: Heart Failure with Preserved Ejection Fraction (HFpEF)

A patient presenting with elevated NT-proBNP and normal ejection fraction most likely has heart failure with preserved ejection fraction (HFpEF), though you must systematically exclude other cardiac and non-cardiac causes of elevated natriuretic peptides before confirming this diagnosis. 1

Diagnostic Criteria for HFpEF

To establish HFpEF, the following conditions must be fulfilled according to the 2016 ESC Guidelines 1:

• Presence of heart failure symptoms and/or signs - including dyspnea, orthopnea, bilateral edema, increased jugular venous pressure, rales, or S3 gallop 1
• Preserved ejection fraction - defined as LVEF ≥50% (or 40-49% for HFmrEF) 1
• Elevated natriuretic peptides - BNP >35 pg/mL and/or NT-proBNP >125 pg/mL in the ambulatory setting 1
• Objective evidence of cardiac structural/functional abnormalities - demonstrated on echocardiography, such as left atrial enlargement, left ventricular hypertrophy, elevated E/e' ratio >9, or elevated pulmonary artery systolic pressure >35 mmHg 1

Critical Differential Diagnoses to Exclude

Before confirming HFpEF, you must systematically rule out other causes of elevated NT-proBNP with normal EF 2, 3:

Cardiac Causes

• Atrial fibrillation - causes elevated BNP independent of ventricular function, with levels 2.59 times higher than sinus rhythm 2, 4, 5
• Acute coronary syndrome - BNP rises significantly during myocardial infarction even without clinical heart failure 2, 3
• Valvular disease - particularly mitral regurgitation, which elevates BNP and carries increased mortality risk 2, 3

Pulmonary Causes

• Pulmonary embolism - significantly elevates BNP, especially in massive PE 2, 3
• Chronic obstructive pulmonary disease with cor pulmonale - substantially elevates BNP, though COPD without cor pulmonale shows minimal elevation 2, 3
• Pulmonary hypertension - elevates natriuretic peptides related to right ventricular dysfunction 1, 3

Renal Dysfunction

• Renal failure - leads to elevated BNP due to decreased clearance, requiring adjusted thresholds for interpretation 1, 2, 3

Systemic Conditions

• Sepsis - can contribute to elevated levels, especially with cardiac involvement 1, 2

Diagnostic Algorithm

Step 1: Confirm HF symptoms/signs are present 1

• Look specifically for: orthopnea, paroxysmal nocturnal dyspnea, jugular venous distension, hepatojugular reflux, bilateral lower extremity edema, pulmonary rales, S3 gallop, tachycardia >120 bpm 1

Step 2: Verify elevated natriuretic peptides meet diagnostic thresholds 1

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

Step 3: Obtain echocardiography to confirm 1:

• LVEF ≥50% 1
• Evidence of diastolic dysfunction: E/e' ratio >9, left atrial enlargement, left ventricular hypertrophy 1
• Elevated pulmonary artery systolic pressure >35 mmHg 1
• Exclude significant valvular disease 1

Step 4: Consider H2FPEF score for diagnostic certainty 1

• Integrates: obesity, atrial fibrillation, age >60 years, ≥2 antihypertensive medications, E/e' >9, PA systolic pressure >35 mmHg 1
• Score <2 = low likelihood of HFpEF; Score ≥6 = high likelihood 1
• Score 2-5 = requires exercise echocardiogram or cardiac catheterization to confirm diagnosis 1

Step 5: If diagnosis remains uncertain, perform stress testing 1

• Exercise echocardiography or invasive measurement of elevated LV filling pressure during exercise may be needed to confirm HFpEF 1

Important Clinical Caveats

Factors That Lower NT-proBNP in HFpEF

• Obesity - paradoxically results in lower BNP values for any given cardiac condition, possibly related to increased clearance 1, 2, 6, 7
• Chronically treated patients - especially those younger than 75 years may have normal-range BNP despite true HFpEF 7
• Reduced myocardial wall stress - HFpEF patients have small LV cavity and thick walls, producing lower stimulus for BNP production compared to HFrEF even with high diastolic pressures 1, 7

Factors That Raise NT-proBNP Without HFpEF

• Advanced age - normal ranges increase significantly in patients >60 years 2, 3
• Female sex - women typically have higher normal values than men 1
• Atrial fibrillation - raises levels independent of ventricular function 2, 4, 5

Common Diagnostic Pitfalls

• Do not rely on BNP alone - natriuretic peptides have high negative predictive value (0.94-0.98) for ruling out HF but lower positive predictive value (0.44-0.57 in non-acute setting) for confirming diagnosis 1
• Always integrate with clinical assessment and echocardiography - BNP should never be used in isolation to establish the diagnosis 1, 2, 3
• Recognize the "grey zone" - BNP 100-400 pg/mL or NT-proBNP 300-900 pg/mL requires comprehensive clinical correlation 8
• Adjust thresholds for obesity - consider lowering threshold values by 20-30% for patients with BMI ≥30 kg/m² 3

Prognostic Implications

Once HFpEF is confirmed, elevated NT-proBNP carries significant prognostic value 4, 9:

• Higher NT-proBNP levels are associated with worse outcomes including increased mortality, heart failure hospitalization, atrial fibrillation, and stroke 3, 8
• For each 100 pg/mL increase in BNP, relative risk of death increases by 35% over 1.5-3 years 2, 8
• Baseline characteristics most strongly associated with higher NT-proBNP in HFpEF include atrial fibrillation, NYHA IV symptoms, lower estimated glomerular filtration rate, and recent heart failure hospitalization 4