What factors can cause falsely low Brain Natriuretic Peptide (BNP) levels?

Factors That Falsely Lower BNP Levels

Obesity is the single most important factor causing falsely low BNP levels, with an inverse relationship between BMI and BNP concentrations that persists even after adjusting for other variables. 1, 2

Primary Causes of Falsely Low BNP

Obesity (Most Important)

• Patients with BMI ≥30 kg/m² should have diagnostic thresholds lowered by 20-30% to avoid missing heart failure diagnoses 1
• BNP can be falsely negative in 20% of heart failure cases in both overweight (BMI 25-29.9) and obese (BMI ≥30) patients using standard cutoffs 3
• For obese patients with BMI >35 kg/m², a cutoff of 55 ng/L (rather than 100 ng/L) is recommended to rule out heart failure 1
• The mechanism involves increased clearance receptors on adipocytes and decreased proBNP substrate not glycosylated at threonine 71, which reduces the amount available for processing into active BNP 1, 4
• Very low BNP levels (<50 pg/mL) occur in 4.9% of hospitalized heart failure patients, with higher BMI being the strongest predictor 5

Androgen Effects

• Androgens (testosterone) reduce both BNP and NT-proBNP levels, which explains why males consistently have lower values than females 1, 2
• This effect appears related to lean body mass and testosterone metabolism 1

Heart Failure With Preserved Ejection Fraction (HFpEF)

• HFpEF patients have inherently lower BNP levels compared to heart failure with reduced ejection fraction due to reduced myocardial wall stress 6
• BNP has reduced specificity for HFpEF due to increased clearance and enhanced degradation of natriuretic peptides 6
• Chronically treated heart failure patients, especially those younger than 75 years, may have normal-range BNP levels despite active disease 6

Analytical and Pre-Analytical Factors

Glycosylation Issues

• Glycosylation of proBNP at amino acid 73 renders it resistant to convertase enzymes, preventing cleavage into active BNP 1
• Glycosylation of the mid-portion of NT-proBNP affects antibody binding and can occasionally result in low measured values 1
• Variable glycosylation explains inter-individual differences in values among otherwise similar patients 1

Assay Cross-Reactivity Problems

• Current BNP assays may have difficulty detecting BNP (amino acids 77-108) in some patients with severe heart failure, despite elevated concentrations by standard immunoassays 1
• Different BNP assays are not analytically equivalent, and results from one assay should not be directly translated to another without validation 1

Clinical Pitfalls to Avoid

Common Mistakes

• Never dismiss slightly elevated BNP simply because it falls below traditional cutoffs in obese patients - adjust thresholds downward by 20-30% for BMI ≥30 kg/m² 1
• Do not attribute low BNP solely to obesity without further cardiac evaluation, as true natriuretic peptide deficiency may exist 5
• Avoid using BNP as a standalone test; it should confirm clinical suspicion rather than replace clinical judgment 1

Interpreting Serial Measurements

• High intra-individual biological variability means changes must be substantial to be clinically meaningful: approximately 85% increase or 46% decrease 1, 2
• Smaller changes may reflect normal biological variation rather than true clinical change 1

Special Populations

• African American patients may exhibit lower natriuretic peptide levels, potentially linked to salt-sensitive hypertension and left ventricular hypertrophy 6
• Younger patients (<75 years) with chronic, well-treated heart failure may have normal-range values despite ongoing disease 6

Practical Algorithm for Low BNP Interpretation

When encountering unexpectedly low BNP in a patient with suspected heart failure:

1. Check BMI first - If ≥30 kg/m², lower diagnostic threshold by 20-30% 1
2. Consider patient sex - Males naturally have lower values than females 1, 2
3. Assess for HFpEF - These patients inherently have lower BNP despite true heart failure 6
4. Evaluate chronicity of treatment - Well-treated chronic heart failure patients may normalize their BNP 6
5. Proceed with echocardiography regardless if clinical suspicion remains high, as BNP deficiency states exist 5