What are the causes of elevated N-terminal pro b-type natriuretic peptide (NT-proBNP) levels?

Causes of Elevated NT-proBNP Levels

Elevated NT-proBNP levels can be caused by various cardiac and non-cardiac conditions, with heart failure being the most common cause, directly related to ventricular wall tension and dysfunction. 1

Primary Cardiac Causes

• Heart failure: The most common cause of elevated NT-proBNP, with levels directly proportional to severity of ventricular dysfunction and wall tension 1

  • Higher levels typically seen in heart failure with reduced ejection fraction (HFrEF) compared to heart failure with preserved ejection fraction (HFpEF) 1
  • Diagnostic cut-offs: BNP >400 pg/mL; NT-proBNP uses age-dependent thresholds 2, 1

• Acute coronary syndromes: Cause elevated NT-proBNP even without overt heart failure, with levels correlating with degree of myocardial damage 1, 3

• Atrial fibrillation: Leads to elevated NT-proBNP independent of ventricular function 1

• Left ventricular hypertrophy: Increases wall stress, leading to higher NT-proBNP production 1

• Valvular heart disease: Particularly mitral regurgitation, associated with higher NT-proBNP levels and mortality 1

• Right ventricular dysfunction: Conditions causing right ventricular overload (pulmonary embolism, pulmonary hypertension) significantly elevate NT-proBNP levels 4

Non-Cardiac Causes

• Renal failure: Leads to elevated NT-proBNP due to decreased clearance 1, 5

  • NT-proBNP levels increase as glomerular filtration rate decreases 5

• Advanced age: Associated with increased normal ranges of NT-proBNP 2, 1

  • Young adults: <25 pg/mL (BNP) and <70 pg/mL (NT-proBNP)
  • Age >60 years: <98 pg/mL for males, <225 pg/mL for females 2

• Pulmonary conditions: Pulmonary embolism, pulmonary hypertension, and COPD can increase NT-proBNP levels 1, 4

  • In pulmonary embolism, NT-proBNP reflects the degree of right ventricular overload 4

• Sepsis: Can cause markedly elevated NT-proBNP levels even without primary cardiac dysfunction 6

  • Critical illness with septic shock consistently shows elevated NT-proBNP 6

• Sex differences: Females typically have higher normal values than males, possibly due to androgen suppression of NT-proBNP synthesis 2, 1

Factors That May Lower NT-proBNP Levels

• Obesity: Results in lower NT-proBNP values for a given cardiac condition, possibly related to increased clearance or suppression by sex steroid hormones produced in lean mass 2, 1

• Treatment effects: Initiation of heart failure medications can decrease NT-proBNP levels 1

Clinical Implications and Interpretation

• Elevated NT-proBNP should not be regarded as a "false positive" but rather as an indicator of "cardio-renal distress" requiring further investigation 3, 7

• NT-proBNP has high negative predictive value (99%) for excluding heart failure when levels are below age and sex-adjusted 95th percentile thresholds 7

• The "grey zone" (BNP 100-400 pg/mL or NT-proBNP 300-900 pg/mL) requires clinical correlation 1, 8

• Even mildly elevated NT-proBNP levels are associated with increased risk of death, heart failure, atrial fibrillation, and stroke 1

• For each 100 pg/mL increase in BNP, relative risk of death increases by 35% over 1.5-3 years 8

Diagnostic Approach

1. Consider NT-proBNP as a continuous variable rather than binary value, with risk increasing proportionally with concentration 1

2. Interpret elevated levels in context of patient's age, sex, renal function, and clinical presentation 2, 1

3. Use NT-proBNP primarily as a rule-out test for heart failure (high sensitivity) when levels are below threshold values 2

4. Consider multiple potential causes when interpreting elevated levels, especially in patients with comorbidities 1, 3