What are the causes of raised pro-brain natriuretic peptide (proBNP) levels?

Causes of Elevated Pro-Brain Natriuretic Peptide (proBNP) Levels

Elevated proBNP levels are primarily caused by cardiac conditions that increase myocardial wall stress, with heart failure being the most common cause, but numerous cardiac and non-cardiac conditions can also lead to increased levels. 1

Primary Cardiac Causes

• Heart Failure: The most common cause of elevated proBNP, with levels directly related to severity of ventricular dysfunction and wall tension 1

  • Higher levels seen in heart failure with reduced ejection fraction (HFrEF) compared to heart failure with preserved ejection fraction (HFpEF) 1
  • Cut-off values for diagnosing heart failure:
    • BNP: >400 pg/mL
    • NT-proBNP: Age-dependent thresholds
      • <50 years: >450 pg/mL
      • 50-75 years: >900 pg/mL

      • 75 years: >1800 pg/mL 1

• Acute Coronary Syndromes: Myocardial ischemia increases BNP expression even without overt heart failure 2

  • Levels correlate with degree of myocardial damage 1
  • Median values in different conditions:
    • Acute myocardial infarction: 203.5 pg/mL
    • Unstable angina: 77.9 pg/mL
    • Non-ACS patients: 27.7 pg/mL 1

• Atrial Fibrillation: Causes elevated proBNP independent of ventricular function 1, 3

• Left Ventricular Hypertrophy: Increased wall stress leads to higher proBNP production 1

• Valvular Heart Disease: Particularly mitral regurgitation, associated with higher proBNP levels and mortality 1

Non-Cardiac Causes

• Renal Failure: Chronic kidney disease leads to elevated proBNP due to decreased clearance 1

  • Special NT-proBNP threshold for severe chronic renal failure in patients <50 years: >1200 pg/mL 1

• Advanced Age: Normal ranges increase with age 1

  • Young adults: <25 pg/mL (BNP), <70 pg/mL (NT-proBNP)
  • 45-59 years: <100 pg/mL (males), <164 pg/mL (females) (NT-proBNP)

  • 60 years: <98 pg/mL (males), <225 pg/mL (females) (NT-proBNP) 1

• Pulmonary Conditions:

  • Pulmonary embolism: Right ventricular strain 1
  • Pulmonary hypertension: Right ventricular dysfunction 1
  • Chronic obstructive pulmonary disease 1

• Systemic Inflammation/Infection: Endotoxemia and sepsis can increase NT-proBNP even in individuals with normal heart function 4

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

Factors That May Lower proBNP Levels

• Obesity: Higher BMI results in lower proBNP values for a given cardiac condition 1

  • Possibly related to increased clearance or suppression by sex steroid hormones produced in lean mass 1

• Treatment Effects: Initiation of heart failure medications can decrease levels 1

  • Diuretics, ACE inhibitors, vasodilators, and beta-blockers can all affect proBNP levels 1, 3

Clinical Implications

• Even mildly elevated proBNP levels are associated with increased risk of death, heart failure, atrial fibrillation, and stroke 1, 5

• For each 100 pg/mL increase in BNP, relative risk of death increases by 35% over 1.5-3 years 1

• In patients with mild to moderate heart failure, each 500 pg/mL increase in NT-proBNP above baseline is associated with a 3.8% increase in mortality risk 1

• Serial measurements may be more valuable than single readings, with increases over time associated with increased risk of adverse outcomes 3

Diagnostic Considerations

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

• Consider multiple potential causes when interpreting elevated levels, especially in patients with comorbidities 1

• Natriuretic peptides should be interpreted as continuous variables rather than binary values, with risk increasing proportionally with concentration 1, 5