Natriuretic Peptides (BNP and NT-proBNP)

B-type natriuretic peptide (BNP) and its inactive N-terminal fragment (NT-proBNP) are released by ventricular myocytes in response to wall stretch and pressure overload. Pro-BNP is cleaved into the active 32 amino acid BNP and the 76 amino acid NT-proBNP. BNP promotes natriuresis, vasodilatation and suppression of renin and aldosterone. Both peptides are measured by immunoassay. BNP has a half life of about 20 minutes, and NT-proBNP about 1 to 2 hours, so NT-proBNP reaches higher concentrations and varies less.

The test is used to exclude heart failure in a patient with dyspnoea, to support the diagnosis, to grade prognosis, and to follow response to treatment. It has high negative predictive value (over 95%) at low cut offs and moderate positive predictive value, because many conditions raise it.

Heart failure affects 1 to 2% of adults and more than 10% of people over 70 years. It causes roughly 1 in 20 hospital admissions in older adults in many countries, and about half of patients have a preserved ejection fraction.

Indications. Acute or chronic dyspnoea of uncertain cause, suspected heart failure in primary care, risk stratification of known heart failure, monitoring of therapy, screening of high risk groups (diabetes, hypertension, prior cardiotoxic therapy), and assessment of pulmonary hypertension and congenital heart disease.

Specimen. BNP: EDTA plasma in a plastic tube, since BNP adheres to glass. NT-proBNP: serum or heparin or EDTA plasma. NT-proBNP is stable for several days at room temperature, and BNP for about 4 hours at room temperature and 24 hours at 2 to 8 °C.

Values are method specific, and local ranges take precedence. The two peptides are not interchangeable. Conversion to SI units: BNP pg/mL multiplied by 0.289 gives pmol/L, and NT-proBNP pg/mL multiplied by 0.118 gives pmol/L.

BNP. Active peptide. Range in health: under 35 pg/mL (under 100 pg/mL in most older adults). Raised: heart failure, left ventricular hypertrophy, valve disease, atrial fibrillation, acute coronary syndrome, pulmonary embolism, pulmonary hypertension, kidney failure, older age, female sex. Lowered: obesity.

In acute dyspnoea, a BNP under 100 pg/mL makes acute heart failure unlikely, 100 to 400 pg/mL is indeterminate, and over 400 pg/mL makes it likely.

BNP is raised by sacubitril (neprilysin inhibition prevents degradation). A patient on sacubitril-valsartan therefore needs NT-proBNP for monitoring.

NT-proBNP. Inactive fragment, cleared by the kidney. Range in health: under 125 pg/mL in people under 75 years. Raised: the same causes as BNP, and more strongly in kidney impairment. Lowered: obesity and African ancestry.

• Acute dyspnoea, rule out: under 300 pg/mL.
• Acute dyspnoea, rule in, age adjusted: over 450 pg/mL under 50 years, over 900 pg/mL at 50 to 75 years, over 1800 pg/mL over 75 years.
• Non-acute setting: under 125 pg/mL makes heart failure unlikely, 125 to 400 pg/mL needs echocardiography within 6 weeks, and over 2000 pg/mL needs urgent specialist assessment within 2 weeks.

A low value is more reliable than a high one. A normal value excludes heart failure with high confidence in the untreated patient, and a raised value only means that the myocardium is under strain and needs a cause.

Causes of raised values.

• Cardiac: heart failure of any phenotype, acute coronary syndrome, atrial fibrillation (typically 2 to 3 times higher), left ventricular hypertrophy, aortic stenosis, mitral regurgitation, cardiomyopathies including amyloid, myocarditis, congenital shunts, cardiotoxicity from chemotherapy, cardiac surgery.
• Right ventricle and lung: pulmonary embolism, pulmonary hypertension, cor pulmonale, severe pneumonia, acute respiratory distress, obstructive sleep apnoea.
• Systemic: kidney failure, sepsis and septic shock, subarachnoid haemorrhage and stroke, cirrhosis with ascites, hyperthyroidism, severe anaemia, burns, advanced age, female sex.

Causes of falsely low values. Obesity (BMI over 30 kg/m² lowers values by about 30 to 50%), African ancestry, treatment with diuretics, ACE inhibitors, beta blockers and mineralocorticoid antagonists, flash pulmonary oedema (early rise delayed), acute mitral regurgitation, mitral stenosis, constrictive pericarditis, cardiac tamponade, and heart failure with preserved ejection fraction, which gives lower values than reduced ejection fraction.

Prognosis and monitoring. Higher values predict death and rehospitalisation. A fall of at least 30% during an admission is associated with better outcome, and a persistently high value at discharge predicts early readmission. Day-to-day biological variation is 30 to 50%, so smaller changes cannot be interpreted.

Heart failure with preserved ejection fraction. Values are lower than expected for the symptoms. A value near the cut off with a compatible clinical picture is not reassuring.

Critical values and findings needing immediate action.

• NT-proBNP over 2000 pg/mL, or BNP over 400 pg/mL, in a patient with breathlessness, hypoxia or oedema.
• Rising value in hospital despite therapy.
• Very high values (NT-proBNP over 10 000 pg/mL) in the setting of hypotension, arrhythmia or syncope.
• Raised value with raised troponin and ECG change.

Interferences and pitfalls.

• Obesity gives falsely reassuring values, and older age, atrial fibrillation and kidney failure give falsely high values.
• Sacubitril-valsartan raises BNP and leaves NT-proBNP unaffected, and this changes interpretation when switching peptide.
• Results from different assays and from BNP and NT-proBNP cannot be compared.
• A normal value does not exclude diastolic dysfunction in a compensated patient on therapy.
• Haemolysis and lipaemia have little effect, and heterophile antibodies rarely interfere.
• Point-of-care assays are less precise at low concentrations.

Special groups.

• Neonates: values are very high in the first days of life and fall rapidly. Persistent raised values suggest a duct dependent lesion or left to right shunt.
• Children: age specific ranges are needed, and a high value supports heart failure, myocarditis or cardiomyopathy.
• Pregnancy: values rise modestly and rise further in pre-eclampsia and peripartum cardiomyopathy.
• Older adults: reference values rise with age, and age adjusted cut offs are needed.
• People of African ancestry: values are lower for the same cardiac state.
• Regions with rheumatic heart disease and Chagas disease: valve and myocardial disease are frequent causes.

Follow up tests. Echocardiography, ECG, chest radiograph, troponin, urea and electrolytes with eGFR, full blood count, thyroid function tests, ferritin and transferrin saturation, liver function tests, HbA1c, urinalysis, lung function, cardiac MRI, coronary angiography, and amyloid screening when infiltrative disease is suspected.