Brain-Type Natriuretic Peptide (BNP)

The most important use of natriuretic peptides is in helping to establish the diagnosis of heart failure (HF) in a patient in the urgent care setting in whom the diagnosis is uncertain.

The reference values of brain-type natriuretic peptide (BNP) and N-terminal (NT) proBNP are different to exclude or confirm a diagnosis of heart failure. These values also depend on age and gender and are higher in elderly persons and women.

Normal findings are as follows ^[1] :

• BNP: < 100 pg/mL
• NT-proBNP: < 300 pg/mL

Critical value ^[1] :

• BNP: >400 pg/mL (heart failure likely)

In patients with a prior diagnosis of heart failure, knowledge of optivolemic natriuretic peptide values is important when interpreting elevated levels of these molecules.

What does a normal value mean?

A value of < 100 pg/mL for BNP and < 300 pg/mL for NT-proBNP makes the diagnosis of congestive heart failure (CHF) less likely in an acutely dyspneic patient. However, as discussed below, conditions exist in which patients may have falsely low values, and these should be kept in mind before making decisions and interpreting values.

What does a high value mean and what condition would be associated with a high value?

A high value of BNP or NT-proBNP in an appropriate clinical setting means that the diagnosis of congestive heart failure is likely. Keep in mind that patients with chronic congestive heart failure may have elevated natriuretic peptide levels at baseline, ^[2] and appropriate clinical judgment should be exercised.

Do other interpretations of this test that have important clinical value?

The single most validated and established use of natriuretic peptides remains the diagnosis of CHF but, as discussed below, other conditions are increasingly being recognized in which natriuretic peptides may have a role.

• Elevated levels of natriuretic peptides are associated with poor long-term prognosis and have an adverse impact on long-term mortality in patients with congestive heart failure ^{[3, 4, 5]} and various other conditions such as coronary artery disease ^{[6, 7, 2]} and atrial fibrillation. The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for managing heart failure have incorporated using natriuretic peptide levels in establishing the prognosis and disease severity of chronic heart failure and acutely decompensated heart failure. ^[8]

• Studies have shown the natriuretic peptides may be a predictor of sudden cardiac death ^[9] and also of response to cardiac resynchronization therapy. ^[10]

• Natriuretic peptides are also being used to evaluate valvular heart diseases.

Other conditions associated with BNP values

Conditions associated with elevated BNP other than CHF are as follows: ^{[11, 12, 8]}

• Acute renal failure and chronic renal failure

• Hypertension (HTN)

• Pulmonary diseases such as pulmonary hypertension, severe chronic obstructive pulmonary disease (COPD), pneumonia, pulmonary embolism, adult respiratory distress syndrome (ARDS)

• Cardiac causes -Myocardial infarction, atrial fibrillation, acute coronary syndrome, cardioversion, valvular heart disease, myocarditis

• Older age

• Female sex

• Liver cirrhosis

• Hyperthyroidism

• Sepsis

• Chemotherapy

A study by Ariss et al suggested that BNP may be useful as a marker for pulmonary hypertension in patients with end-stage renal disease (ESRD). ESRD patients in the study who had pulmonary hypertension (pulmonary artery pressure of 25 mmHg or above) had a higher BNP level than did those without such hypertension (1619 pg/mL vs 352 pg/mL, respectively). ^[13]

Conditions associated with lower than expected BNP are as follows:

• Obesity

• Flash pulmonary edema

• Pericardial constriction

The test can be drawn at any time during the day. The patient does not need to be fasting and no specific preparation from the patient’s side is required.

The test is a spot blood sample. Specifics for collection and panels are as follows: ^{[14, 15]}

BNP

See the list below:

• Specimen type - Blood plasma

• Container - Vacutainer, lavender top (EDTA)

• Collection method - Venipuncture

• Specimen volume - 1 mL

• Other instructions - Spin down and freeze plasma immediately; patient age and sex required

NT-proBNP

See the list below:

• Specimen type - Blood serum

• Container - Vacutainer, red/black top (serum gel)

• Collection method - Venipuncture

• Specimen volume - 0.5 mL

• Other instructions - Patient age and sex required

Description

Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality. The diagnosis of heart failure remains essentially clinical based on history, physical examination, and chest radiograph findings. However, clinical findings and examination alone are often inadequate in diagnosing heart failure as multiple other conditions that affect the cardiopulmonary system mimic the symptoms of heart failure. This confounds the diagnosis and delays the initiation of appropriate management. In this setting, the existence of a biomarker that could accurately identify heart failure as the cause of patient’s symptoms would be extremely helpful in guiding timely initiation of appropriate management.

Natriuretic peptides, namely BNP and NT-proBNP, present themselves as such markers and are now being widely used in diagnosing and managing heart failure.

Chemistry

Natriuretic peptides are protein molecules that are secreted by the ventricular musculature in response to volume or pressure overload. The BNP is a 32 amino acid protein molecule that is generated from the precursor known as proBNP in the ventricular musculature. After a volume or pressure overload, ventricular musculature secretes pre-proBNP, which is cleaved into an 108 amino acid proBNP, which is further cleaved into biologically active BNP (32 amino acids) and the inert NT-proBNP (76 amino acids). ^[16] The important differences between BNP and NT-proBNP are illustrated in Table 1. See the image below.

Normal actions

The normal actions of the natriuretic peptides are to aid the heart in dealing with the state of volume overload and stretch. The BNP is a biologically active molecule and causes natriuresis, vasodilation, and diuresis, all of which leads to improved myocardial relaxation. These peptides also counteract the actions of the renin-angiotensin aldosterone system. Compared to BNP, NT-proBNP is biologically inactive.

Natriuretic peptides are synthesized and released in response to ventricular stress and very little is stored in the forms of granules. Thus, in acute decompensation, a lag often occurs between the appearance of the natriuretic peptides and the onset of clinical deterioration.

Metabolism

The precise mechanism of metabolism of natriuretic peptides is unclear but several different potential pathways exist. For BNP, there is metabolism by neutral endopeptidases, CNP receptor (natriuretic peptide receptor-C)-mediated degradation, and, to a lesser extent, metabolism by the kidneys. For the NT-proBNP, renal clearance is greater than in BNP in addition to clearance by some other organs with high blood flow such as liver and muscles. ^[16]

Table 1: Common Differences Between BNP and NT–proBNP (Open Table in a new window)

Indications/Applications

The single most clinically relevant use of BNP and NT-proBNP remains the diagnosis of heart failure as the prime cause of a patient’s symptoms when the diagnosis is uncertain. ^[17] This indication is supported by multiple evidence-based guidelines. ^{[17, 18, 19, 8]} . The early use of BNP in this setting has been shown to minimize inaccuracies, establish timely diagnosis, prevent inappropriate delay in initiation of treatment, and reduce hospital length of stay and treatment costs. At the same time, elevated natriuretic peptide levels in isolation should not be used to confirm or exclude heart failure as the cause of a patient’s symptoms. ^[17]

Beyond the above-mentioned indication, elevations in BNP and NT-proBNP are noted in numerous other settings. While the use of natriuretic peptides in most of these settings is still investigational, their utility is increasingly being recognized.

• Congestive heart failure: Natriuretic peptides are increasingly being studied to guide adequacy of therapy in heart failure patients. ^{[20, 21]} The results have been conflicting so far, with some trials showing benefit and some failing to show significant improvement. However, 2 large meta-analysis have shown significant reduction in all-cause mortality with the use of B-type natriuretic peptide–guided therapy compared with usual clinical care. ^{[22, 23]} Current ACC/AHA guidelines state that natriuretic peptide–guided heart failure therapy can be useful to achieve optimal dosing of guideline-directed medical therapy in select clinically euvolemic patients followed in a well-structured heart failure disease management program (class IIa, level of evidence B). ^[8]

• Natriuretic peptides also have a prognostic value in patients with stable as well as decompensated heart failure, as higher levels are predictive of increased morbidity and mortality. ^{[24, 25]} The current ACC/AHA guidelines endorse using natriuretic peptides for the purpose of establishing prognosis and disease severity in patients with stable and acutely decompensated heart failure (class I, level of evidence A). ^[8]

• Coronary artery disease (CAD): Plasma levels of natriuretic peptides are often elevated in patients with acute coronary syndrome. ^[26] Both natriuretic peptides have been studied in patients with CAD and have been found to have a strong prognostic value in patients with stable CAD as well as acute coronary syndromes, with higher BNP or NT-proBNP values associated with a worse prognosis. ^{[27, 28]}

• Valvular diseases: The levels of natriuretic peptides increase with increasing severity of valvular lesions. The levels are not as high as would be seen in congestive heart failure but are still higher than usual, and elevated levels have been associated with poorer outcomes.

• Predictors of sudden cardiac death and response to cardiac resynchronization therapy (CRT): Some studies have demonstrated that BNP levels may be used to predict the response to cardiac resynchronization therapy as patients with higher pre-implantation BNP were noted to have better response to CRT. ^[10] Studies have also shown that CRT exerts an early and sustained reduction in NT-proBNP levels, and the levels of these natriuretic peptides may be used to monitor response to CRT. ^[29] BNP has also been shown to be a predictor of defibrillation in patients who undergo implantable cardioverter–defibrillator implantation. ^[30] Studies have also shown that natriuretic peptides may be used to identify patients at risk of sudden cardiac death in the setting of heart failure as well as myocardial infarction. ^{[9, 31]}

Considerations

Conditions associated with false readings

Falsely low levels of natriuretic peptides have been noted in multiple clinical conditions such as obesity, flash pulmonary edema, and causes of heart failure upstream of the left ventricle, such as severe mitral regurgitation, mitral stenosis, and constrictive pericarditis.

• Obesity: Obese patients have been shown to have lower natriuretic peptide levels despite overt clinical signs and symptoms of heart failure. This has been repeatedly demonstrated in multiple studies. ^{[32, 33, 34]} The exact reasoning for this is unclear, but BNP retains a prognostic capacity, with higher levels consistently associated with a poorer prognosis. ^[35] A lower cutoff value for BNP has been proposed, ^[36] but the exact value in obese patients remains debatable.

• Flash pulmonary edema: In the first 1-2 hours after the onset of flash pulmonary edema, the levels of BNP may be lower than expected. This delay is present as the natriuretic peptides are synthesized in a ventricle that is under acute pressure or volume overload, and very little of it is stored in the muscle at baseline for release during decompensation.

• Heart failure due to causes upstream from left ventricle: When the symptoms of heart failure are from causes upstream from the left ventricle, such as mitral regurgitation or mitral stenosis, then even though the patient has significant symptoms of heart failure, the BNP levels may be only mildly elevated. Similarly, patients with heart failure from constrictive pericarditis or restrictive cardiomyopathy may have significant symptoms of heart failure but only mildly elevated BNP levels. ^{[37, 38]}

Falsely high levels of BNP and NT-proBNP may be seen in females, with advancing age and in the presence of renal failure.

• Females: The levels of both BNP and NT-proBNP are higher in females compared to males in all age groups. ^{[39, 40]} The exact reason for this is still under investigation but may have to do with either the impact of estrogen, with higher estrogen levels causing higher BNP levels, ^[41] or the effect of testosterone on lowering the levels of BNP. ^[42]

• Advancing age: With advancing age, the levels of both the natriuretic peptides increase. ^{[43, 44]} The exact reasoning is unknown and may be due to alterations in multiple levels in synthesis, secretion, and metabolism.

• Renal failure: The levels of both BNP and NT-proBNP are elevated in the setting of chronic kidney disease (glomerular filtration rate < 60 mL/min/1.7 m²) even in the absence of heart failure. This makes both BNP and NT–proBNP less accurate for diagnosing heart failure as the cause of the patient’s symptoms in patients with chronic kidney disease. Some studies have suggested using higher cutoff values of BNP ^[45] and NT-proBNP ^[46] for diagnosis of CHF in the setting of chronic kidney disease, but the absolute values remain debatable. The values of natriuretic peptides also fluctuate with hemodialysis. ^[47] At the same time, elevated levels of natriuretic peptides have a prognostic value in chronic kidney disease because patients with high natriuretic peptide levels do worse than those with lower natriuretic peptide levels.

• High cardiac output states: Conditions such as sepsis, cirrhosis, and hyperthyroidism, which are associated with high cardiac output, may cause elevated levels of natriuretic peptides. The exact mechanism is unclear, and BNP in the diagnosis of heart failure as a cause of symptoms is less accurate in these settings. ^{[48, 49, 50]}

A "gray zone" exists depending on age when interpreting the natriuretic peptides in diagnosis of heart failure, as shown in the table below: ^{[12, 51, 52]}

Table 2. Gray Zone Age-Related Values for BNP and NT-proBNP (Open Table in a new window)

When the values of natriuretic peptides fall within this range, the final diagnosis of heart failure requires careful physician evaluation and additional testing for confirmation. At the same time, clinicians should keep in mind that there are conditions other than CHF, as stated above, that may cause mild elevation in natriuretic peptide levels, and greater attention should be paid to these conditions as well. Note that the level of BNP would be elevated in both in the setting of systolic heart failure and heart failure with preserved ejection fraction, and the value of BNP cannot be used to differentiate between the two types of heart failure. ^[53]

A study by Reynen et al indicated that urinary levels of NT-proBNP also have cardiovascular associations, being, like plasma levels, predictive of all-cause mortality and major adverse cardiac events, in the presence of acute chest pain. Urinary and plasma NT-proBNP levels were reported to be greatest in patients suffering from troponin-positive acute coronary syndrome and congestive heart failure. ^[54]