Interpreting NT-proBNP and BNP in Clinical Decision-Making

Definition and Pathophysiology

B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are circulating markers of myocardial wall stress. They are released principally by ventricular cardiomyocytes in response to increased transmural stress and ventricular stretch. Atrial natriuretic peptide is produced predominantly by atrial tissue; its midregional pro-ANP assay may provide information comparable to BNP and NT-proBNP in heart failure (HF).

The biologically active natriuretic peptides promote vasodilation, renal sodium and water excretion, and reduction of cardiac fibrosis through activation of the natriuretic peptide-A receptor. NT-proBNP is an inactive cleavage product and has no direct biologic effect.

BNP and NT-proBNP have different clearance characteristics. Both undergo passive clearance through highly perfused organs, including the kidneys. BNP is additionally removed through the natriuretic peptide clearance receptor and degraded by circulating and tissue enzymes, including neprilysin. Their respective half-lives therefore differ substantially: approximately 20 minutes for BNP and 90 minutes for NT-proBNP. Consequently, plasma concentrations of the two peptides are not interchangeable.

Natriuretic peptide concentrations reflect haemodynamic stress, but their release is not specific to left ventricular systolic dysfunction. Levels may also rise with:

• Left ventricular diastolic dysfunction

• Valvular heart disease

• Pulmonary hypertension

• Ischaemic heart disease

• Atrial arrhythmias

• Pericardial disease, including constriction

• Right ventricular dysfunction caused by pulmonary embolism

• Infiltrative cardiomyopathies, particularly cardiac amyloidosis

• Sepsis and other hyperdynamic states

In cardiac amyloidosis, BNP or NT-proBNP may be markedly elevated even when overt congestion is not apparent. Such a discrepancy should prompt consideration of an infiltrative cardiomyopathy within the appropriate clinical context.

Several patient-related factors influence interpretation. Natriuretic peptide concentrations generally increase with age and are higher in patients with impaired renal function, reflecting both reduced clearance and the high prevalence of structural heart disease in this population. Obesity is associated with lower-than-expected BNP and NT-proBNP concentrations despite comparable or greater ventricular wall stress, probably because of suppression of natriuretic peptide production or post-translational modification rather than a simple clearance effect.

Treatment also affects interpretation. Angiotensin receptor–neprilysin inhibitors may increase BNP concentrations, although the effect is not universal and may be transient. Because NT-proBNP is not a neprilysin substrate, it remains more closely related to the clinical state during treatment with an angiotensin receptor–neprilysin inhibitor.

Clinical Applications

Natriuretic peptides have three principal roles:

• Supporting or excluding the diagnosis of HF

• Estimating disease severity and prognosis

• Contributing to longitudinal assessment and risk stratification

They are useful in both acute and ambulatory presentations, but the appropriate thresholds differ substantially according to the clinical setting. Values obtained in the emergency department for acute dyspnoea should not be transferred directly to patients with less acute outpatient symptoms.

Natriuretic peptides supplement, rather than replace, clinical assessment. The result should be integrated with the history, examination, ECG, echocardiography, and other relevant investigations.

Clinical Presentation and Symptoms

Natriuretic peptide testing is particularly useful when symptoms suggest HF but the diagnosis remains uncertain. Acute HF generally produces higher BNP and NT-proBNP concentrations than chronic, stable disease, and greater volume overload is usually associated with higher levels. However, this relationship is not universal.

In ambulatory patients, dyspnoea may be less intense and peptide concentrations are generally lower. In this setting, testing is principally used to exclude HF, with thresholds selected for a high negative predictive value. An elevated result should generally lead to further assessment, including echocardiography where clinically appropriate.

Symptoms and signs that support testing include:

• Dyspnoea

• Peripheral oedema

• Symptoms suggestive of acute HF

• Unexplained exertional limitation

• Clinical concern for cardiomyopathy or structural heart disease

In the peri-operative setting, dyspnoea or peripheral oedema without a clear non-cardiac explanation should prompt ECG and BNP or NT-proBNP measurement. If the natriuretic peptide is elevated, transthoracic echocardiography is recommended before non-cardiac surgery.

Evaluation and Physical Examination

Natriuretic peptide results should be interpreted alongside a structured clinical evaluation. The examination should establish whether symptoms are accompanied by evidence of congestion, impaired perfusion, valvular disease, pulmonary hypertension, arrhythmia, or another cardiovascular disorder.

Particular attention is warranted when peptide concentrations appear disproportionate to the apparent clinical findings. Marked elevation without obvious congestion may occur in infiltrative cardiomyopathy, whereas a relatively low value does not reliably exclude HF in obesity.

For pre-operative assessment:

• An accurate history and clinical examination are recommended in all patients scheduled for non-cardiac surgery.

• In patients with dyspnoea and/or peripheral oedema, ECG and BNP or NT-proBNP testing are indicated unless a definite non-cardiac explanation exists.

• Elevated BNP or NT-proBNP in this setting should be followed by transthoracic echocardiography.

• In patients with suspected or known HF undergoing high-risk surgery, left ventricular function should be assessed by echocardiography and BNP or NT-proBNP should be measured unless these assessments have been performed recently.

• Patients with HF should receive optimal guideline-directed medical therapy and regular assessment of volume status and organ perfusion.

Routine testing is not appropriate in low-risk patients undergoing low- or intermediate-risk non-cardiac surgery when there is no known cardiovascular disease, cardiovascular risk factor burden, or symptom or sign suggestive of cardiovascular disease.

Diagnostic Interpretation

Acute Heart Failure

The values below are suggested for clinical applications of BNP and NT-proBNP in acute presentations.

The reported performance of the exclusion thresholds is high. BNP below 30–50 pg/mL has a sensitivity of approximately 97% and a negative predictive value of approximately 96% for excluding acutely decompensated HF. NT-proBNP below 300 pg/mL has a sensitivity of approximately 99% and a negative predictive value of approximately 99%.

For identifying acute HF, a single BNP threshold of 100 pg/mL has reported sensitivity of 90%, specificity of 76%, positive predictive value of 79%, and negative predictive value of 89%. A single NT-proBNP threshold of 900 pg/mL has reported sensitivity of 90%, specificity of 85%, positive predictive value of 76%, and negative predictive value of 94%.

The multiple-cutoff BNP strategy identifies a low-probability range below 100 pg/mL, an intermediate or “grey-zone” range of 100–400 pg/mL, and a higher-probability range above 400 pg/mL. The corresponding NT-proBNP approach is age stratified. These values should not be applied mechanically; age, renal function, obesity, rhythm, valvular disease, and the clinical phenotype all influence the result.

Ambulatory or Less Acute Dyspnoea

For outpatient evaluation, lower thresholds are required than those used for acute dyspnoea.

The reported negative predictive value of the outpatient BNP thresholds is approximately 96% in asymptomatic patients and 98% in symptomatic patients. For NT-proBNP, the age-stratified thresholds have reported negative predictive values of approximately 91% for patients younger than 75 years and 98% for those aged 75 years or older.

An elevated outpatient result does not establish HF by itself. It indicates the need for additional diagnostic evaluation, commonly including echocardiography.

Heart Failure Phenotype and Severity

Natriuretic peptide concentrations tend to increase with worsening NYHA functional class. They are generally higher in HFrEF than in HFmrEF or HFpEF, although diastolic function makes an independent contribution to the concentration.

Levels are typically higher during acute HF than during chronic stable disease. A patient’s stable baseline value can therefore be clinically useful when later symptoms develop, because changes from the individual baseline may be more informative than an isolated measurement.

Biomarkers and Laboratory Findings

Prognostic Information in Heart Failure

BNP and NT-proBNP provide prognostic information across the spectrum of HF, even after adjustment for history, examination findings, echocardiographic measurements, and cardiopulmonary exercise testing.

Serial assessment adds prognostic information beyond a single measurement:

• Persistently high or rising levels in ambulatory HF identify a particularly high-risk population.

• In acute HF, failure to achieve a substantial reduction by hospital discharge is associated with higher morbidity and mortality.

• A decline of at least 30% by hospital discharge has been suggested as a desirable response.

• In the cardiac response criteria presented in the source material, a response is defined as a decline of 30% or 300 pg/mL, whichever is greater; progression is defined as an increase of 30% or 300 pg/mL.

The source material also describes an association between reduction of NT-proBNP to below 1000 pg/mL by 12 months and reverse left ventricular remodelling and improved outcomes, irrespective of the treatment strategy used. This supports the importance of treatment response rather than the use of biomarker concentration as an isolated therapeutic target.

Other Biomarkers in Heart Failure

A broad range of biomarkers has prognostic associations in HF. Inverse relationships with survival have been described for neurohormonal and inflammatory markers, including norepinephrine, renin, arginine vasopressin, aldosterone, BNP, NT-proBNP, endothelin-1, tumour necrosis factor, soluble tumour necrosis factor receptors, C-reactive protein, galectin-3, pentraxin-3, and soluble ST2.

Cardiac troponins may be elevated in non-ischaemic HF and predict adverse cardiac outcomes and incident HF. Anaemia is associated with more symptoms, worse NYHA functional status, increased HF hospitalization, and reduced survival. Iron deficiency is also common and is associated with increased mortality and poorer quality of life, even when anaemia is absent.

The source material defines iron deficiency in HF as:

• Ferritin <100 µg/L, or

• Ferritin 100–299 µg/L with transferrin saturation <20%

A standard diagnostic evaluation should be undertaken in anaemic patients, and reversible causes should be treated according to applicable practice guidance. Routine blood transfusion is not recommended for stable HF anaemia on the basis of the provided material. Erythropoiesis-stimulating therapy with darbepoetin alfa did not improve the described clinical outcomes, and the 2022 ACC/AHA/HFSA guidance cautions against erythropoietin-stimulating agents in HFrEF.

Acute Pulmonary Embolism

Acute pulmonary embolism produces right ventricular pressure overload and myocardial stretch, stimulating BNP and NT-proBNP release. Concentrations therefore reflect the severity of right ventricular dysfunction and haemodynamic compromise.

Among unselected patients with acute pulmonary embolism, 51% had elevated BNP or NT-proBNP at admission. In this group, the reported risk of early death was 10%, while the risk of an adverse clinical outcome was 23%.

In normotensive pulmonary embolism, elevated natriuretic peptides have limited specificity and positive predictive value for early mortality. Conversely, low concentrations have high sensitivity and negative predictive value for excluding an unfavourable early outcome.

An NT-proBNP concentration below 500 pg/mL was used to select patients for home treatment in a multicentre management study. When greater prognostic specificity is desired, a threshold of at least 600 pg/mL may be more appropriate.

Lactate provides complementary information. An arterial plasma lactate concentration of at least 2 mmol/L indicates an imbalance between tissue oxygen supply and demand and predicts pulmonary-embolism-related complications in both unselected and initially normotensive patients.

Acute Coronary Syndromes

In acute coronary syndromes, natriuretic peptides add prognostic information to cardiac troponin, clinical variables, and ECG findings. BNP and NT-proBNP help predict:

• Mortality

• Acute HF

• Development of atrial fibrillation

High-sensitivity troponin concentrations and renal function also contribute importantly to risk assessment. Serum creatinine and estimated glomerular filtration rate should be determined in patients with acute coronary syndromes because they influence prognosis and are components of the GRACE risk score.

Valvular Heart Disease

BNP and troponin can assist in monitoring the progression of valvular heart disease and in determining the timing of intervention. In valvular disease, the ratio of measured BNP or NT-proBNP to the assay’s upper limit of normal for the patient’s age and sex is an independent and incremental predictor of mortality.

Accumulation of several elevated cardiovascular stress biomarkers in patients undergoing aortic valve replacement is associated with higher all-cause and cardiovascular mortality and more frequent rehospitalization.

Adult Congenital Heart Disease

BNP and NT-proBNP are the best-studied natriuretic peptide biomarkers in adults with congenital heart disease. They provide important prognostic information, but their diagnostic value for HF varies according to the underlying lesion and type of repair because cutoffs are not uniform.

They are most useful in patients with biventricular circulation and least useful in those with Fontan circulation. Serial testing can identify patients at risk of adverse events. Natriuretic peptides may also be elevated in cyanotic heart disease because hypoxia can stimulate peptide secretion.

Pregnancy

During pregnancy and the early postpartum period, natriuretic peptide values within the normal range have a strong negative predictive value for HF, whereas the positive predictive value is lower. In women with cardiomyopathy, adult congenital heart disease, or valvular disease, baseline and individualized serial measurements should be considered when assessing possible cardiac complications.

The provided pregnancy data include the following findings:

• An NT-proBNP concentration above 125 pg/mL was found in 20% of pregnant individuals in one general population compared with 8% of non-pregnant individuals.

• NT-proBNP may remain higher throughout pregnancy in women with high-risk lesions, structural heart disease, left ventricular systolic dysfunction, or congenital heart disease despite clinical stability.

• Patients who developed HF had a higher median NT-proBNP than those who did not, although there was substantial overlap.

• NT-proBNP below 200 pg/mL had a specificity of 91% and a negative predictive value of 95% for predicting HF and pre-eclampsia in the cited study.

• BNP below 100 pg/mL or NT-proBNP below 128 pg/mL during pregnancy has a high negative predictive value for excluding HF.

Routine troponin measurement alone is not recommended during pregnancy because standardized pregnancy and postpartum values have not been established.

Peri-operative Risk Assessment

BNP and NT-proBNP quantify haemodynamic cardiac wall stress, while high-sensitivity cardiac troponin T or I quantifies myocardial injury. Both biomarker groups complement clinical assessment and ECG in predicting peri-operative cardiac complications.

Elevated BNP or NT-proBNP is associated with peri-operative cardiovascular death, cardiac arrest, acute HF, and tachyarrhythmias. In the peri-operative setting, BNP and NT-proBNP should be interpreted quantitatively as markers of HF, taking account of age, sex, obesity, renal dysfunction, and known cardiac disease.

The source material defines abnormal concentrations for peri-operative assessment as:

• BNP ≥35 pg/mL

• NT-proBNP ≥125 pg/mL

In patients with known cardiovascular disease, cardiovascular risk factors including age ≥65 years, or symptoms suggestive of cardiovascular disease, high-sensitivity troponin T or I should be measured before intermediate- or high-risk non-cardiac surgery and again at 24 and 48 hours afterwards. BNP or NT-proBNP should not be measured routinely in low-risk patients undergoing low- or intermediate-risk procedures.

Treatment and Management

Use of Natriuretic Peptides to Guide Therapy

Although BNP and NT-proBNP are strong prognostic markers, trials evaluating biomarker-guided pharmacological titration in HFrEF have produced conflicting results. The available evidence does not establish a routine benefit beyond careful implementation of guideline-recommended therapy.

Routine measurement of BNP or NT-proBNP solely to guide titration of HFrEF treatment is therefore not supported. Biomarker trends may nevertheless contribute to clinical assessment, particularly when interpreted with symptoms, signs, volume status, ventricular function, and treatment response.

A falling natriuretic peptide concentration during treatment is generally associated with improved prognosis. However, treatment decisions should not be based on the peptide value in isolation.

General Management Principles

Management should address the underlying cardiovascular disorder and the haemodynamic state reflected by the biomarker. The source material supports the following principles:

• Apply guideline-recommended HF therapy assiduously rather than relying on biomarker-guided titration alone.

• Assess and treat reversible causes of anaemia.

• Identify and treat iron deficiency when present.

• In peri-operative HF, optimize medical treatment according to current HF guidelines.

• Monitor volume status and organ perfusion regularly.

• Exercise particular caution with peri-operative fluid administration in cardiomyopathy, because postoperative mobilization of intra-operative fluids may cause hypervolaemia and pulmonary congestion.

• In obstructive hypertrophic cardiomyopathy, avoid factors and medications that increase left ventricular outflow tract obstruction and provide appropriate pharmacological and intravascular fluid management when required.

• In pregnancy, use natriuretic peptides as an adjunct to clinical assessment and echocardiography rather than as isolated diagnostic tests.

Drugs and Practical Considerations

The provided material does not supply a comprehensive pharmacological regimen for HF based on BNP or NT-proBNP, and no specific HF drug doses are given.

Important medication-related considerations include:

• Angiotensin receptor–neprilysin inhibitors may transiently increase BNP; NT-proBNP is not a neprilysin substrate and may therefore be more useful for monitoring the clinical trajectory during treatment.

• Erythropoiesis-stimulating agents are not recommended for the management of anaemia in HFrEF according to the cited ACC/AHA/HFSA guidance.

• Routine blood transfusion is not recommended for stable HF-associated anaemia on the basis of the source material.

• In peri-operative care, pre-existing HF medication should be optimized according to current HF guidance, with attention to renal function, volume status, and organ perfusion.

Guideline Recommendations

Heart Failure

The principal recommendation is that BNP and NT-proBNP should not be measured routinely to guide pharmacological titration in HFrEF, because biomarker-guided strategies have yielded conflicting results and have not demonstrated a consistent advantage over assiduous use of guideline-recommended therapy.

Non-cardiac Surgery

The relevant recommendations are summarized below.

Other Clinical Settings

Across valvular disease, adult congenital heart disease, acute coronary syndromes, pulmonary embolism, pregnancy, and peri-operative assessment, BNP and NT-proBNP are principally adjunctive biomarkers. Their meaning depends on the clinical setting, the underlying cardiac lesion, renal function, age, obesity, rhythm, and treatment.

Limitations and Common Interpretive Errors

Treating the Value as Disease-Specific

An elevated BNP or NT-proBNP indicates myocardial stress but does not identify a single cause. Pulmonary hypertension, right ventricular strain, valvular disease, atrial arrhythmia, pericardial disease, sepsis, pulmonary embolism, and infiltrative cardiomyopathy may all produce elevation.

Applying Acute Thresholds to Outpatients

Emergency-department thresholds for acute dyspnoea should not be transferred to ambulatory patients. Outpatient evaluation requires lower thresholds optimized primarily for exclusion of HF.

Ignoring Low Values in Obesity

Obesity can result in unexpectedly low peptide concentrations. A low result should therefore be interpreted with caution when clinical evidence strongly suggests HF.

Ignoring Renal Dysfunction and Age

Both age and impaired renal function increase BNP and NT-proBNP concentrations. These factors may reduce specificity and should be incorporated into interpretation.

Substituting Biomarkers for Clinical Assessment

Natriuretic peptides strengthen diagnostic and prognostic assessment but do not replace history, examination, ECG, echocardiography, or other targeted investigations.

Using BNP and NT-proBNP Interchangeably

Their different clearance mechanisms and half-lives mean that absolute concentrations cannot be directly equated. Trends should ideally be followed using the same analyte and assay.

Misinterpreting BNP During Angiotensin Receptor–Neprilysin Inhibition

BNP may rise with angiotensin receptor–neprilysin inhibitor therapy. NT-proBNP is not a neprilysin substrate and may better reflect the clinical course in this context.

Prognosis and Follow-up

BNP and NT-proBNP are powerful prognostic markers across acute and chronic HF. Higher concentrations generally indicate greater risk, while persistently elevated or rising values identify patients at increased risk of future adverse events. In chronic ambulatory HF, increases may precede clinical events by weeks to months.

Serial measurements can provide information beyond the initial value:

• A reduction during acute HF treatment is associated with improved prognosis.

• Lack of a robust decrease by hospital discharge is associated with greater morbidity and mortality.

• Rising values during chronic follow-up identify a high-risk population.

• Response categories can be defined using percentage and absolute changes from baseline.

Follow-up should remain clinically driven. Serial BNP or NT-proBNP may be useful when assessing an evolving clinical picture, treatment response, or prognosis, but routine biomarker-guided titration is not supported. The most reliable interpretation combines the biomarker trajectory with symptoms, physical findings, volume status, renal function, ECG, echocardiography, and the underlying cardiovascular diagnosis.