Natriuretic Peptides (ANP/BNP): Cardiac Biomarkers

When your heart stretches under pressure, it doesn't just pump harder—it talks back. The language it speaks comes through a family of signaling molecules called natriuretic peptides, hormones that play a central role in regulating blood pressure, fluid balance, and cardiac function. Among them, B-type natriuretic peptide (BNP) has become the gold-standard biomarker for diagnosing heart failure, guiding treatment decisions, and predicting outcomes in millions of patients worldwide.

Natriuretic peptides are the body's built-in safeguard against volume overload. When blood volume rises or the heart chambers stretch, cardiomyocytes secrete these peptides to trigger a cascade of protective responses: blood vessels dilate, kidneys excrete sodium and water, and harmful hormonal pathways get suppressed. This system doesn't just respond to heart failure—it actively fights against it.

Beyond the clinic, natriuretic peptides are reshaping cardiovascular therapy. Drugs like nesiritide deliver synthetic BNP to acutely decompensated patients, while neprilysin inhibitors (sacubitril/valsartan) block the enzymes that break down these peptides, amplifying their protective effects. Even outside cardiology, C-type natriuretic peptide (CNP) is now FDA-approved for treating achondroplasia, a skeletal growth disorder, demonstrating the far-reaching biological impact of this peptide family.

Understanding natriuretic peptides means understanding how the heart regulates itself at the molecular level—and how clinicians can harness those mechanisms to save lives.

Quick Reference
What Are Natriuretic Peptides?
Structure and Molecular Characteristics
Mechanisms of Action
Clinical Applications
Research Applications
Safety and Considerations
Frequently Asked Questions
The Bottom Line
Disclaimer
References

Quick Reference

Peptide	ANP (Atrial Natriuretic Peptide)	BNP (B-type Natriuretic Peptide)	CNP (C-type Natriuretic Peptide)
Alternative Names	Atrial natriuretic factor (ANF), Atriopeptin	Brain natriuretic peptide, B-type natriuretic peptide	C-type natriuretic peptide
Amino Acid Length	28 amino acids (mature form)	32 amino acids (mature form)	22 amino acids (mature form)
Primary Source	Atrial cardiomyocytes	Ventricular cardiomyocytes	Endothelial cells, brain, chondrocytes
Main Receptor	NPR-A (natriuretic peptide receptor-A)	NPR-A	NPR-B (natriuretic peptide receptor-B)
Signal Molecule	Cyclic GMP (cGMP)	Cyclic GMP (cGMP)	Cyclic GMP (cGMP)
Primary Functions	Natriuresis, diuresis, vasodilation, RAAS inhibition	Natriuresis, diuresis, vasodilation, anti-fibrotic effects	Local vascular regulation, bone growth, anti-fibrotic effects
Clinical Use	Research; biomarker for heart failure	Diagnostic biomarker for heart failure (BNP, NT-proBNP); therapeutic agent (nesiritide)	Research; therapeutic agent for achondroplasia (vosoritide)
Half-Life	~2-3 minutes	~18-20 minutes	Rapidly cleared from circulation
Clearance	Neprilysin, NPR-C receptor-mediated	Neprilysin, NPR-C receptor-mediated	Neprilysin, NPR-C receptor-mediated

What Are Natriuretic Peptides?

Natriuretic peptides are a family of hormone molecules secreted primarily by the heart in response to mechanical stretch and hemodynamic stress. The name "natriuretic" derives from their signature effect: promoting sodium (natrium in Latin) excretion through the kidneys. But their influence extends far beyond renal sodium handling—they regulate blood pressure, oppose the renin-angiotensin-aldosterone system (RAAS), prevent cardiac remodeling, and modulate vascular tone.

The natriuretic peptide family includes three principal members:

ANP (Atrial Natriuretic Peptide): Synthesized and secreted by atrial cardiomyocytes when the atria stretch due to increased blood volume. ANP acts as an endocrine hormone, traveling through the bloodstream to exert systemic effects on kidneys, blood vessels, and adrenal glands.
BNP (B-type Natriuretic Peptide): Originally isolated from porcine brain tissue in 1988—hence "brain" natriuretic peptide—but subsequent research revealed that BNP is predominantly produced by ventricular cardiomyocytes in response to ventricular wall stress. It shares similar functions with ANP but is secreted from a different cardiac chamber and has a longer half-life.
CNP (C-type Natriuretic Peptide): Unlike ANP and BNP, CNP is produced primarily by endothelial cells, the brain, and chondrocytes. CNP acts locally as a paracrine/autocrine regulator rather than a circulating hormone. It lacks direct natriuretic effects but plays important roles in vascular function, cardiac remodeling, and skeletal growth.

All three peptides share a conserved 17-amino acid ring structure formed by a disulfide bond between two cysteine residues. This ring structure is essential for receptor binding and biological activity. Despite their structural similarities, these peptides bind to different receptors and serve distinct physiological roles.

The natriuretic peptide system operates as the body's natural counter-regulatory mechanism against volume overload and cardiovascular stress. When the heart chambers stretch—whether from high blood pressure, heart failure, or fluid retention—cardiomyocytes respond by releasing ANP and BNP. These peptides then activate protective pathways that reduce preload, lower blood pressure, and inhibit harmful neurohumoral systems like RAAS and the sympathetic nervous system.

Structure and Molecular Characteristics

Molecular Structure

All natriuretic peptides share a characteristic structural motif: a 17-amino acid ring formed by a disulfide bridge between two cysteine residues. This ring structure is essential for binding to natriuretic peptide receptors and triggering downstream signaling. The amino acid sequences flanking this ring differ among ANP, BNP, and CNP, conferring receptor selectivity and specific biological functions.

ANP (Atrial Natriuretic Peptide):

Mature circulating form: 28 amino acids
Synthesized as a 151-amino acid preprohormone (preproANP)
Processed to 126-amino acid proANP, stored in atrial granules
Cleaved by corin protease to release active 28-amino acid ANP and inactive 98-amino acid NT-proANP
Molecular weight: ~3 kDa

BNP (B-type Natriuretic Peptide):

Mature circulating form: 32 amino acids
Synthesized as a 134-amino acid preprohormone (preproBNP)
Processed to 108-amino acid proBNP
Cleaved to release active 32-amino acid BNP and biologically inactive 76-amino acid NT-proBNP
Both BNP and NT-proBNP circulate in blood; NT-proBNP has a longer half-life (~60-120 minutes vs. ~20 minutes)
Molecular weight: ~3.5 kDa (BNP), ~8.5 kDa (NT-proBNP)

CNP (C-type Natriuretic Peptide):

Two bioactive forms: CNP-22 (primary circulating form) and CNP-53
Synthesized as a 126-amino acid preprohormone
Processed to CNP-53, which is further cleaved to CNP-22
Most highly conserved natriuretic peptide across species (100% homology in mammals)
Molecular weight: ~2.2 kDa (CNP-22)

Receptor Binding and Selectivity

Natriuretic peptides exert their effects by binding to three receptor subtypes:

NPR-A (Natriuretic Peptide Receptor-A):

Also known as guanylyl cyclase-A (GC-A)
Primary receptor for ANP and BNP
Transmembrane receptor with intrinsic guanylyl cyclase activity
Upon ligand binding, catalyzes conversion of GTP to cyclic GMP (cGMP)
Highly expressed in kidneys, adrenal glands, blood vessels, and heart

NPR-B (Natriuretic Peptide Receptor-B):

Also known as guanylyl cyclase-B (GC-B)
Selective receptor for CNP
Transmembrane receptor with guanylyl cyclase activity
Produces cGMP upon CNP binding
Highly expressed in brain, endothelium, chondrocytes, and vascular smooth muscle

NPR-C (Natriuretic Peptide Receptor-C):

Clearance receptor lacking guanylyl cyclase activity
Binds all three natriuretic peptides (ANP, BNP, CNP)
Controls local peptide concentrations through receptor-mediated internalization and degradation
Most abundant natriuretic peptide receptor in most tissues
Acts as a "decoy" receptor to regulate peptide availability

Degradation and Clearance

Natriuretic peptides are rapidly cleared from circulation through two main mechanisms:

Neprilysin-mediated degradation: Neprilysin (neutral endopeptidase, NEP) is a membrane-bound metalloproteinase that cleaves and inactivates natriuretic peptides. This enzyme is the primary degradation pathway for ANP and BNP. Inhibiting neprilysin (e.g., with sacubitril) increases circulating levels of natriuretic peptides and amplifies their protective effects.
NPR-C-mediated clearance: The NPR-C receptor binds natriuretic peptides and internalizes them for lysosomal degradation. This receptor-mediated clearance mechanism provides a second pathway for controlling peptide concentrations in tissues.

The relative contributions of these clearance mechanisms vary by peptide and tissue. NT-proBNP, the inactive N-terminal fragment of proBNP, is not degraded by neprilysin, making it a more stable biomarker with a longer half-life than BNP itself.

Mechanisms of Action

Natriuretic peptides regulate cardiovascular homeostasis through a coordinated set of effects on the kidneys, blood vessels, adrenal glands, and heart. These effects are mediated primarily through cGMP, a second messenger that activates cGMP-dependent protein kinases (PKGs), regulates phosphodiesterases, and modulates cyclic nucleotide-gated ion channels.

Renal Effects: Natriuresis and Diuresis

The kidneys are a primary target of ANP and BNP. These peptides increase sodium and water excretion through several mechanisms:

Increased glomerular filtration rate (GFR): ANP dilates afferent arterioles and constricts efferent arterioles, increasing the filtration pressure gradient. This raises GFR, delivering more sodium to the nephron.
Inhibition of sodium reabsorption: ANP and BNP directly inhibit sodium reabsorption in the cortical collecting duct and inner medullary collecting duct by closing epithelial sodium channels (ENaC). This increases sodium delivery to the distal nephron and boosts urinary sodium excretion.
Suppression of renin and aldosterone: ANP and BNP inhibit renin secretion from juxtaglomerular cells and aldosterone release from the adrenal cortex. Since aldosterone promotes sodium retention, suppressing it amplifies natriuresis.

These effects collectively reduce extracellular fluid volume, lower blood pressure, and relieve cardiac preload.

Vascular Effects: Vasodilation

ANP and BNP are potent vasodilators. By stimulating NPR-A on vascular smooth muscle and endothelial cells, they increase intracellular cGMP, which activates PKG. PKG phosphorylates targets that reduce intracellular calcium, relax smooth muscle, and dilate blood vessels.

CNP acts as a local vasodilator through NPR-B signaling in endothelial cells and vascular smooth muscle. Unlike ANP and BNP, CNP functions primarily as a paracrine regulator, since it is rapidly cleared from the circulation and present at low concentrations in plasma.

Vasodilation reduces systemic vascular resistance, lowers afterload on the heart, and improves cardiac output—effects that are especially beneficial in heart failure.

Neurohumoral Antagonism: Inhibition of RAAS and Sympathetic Activity

One of the most important functions of natriuretic peptides is opposing the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, both of which are activated in heart failure and hypertension.

RAAS suppression: ANP and BNP inhibit renin release, aldosterone secretion, and angiotensin signaling. This counters the salt-retaining, vasoconstricting effects of RAAS.
Sympathetic inhibition: ANP reduces sympathetic outflow from the central nervous system and inhibits norepinephrine release from sympathetic nerve terminals.

By antagonizing these systems, natriuretic peptides prevent the vicious cycle of volume retention, vasoconstriction, and cardiac remodeling that drives heart failure progression.

Cardiac Effects: Anti-Hypertrophic and Anti-Fibrotic Actions

ANP and BNP act directly on cardiac tissue to prevent pathological remodeling. In cardiomyocytes, these peptides inhibit hypertrophic signaling pathways activated by angiotensin II, endothelin-1, and mechanical stress. They also suppress fibroblast proliferation and collagen deposition, limiting cardiac fibrosis.

CNP plays a prominent role in local cardiac remodeling. It is produced by endothelial cells, fibroblasts, and cardiomyocytes within the heart and acts in a paracrine manner to coordinate cardiac structure, function, and coronary vasoreactivity.

These anti-hypertrophic and anti-fibrotic effects are protective in heart failure, hypertension, and myocardial infarction.

Metabolic Effects

Recent research has revealed that natriuretic peptides influence energy metabolism. ANP and BNP stimulate lipolysis in white adipose tissue, promote fat oxidation in skeletal muscle, and increase thermogenesis in brown adipose tissue. These effects may explain associations between low natriuretic peptide levels and metabolic syndrome, obesity, and type 2 diabetes.

Skeletal Effects: CNP and Bone Growth

Unlike ANP and BNP, CNP does not have direct natriuretic activity. Instead, CNP plays a specialized role in skeletal growth by stimulating chondrocyte proliferation and endochondral ossification. CNP activates NPR-B in the growth plate, counteracting the inhibitory effects of fibroblast growth factor receptor 3 (FGFR3) on bone growth.

Knockout mice lacking CNP (Nppc-/-) exhibit severe dwarfism, with femurs, tibiae, and vertebrae measuring only 50-80% of normal length. This discovery led to the development of vosoritide, a CNP analog approved for treating achondroplasia, a genetic skeletal disorder caused by overactive FGFR3 signaling.

Clinical Applications

BNP and NT-proBNP as Diagnostic Biomarkers for Heart Failure

The most established clinical application of natriuretic peptides is diagnosing heart failure. When the heart fails to pump efficiently, blood backs up into the ventricles, stretching the ventricular walls. This mechanical stretch triggers BNP secretion. As a result, BNP levels rise in proportion to the severity of ventricular dysfunction and hemodynamic stress.

Both BNP and its inactive cleavage fragment NT-proBNP are measured clinically. NT-proBNP has a longer half-life (~60-120 minutes vs. ~20 minutes for BNP) and is not degraded by neprilysin, making it a more stable biomarker. However, both perform equally well for diagnosing heart failure in acute care settings.

Diagnostic Performance:

Large-scale studies have established the diagnostic accuracy of natriuretic peptide testing:

Breathing Not Properly study: In 1586 emergency department patients presenting with acute dyspnea, BNP levels were the single most accurate predictor of heart failure. Using a cutoff of 100 pg/mL, sensitivity was 90% and specificity was 76%.
PRIDE study: In 600 emergency department patients with acute dyspnea, NT-proBNP at a cutoff of 300 pg/mL had 99% negative predictive value for ruling out acute heart failure.
Meta-analyses: Pooled sensitivity for BNP is 80-97% and for NT-proBNP is 86-96%, with excellent negative likelihood ratios (0.08-0.30), making these tests particularly useful for excluding heart failure.

Diagnostic Cutoffs:

Guidelines from the American College of Cardiology, American Heart Association, European Society of Cardiology, and Japanese Circulation Society recommend the following cutoffs:

Biomarker	Acute Heart Failure (Emergency Department)	Chronic Heart Failure (Outpatient)
BNP	≥100 pg/mL suggests heart failure	≥35 pg/mL suggests heart failure
NT-proBNP	≥300 pg/mL (age <50), ≥450 pg/mL (age 50-75), ≥900 pg/mL (age >75)	≥125 pg/mL suggests heart failure

Factors Affecting Interpretation:

Several factors influence natriuretic peptide levels and must be considered when interpreting results:

Age: NT-proBNP increases with age. Median NT-proBNP in healthy individuals is 21 pg/mL at age <30, 38 pg/mL at age 50-59, and 281 pg/mL at age ≥80 in males; and 51 pg/mL at age <30, 66 pg/mL at age 50-59, and 240 pg/mL at age ≥80 in females.
Sex: Natriuretic peptide levels are 10-100% higher in women than men at any given age.
Obesity: BNP and NT-proBNP levels are lower in obese patients, likely due to increased expression of NPR-C clearance receptors in adipose tissue. This can lead to false negatives in overweight patients.
Chronic kidney disease: Reduced renal clearance increases circulating levels of NT-proBNP (but not BNP), which can lead to false positives in patients with impaired renal function.
Atrial fibrillation: Elevated atrial stretch in atrial fibrillation increases ANP secretion, which may elevate BNP levels even without ventricular dysfunction.

Prognostic Value in Heart Failure

Beyond diagnosis, natriuretic peptide levels predict outcomes in heart failure. Higher BNP or NT-proBNP levels correlate with increased risk of death, hospitalization, and disease progression. Serial measurements can track response to therapy: declining levels indicate effective treatment, while persistently elevated or rising levels suggest inadequate response.

Some clinical trials have tested "biomarker-guided therapy," where clinicians intensify heart failure treatment based on natriuretic peptide levels rather than symptoms alone. Results have been mixed, with some trials showing benefit and others showing no advantage over symptom-guided care. Current guidelines do not universally recommend biomarker-guided therapy, but serial natriuretic peptide testing remains a useful tool for monitoring disease trajectory.

Nesiritide: Recombinant BNP for Acute Decompensated Heart Failure

Nesiritide is a recombinant form of human BNP-32, manufactured using recombinant DNA technology in E. coli. It was approved by the U.S. Food and Drug Administration (FDA) in 2001 for treating acute decompensated heart failure (ADHF) in patients with dyspnea at rest or with minimal activity.

Mechanism and Hemodynamic Effects:

Nesiritide binds to NPR-A receptors on vascular smooth muscle and endothelial cells, producing cGMP-mediated vasodilation. Intravenous infusion results in:

Balanced arterial and venous dilation
Decreased pulmonary capillary wedge pressure (PCWP) and right atrial pressure
Reduced systemic vascular resistance
Increased stroke volume and cardiac output
No increase in heart rate

These hemodynamic effects provide rapid symptom relief in patients with acute heart failure.

Clinical Trials and Safety Concerns:

Early enthusiasm for nesiritide was tempered by safety concerns. Meta-analyses suggested increased risks of worsening renal function and 30-day mortality. These findings led to the ASCEND-HF trial, a large randomized controlled trial enrolling 7,141 patients hospitalized with acute heart failure.

ASCEND-HF results (2011):

Nesiritide provided modest improvement in dyspnea compared to placebo.
No significant effect on 30-day mortality or rehospitalization.
No increase in worsening renal function or mortality at recommended doses.

Based on these findings, nesiritide remains FDA-approved but is used less frequently than in the past. Current guidelines consider it a reasonable option for selected patients with ADHF but do not recommend it as first-line therapy.

Sacubitril/Valsartan: Neprilysin Inhibition to Boost Natriuretic Peptides

If exogenous natriuretic peptides (nesiritide) have limited benefit, what about preventing their degradation? This is the rationale behind sacubitril/valsartan (Entresto), an angiotensin receptor-neprilysin inhibitor (ARNI) approved for chronic heart failure with reduced ejection fraction (HFrEF).

Mechanism:

Sacubitril is a prodrug metabolized to sacubitrilat, a potent inhibitor of neprilysin, the enzyme that degrades ANP, BNP, and other vasoactive peptides. By blocking neprilysin, sacubitril increases circulating levels of natriuretic peptides, prolonging their protective cardiovascular effects.

Sacubitril is combined with valsartan, an angiotensin II receptor blocker (ARB), because neprilysin inhibition alone can increase angiotensin II levels. The combination provides dual benefit: enhanced natriuretic peptide signaling and blockade of deleterious angiotensin II effects.

PARADIGM-HF Trial:

The landmark PARADIGM-HF trial (2014) compared sacubitril/valsartan to enalapril (an ACE inhibitor) in 8,442 patients with chronic HFrEF. Results were striking:

20% reduction in cardiovascular death (hazard ratio 0.80, 95% CI 0.71-0.89, P<0.001)
20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization (hazard ratio 0.80, 95% CI 0.73-0.87, P<0.001)
16% reduction in all-cause mortality

Sacubitril/valsartan was so effective that the trial was stopped early for overwhelming benefit. The drug received FDA approval in 2015 and is now a cornerstone of guideline-directed medical therapy for HFrEF.

Biomarker Considerations:

Because sacubitril inhibits neprilysin, BNP levels increase in patients taking the drug. Clinicians should not interpret elevated BNP as worsening heart failure in patients on sacubitril/valsartan. Instead, NT-proBNP should be used for monitoring, since it is not a substrate for neprilysin and remains a reliable biomarker during neprilysin inhibition.

Vosoritide: CNP Analog for Achondroplasia

While ANP and BNP dominate cardiovascular applications, CNP has found an unexpected clinical use in skeletal medicine. Vosoritide is a modified recombinant human CNP analog developed for treating achondroplasia, the most common form of dwarfism.

Mechanism:

Achondroplasia is caused by gain-of-function mutations in FGFR3, which inhibit chondrocyte proliferation and endochondral bone growth. CNP activates NPR-B in growth plate chondrocytes, counteracting FGFR3 signaling and restoring bone growth.

Vosoritide is a long-acting CNP analog designed to resist neprilysin degradation, prolonging its half-life and biological activity.

Clinical Efficacy:

Phase 2 and 3 trials demonstrated that daily subcutaneous vosoritide significantly increases annualized growth velocity in children with achondroplasia:

Mean increase in growth velocity: ~1.5-1.6 cm/year compared to placebo
Long-term benefit: Three-year data showed an additional height gain of 5.75 cm (95% CI 4.93-6.57 cm) compared to untreated children
Safety: Favorable safety profile over up to 6 years of continuous treatment

Vosoritide was approved by the European Medicines Agency (EMA) in August 2021 and by the FDA in November 2021 for children with achondroplasia aged ≥5 years whose epiphyses are not closed. This represents the first pharmacological treatment for achondroplasia and highlights the therapeutic potential of CNP signaling beyond cardiovascular medicine.

Research Applications

Cardiovascular Disease Research

Natriuretic peptides are widely used as biomarkers and mechanistic tools in cardiovascular research:

Animal models of heart failure: Genetic knockout or overexpression of natriuretic peptides and their receptors helps elucidate their roles in cardiac physiology and pathology.
Biomarker discovery: Researchers are exploring novel natriuretic peptide fragments, post-translational modifications, and glycosylated forms as refined biomarkers for heart failure subtypes.
Drug development: Several next-generation therapies targeting the natriuretic peptide pathway are in development, including novel neprilysin inhibitors, NPR-A agonists, and long-acting CNP analogs for cardiovascular disease.

Metabolic Research

The discovery that natriuretic peptides regulate adipose tissue lipolysis, muscle fat oxidation, and energy expenditure has opened a new research area linking cardiac and metabolic health. Studies are investigating whether boosting natriuretic peptide signaling can improve metabolic outcomes in obesity, diabetes, and metabolic syndrome.

Bone Biology and Growth Disorders

CNP's role in skeletal growth has sparked research into other growth plate disorders, including hypochondroplasia, thanatophoric dysplasia, and growth hormone deficiency. Vosoritide and other CNP analogs are being tested in these conditions.

Safety and Considerations

Physiological Roles and Safety Profile

Natriuretic peptides are endogenous hormones with well-established physiological roles. When used therapeutically, their safety profiles reflect their mechanisms of action.

Nesiritide:

Most common side effect: hypotension (dose-dependent)
Headache, nausea, and dizziness may occur
Contraindicated in patients with cardiogenic shock or systolic blood pressure <90 mmHg
Early concerns about worsening renal function and increased mortality were not confirmed in large-scale trials (ASCEND-HF)

Sacubitril/Valsartan:

Side effects: Hypotension, hyperkalemia, worsening renal function, angioedema (rare)
Contraindicated in patients with history of angioedema related to ACE inhibitors or ARBs
Requires 36-hour washout period after stopping ACE inhibitors to minimize angioedema risk
Should not be used in pregnancy (teratogenic effects of ARB component)

Vosoritide:

Common side effects: Injection site reactions, vomiting, decreased blood pressure (transient)
Generally well tolerated in pediatric populations
Long-term safety data up to 6 years show no major safety signals

Special Populations

Chronic Kidney Disease:

NT-proBNP levels are elevated in CKD due to reduced renal clearance. Higher diagnostic cutoffs should be used.
BNP is less affected by renal function than NT-proBNP, but interpretation still requires caution.

Obesity:

Natriuretic peptide levels are lower in obese patients. Standard cutoffs may miss heart failure in overweight individuals.
Consider using lower diagnostic thresholds or alternative biomarkers in obese patients.

Atrial Fibrillation:

Atrial stretch in AF increases ANP secretion and may elevate BNP levels independent of ventricular function.
Interpret natriuretic peptide levels cautiously in patients with AF.

Pregnancy:

BNP and NT-proBNP levels may be mildly elevated in normal pregnancy due to hemodynamic changes.
Sacubitril/valsartan is contraindicated in pregnancy due to ARB component.

Frequently Asked Questions

What is the difference between BNP and NT-proBNP?

BNP and NT-proBNP are both derived from the same precursor molecule, proBNP, which is cleaved into active 32-amino acid BNP and inactive 76-amino acid NT-proBNP. They are released in equimolar amounts. The key differences:

Half-life: BNP has a half-life of ~20 minutes; NT-proBNP has a half-life of ~60-120 minutes, making NT-proBNP more stable in blood samples.
Degradation: BNP is degraded by neprilysin; NT-proBNP is not, making NT-proBNP the preferred biomarker in patients on sacubitril/valsartan.
Renal clearance: NT-proBNP is more affected by kidney function than BNP.

Both are equally accurate for diagnosing heart failure in most clinical settings.

How accurate is BNP for diagnosing heart failure?

BNP and NT-proBNP are highly accurate for ruling out heart failure. In emergency department studies, BNP at a cutoff of 100 pg/mL has 90% sensitivity and 76% specificity. The negative predictive value is very high (>95%), meaning a normal BNP level effectively rules out acute heart failure. However, specificity is lower, so elevated BNP levels should be interpreted in clinical context, considering other causes of elevated natriuretic peptides (e.g., atrial fibrillation, pulmonary embolism, chronic kidney disease).

Can natriuretic peptides be used to guide heart failure treatment?

Some studies have tested biomarker-guided therapy, where clinicians adjust heart failure medications based on BNP or NT-proBNP levels rather than symptoms alone. Results have been mixed: some trials showed improved outcomes, while others found no benefit over symptom-guided care. Current guidelines do not universally recommend biomarker-guided therapy, but serial natriuretic peptide measurements can help monitor treatment response and disease progression. Declining levels suggest effective treatment; persistently high or rising levels indicate need for therapy intensification.

Is nesiritide still used for heart failure?

Nesiritide is FDA-approved for acute decompensated heart failure but is used less frequently than in the past. The ASCEND-HF trial showed modest symptomatic benefit but no reduction in mortality or rehospitalization. Current heart failure guidelines consider nesiritide a reasonable option for selected patients with acute heart failure but do not recommend it as first-line therapy. Vasodilators like nitroglycerin and newer therapies like sacubitril/valsartan are more commonly used.

What is sacubitril/valsartan and how does it work?

Sacubitril/valsartan (Entresto) is an angiotensin receptor-neprilysin inhibitor (ARNI) used to treat chronic heart failure with reduced ejection fraction. Sacubitril inhibits neprilysin, the enzyme that degrades natriuretic peptides, increasing circulating levels of ANP and BNP. Valsartan blocks angiotensin II receptors. The combination enhances natriuretic peptide signaling while preventing the adverse effects of increased angiotensin II. The PARADIGM-HF trial showed that sacubitril/valsartan reduced cardiovascular death by 20% and heart failure hospitalization by 21% compared to enalapril, making it a cornerstone of modern heart failure therapy.

Do natriuretic peptides cause weight loss?

Natriuretic peptides have metabolic effects beyond cardiovascular regulation. ANP and BNP stimulate lipolysis in white adipose tissue, promote fat oxidation in skeletal muscle, and increase thermogenesis in brown adipose tissue. These effects can modestly increase energy expenditure and fat mobilization. However, natriuretic peptides are not weight-loss drugs and are not used therapeutically for obesity. Research suggests that low natriuretic peptide levels may contribute to metabolic syndrome, but more studies are needed to understand the clinical implications.

Vosoritide is a modified recombinant CNP analog approved for treating achondroplasia, a skeletal growth disorder. CNP activates NPR-B receptors in growth plate chondrocytes, stimulating bone growth. In achondroplasia, mutations in FGFR3 inhibit chondrocyte proliferation, causing short stature. Vosoritide counteracts FGFR3 signaling, restoring growth. Clinical trials showed that vosoritide increases growth velocity by ~1.5 cm/year in children with achondroplasia. It was approved by the FDA and EMA in 2021, representing the first pharmacological treatment for achondroplasia.

Are there risks to taking sacubitril/valsartan?

Sacubitril/valsartan is generally well tolerated but has potential side effects. The most common are hypotension (low blood pressure), hyperkalemia (high potassium), and worsening renal function, similar to ACE inhibitors and ARBs. Angioedema (swelling of the face, lips, or throat) is a rare but serious risk, more common in patients with prior history of angioedema from ACE inhibitors. Sacubitril/valsartan is contraindicated in pregnancy due to the teratogenic effects of the ARB component. Patients starting the drug should have blood pressure, kidney function, and potassium levels monitored.

The Bottom Line

Natriuretic peptides are the heart's endogenous defense against volume overload and cardiovascular stress. ANP and BNP regulate blood pressure, fluid balance, and cardiac remodeling by promoting natriuresis, vasodilation, and neurohumoral antagonism. CNP functions locally to regulate vascular tone, cardiac structure, and skeletal growth.

BNP and NT-proBNP have become gold-standard biomarkers for diagnosing heart failure, with sensitivity exceeding 90% and excellent negative predictive value. These tests help clinicians quickly identify or exclude heart failure in patients presenting with dyspnea, guiding treatment decisions and predicting outcomes.

Therapeutic applications are reshaping cardiovascular medicine. Nesiritide, a recombinant BNP, provides hemodynamic support in acute decompensated heart failure but has fallen out of favor due to limited mortality benefit. Sacubitril/valsartan, a neprilysin inhibitor that boosts endogenous natriuretic peptide levels, has demonstrated a 20% reduction in cardiovascular death in chronic heart failure and is now a cornerstone of guideline-directed therapy. Beyond cardiology, vosoritide—a CNP analog—has become the first FDA-approved treatment for achondroplasia, highlighting the broad biological impact of natriuretic peptide signaling.

Natriuretic peptides bridge basic cardiovascular physiology, clinical diagnostics, and cutting-edge therapeutics. Understanding this system means understanding how the heart communicates stress, how clinicians diagnose disease, and how modern drugs save lives.

Disclaimer

This article is for educational purposes only and does not constitute medical advice. Natriuretic peptide testing, nesiritide, sacubitril/valsartan, and vosoritide are prescription therapies that should only be used under the supervision of a qualified healthcare provider. If you have symptoms of heart failure (shortness of breath, swelling, fatigue) or concerns about your cardiovascular health, consult a physician. Do not start, stop, or change any medication without medical guidance.

PeptideJournal.org does not sell peptides or have financial relationships with peptide vendors. This content is produced solely for educational purposes.

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