The natriuretic peptides are a family of ring shaped vasoactive hormones showing considerable sequence homology. Four natriuretic peptides have been described, named A–D type (see Figure 1). Of these, commercial immunoassays have been developed for B type natriuretic peptide (BNP) and the N terminus of the prohormone, N terminal pro BNP (NTproBNP). There has been an explosion of clinical studies on the role and clinical application of BNP/NTproBNP, which will be the subject of this article.

Figure 1: Structure of Natriuretic Peptides

Common amino acids with sequence homology are shown in maroon.

BNP was originally discovered in the porcine brain, where it was thought to be a neurotransmitter, hence its original name – brain natriuretic peptide. There is a much larger concentration in the ventricles of the heart, hence the current term, B type natriuretic peptide. There appears to be little storage of BNP in the ventricle, the main source. BNP is produced by direct synthesis in response to the degree of ventricular stretch, so acts as a marker of ventricular dilatation. The messenger RNA for proBNP is unstable so there is active regulation of BNP levels according to ventricular wall tension. The initial transcription product contains a leader sequence, which is cleaved to yield proBNP (see Figure 2). This is then cleaved either on secretion or after secretion (exactly when is not clear) to NTproBNP and BNP.

Figure 2: BNP Transcription and Translation

Adapted from Nakao K et al., J. Hypertens. (1992); 10: pp. 1,111–1,114.

There are two receptors, natriuretic peptide receptor- A (NPR-A) and -B (NPR-B), which have an extracellular binding site, a transmembrane domain and an intracellular domain with a protein kinase-like region and a guanyl cyclase site. The intact ring structure is essential for receptor binding. Receptor binding results in generation of cyclic guanosine monophosphate (GMP) as second messenger. The half-life of BNP is short (20 minutes) and NTpBNP is 60 minutes under normal conditions. BNP binds to a third receptor, NPR-C, that clears it from the blood by binding, endocytosis and lysosomal degradation. The ring structure is also cleaved by a membranebound neutral endopeptidase, found in the kidneys and vascular tree, which inactivates the molecule.

Clinical Role of Natriuretic Peptides

The natriuretic peptides are relatively recently described although studies have indicated their potential clinical value. The advent of commercially available immunoassay systems has propelled BNP measurement from research applications to mainstream clinical practice. Current analytical techniques are robust and precise. (1–3) Clinical studies have shown that there is little difference between BP or NTproBNP measurement for the majority of clinical situations. The major difference between the two molecules is the stability with NTproBNP, as would be expected, which is much more stable. (4) The major clinical application of BNP/NTproBNP measurement is discussed in the following sections.

Detection of Ventricular Dysfunction (Cardiac Failure)

Cardiac failure is a major public health burden and is predicted to be the largest developing single health problem in the EU. (5,6) The European Cardiac Society (ECS) has estimated that the prevalence is 0.2% to 4% of the population, some 10 million in the ECS area. Accurate diagnosis of cardiac failure is important – the morbidity and mortality of cardiac failure is high. In women, the mortality of cardiac failure exceeds that of most cancers apart from lung cancer. The median survival is from three to four years. There are effective therapies including diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin 2 receptor blockers and beta-blockers such as carvedilol and bisoprolol. All of these agents are effective, improving quality of life and survival. Treatment with ACE inhibitors, to reduce inappropriate cardiac remodelling, is most effective when introduced early.

Clinical assessment of suspected heart failure (HF) has a sensitivity of 33% to 55%. The electrocardiogram (ECG) and chest radiograph have diagnostic sensitivities in the range of 55% to 65%. Detection of the underlying pathophysiology is by cardiac imaging, echocardiography, radionucleide ventriculography or cardiac magnetic resonance imaging (CMRI). Echocardiography is routinely available in most hospitals but there is often inadequate service provision and HF due to diastolic dysfunction (impaired cardiac relaxation and dilation during ventricular filling), or restrictive cardiomyopathy (as occurs in amyloidosis, sarcoidosis and other infiltrative conditions) may be difficult to assess by this technique. Radionucleide ventriculography requires radioactive isotopes and is not widely available. Similarly CMRI, although free from ionising radiation, requires expensive equipment and is not widely available.