What Are Natriuretic Peptides

"It's now established that measuring [BNP and NT-proBNP] levels, in conjunction with clinical judgment, increases the ability to distinguish between congestive heart failure and noncardiac causes such as chronic obstructive pulmonary disease in patients presenting to the emergency department with acute shortness of breath."

William Check, PhD. CAP Today. 2004.¹

The heart, in addition to being a very efficient pump beating about 100,000 cycles per day, is also an important endocrine organ.² As part of its endocrine function, cardiomyocytes in the heart muscle produce and secrete a family of related peptide hormones, called Cardiac Natriuretic Hormones (CNHs) or Natriuretic Peptides. The volume of CNHs is greatly increased in diseases characterized by an expanded fluid volume, including heart failure (HF), renal failure, and liver cirrhosis.³

The natriuretic peptides are natural antagonists to the renin-angiotensin-aldosterone system, and their role in regulating fluid balance appears to be particularly important in patients with hemodynamic stress such as heart failure.² In addition, CNHs have several physiologic actions:³

• Vasodilation and hypotensive effect
• Promotion of natriuresis and diuresis
• Inhibition of the sympathetic nervous system
• Facilitation of complex interactions with the neurohormonal system, including the renin-angiotensin-aldosterone system, endothelin, cytokines and vasopressin
• Inhibition of the pathophysiologic mechanisms responsible for ventricular and vascular hypertrophy and remodeling
• Beneficial effects on endothelial dysfunction secondary to the atherosclerotic process, including blunting of shear stress and regulation of coagulation and fibrinolysis, as well as inhibition of platelet activation.

An important pathophysiologic mechanism in cardiovascular disease is the imbalance between the vasoconstrictive/antinatriuretic action of some neuroendocrine factors, including the renin-angiotensin-aldosterone system vasopressin, endothelins and the sympathetic nervous system: and the counterregulatory vasodilatory / natriuretic response, mainly represented by CNHs. As cardiac performance decreases, all neurohormonal systems are progressively stimulated in an attempt to sustain cardiac output and circulatory homeostasis. However, the activation of neurohormonal mechanisms may worsen the hemodynamics, have direct adverse effects on myocardial function and stimulate the CNH system. Based on this hypothesis, the large increases in circulating concentrations of CNHs in HF could even be related to activation of the neuroendocrine system and, thus, be considered an adaptive and potentially protective response mechanism in CVD.³

The CNHs include:

• Atrial natriuretic peptide (ANP)– As the name implies, this Natriuretic Peptide is released primarily from the atrium of the heart and also from the ventricles. Based on the biochemical and physiologic characteristics of the different peptides, ANP may be a better marker of acute overload and/or rapid cardiovascular hemodynamic changes than BNP or the propeptides. For example, in patients with chronic renal failure, circulating concentrations of ANP are more affected by body position, and are decreased to a higher extent by a hemodialysis session, than are concentrations of BNP or NT-proBNP.
• BNP and their related peptides-The cardiac natriuretic peptide was initially discovered in the porcine brain and, thus, is termed brain natriuretic peptide (BNP). The BNP mRNA content of the cardiac ventricles represents approximately 77% of its content of the heart and is secreted mainly in the left ventricles.⁴
• C-type natriuretic peptide and urodilatin, structurally related to the ANP / BNP peptide family, are predominantly secreted by noncardiac tissues (e.g., endothelium and kidney, respectively).^3,4

BNP and NT-proBNP assays show better diagnostic accuracy and clinical performance as prognostic markers in HF patients than ANP assays. This finding is most likely attributable to the prevalent ventricular production of BNP. Increased CNH concentrations indicate that the neuroendocrine system is activated, and the neuroendocrine system is the most important pathophysiologic mechanism for the progression of HF.³ Based on the lack of specificity of the A- and C-type Natriurectic Peptides, the focus of this section will be on BNP and NT-proBNP.

"...the potential clinical usefulness of CNHs [especially B-type natriuretic peptide (BNP) or the NH₂-terminal fragment of proBNP (NT-proBNP)] for screening of heart disease, for stratification of patients with congestive heart failure, for detection of left ventricular systolic and/or diastolic dysfunction, and for differential diagnosis of dyspnea has been confirmed more recently. Further, the Task Force of the European Society of Cardiology for the Diagnosis and Treatment of Chronic HF recommended that a CNH assay should be included in the first step of the algorithm for the diagnosis of HF along with electrocardiography (ECG) and chest x-rays."

A. Clerico and M. Emdin. Clinical Chemistry. 2004.³

Provided as a courtesy from Dr. Alan H.B. Wu. Hartfield Hospital. Hartfield, CT.

As the ventricles of the compensated heart cells stretch (wall stress) or in association with ventricular tension, BNP is synthesized as a prohormone proBNP and is secreted into the blood stream with cleavage into an N-terminal fragment, termed NT-proBNP (1-76 aa) and a bioactive C-terminal fragment, termed BNP-32 (77-108 aa).⁴

All CNHs derive from preprohormones (i.e., preproANP and preproBNP) containing a signal peptide sequence at the NH₂-terminal end. The prohormones (i.e., proANP and proBNP) are produced by cleavage of signal peptide and then are further split into inactive longer NH₂-terminal fragments (i.e., NT-proANP and NT-proBNP) and a biologically active shorter COOH-terminal peptide (i.e., ANP and BNP), which are secreted in the blood in equimolar amounts. However, because ANP and BNP have shorter plasma half-lives, they also have lower concentrations than NT-proANP and NT-proBNP. ³

"There is no doubt that plasma BNP and NT-proBNP testing has revolutionized the way we approach the diagnosis and management of heart failure over the last few years. However, like most diagnostic tests, the validity of the test results has to complement clinical findings to define a disease process...there is an unsurpassed excitement in the heart failure community that significant advances in our understanding of how these present and future cardiac biomarkers can better characterize patients' disease states and individualize therapy."

R.H. Christenson et al. National Academy of Clinical Biochemistry. 2004.²

Several physiologic factors modify or regulate the circulating concentration of both BNP and NT-proBNP:^2,3

• Circadian variations
• Age
• Gender
• Renal insufficiency
• Left ventricular dysfunction
• Clinical evidence of heart failure
• Presence of myocardial necrosis
• More severe angiographic coronary artery disease

The wide variation in circulating concentrations of CNHs in healthy adults in relation to aging and gender could have particular clinical relevance. It has been shown that the diagnostic accuracy of CNH assays for community screening is gender dependent. For example, the BNP concentration is, on average, 36% higher in women than in men at age <50 years. Further, women during their fertile adult period have higher CNH values, which could be explained by the physiologic stimulation of female sex steroid hormones.³

In addition, eating habits (especially sodium intake), clinical conditions and drugs (e.g., corticosteroids, sex steroid hormones, thyroid hormones, diurectics, angiotensin-converting enzyme inhibitors, as well as andrenergic agonists and antagonists) may impact the assay results.³

The increase in CNHs with aging may be attributable to the paraphysiologic decrease in myocardial function and other organs, including the kidney, which is typical of senescence. It may also be attributable to a decrease in their clearance rate, as maximum binding capacity of clearance (C-type) receptors for CNHs was reported in platelets of elderly persons.³

For more information on Natriuretic Peptides, please click on the following topics:

What Are Natriuretic Peptides?

Clinical Relevance of CNH Assays

Comparison of CNH Assays

Save Money and Resources with Natriuretic Peptides

References