Rahul Sakhuja Cardiology Division and Department of Medicine, Massachusetts General Hospital, Harvard Medical School , James L Januzzi Cardiology Division and Department of Medicine, Massachusetts General Hospital, Harvard Medical School

Originally printed in:
» US Cardiology 2004 - August 2004

Introduction

With nearly 500,000 new cases per year and direct costs estimated as high as US$38 billion annually, congestive heart failure (CHF) has become a major priority in modern medicine. This crisis will continue to grow as the population ages, thus the discernment of new diagnostic and therapeutic strategies to improve prognosis and reduce costs is critical. (1)

The irony is that therapies with great benefit for patients with CHF exist, such as angiotensin converting enzyme (ACE) inhibitors and beta-blockers. However, these agents are under-utilized, and when employed may be dosed inadequately. (2,3) Accordingly, a widely available and accurate diagnostic tool to identify those with CHF would be essential in order to identify those patients eligible for proven therapies in CHF. Such a diagnostic tool for early diagnosis would theoretically lead to earlier initiation of these beneficial medicines while potentially assisting in chronic out-patient management of such patients. As CHF is the leading cause of hospitalization in adults over 65, achieving such early diagnosis and initiation of therapy would thus prevent hospitalizations and reduce the considerable costs of CHF. (4)

Markers of cardiac neurohormonal activation, particularly B-type natriuretic peptides, have been identified as possible tools to identify and treat patients with CHF.While most studies to date have focused on the diagnostic utility of B-type natriuretic peptide (BNP), more recent research has revealed that the amino-terminal fragment of the BNP molecule (NTproBNP), a marker with great diagnostic and prognostic power, is a marker for CHF. Recently, a new automated immunoassay has made NT-proBNP testing a reality for diagnostic, prognostic, and possibly therapeutic, purposes in CHF.(5) This paper reviews some of the growing evidence behind the use of NT-proBNP in patients with CHF.

Biology of Natriuretic Peptides

The natriuretic peptides are a family of molecules consisting of several structurally-related hormones. At present, the natriuretic peptide family includes atrial natriuretic peptide (ANP), B-type (or brain) natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and dendroaspis natriuretic peptide (DNP).

In particular, the B-type natriuretic peptide family has gained popularity as candidate markers for CHF. Biologically, these neurohormones affect body fluid homeostasis (through natriuresis and diuresis) and vascular tone (through decreased angiotensin II, norepinephrine synthesis), both essential components in the pathophysiology of CHF. (6)

B-type natriuretic peptides are produced initially as a 134 amino acid pre-pro-peptide, which is cleaved into proBNP108, a precursor molecule stored in secretory granules in myocytes (see Figure 1). Upon release, proBNP108 is cleaved by a protease known as furin into N-terminal (NT)-proBNP (a 76 amino acid biologically-inert portion), and BNP (which is biologically active). In humans, NT-proBNP and BNP are found in largest concentration in the left ventricular (LV) myocardium, but are also detectable in atrial tissue as well as in the myocardium of the right ventricle.

Figure 1: Biology of NT-proBNP and BNP

 

Both NT-proBNP and BNP are derived from a common intracellular 108 amino acid precursor, which is cleaved into the two
circulating fragments (NT-proBNP and BNP), as depicted.

Among the many signals for B-type natriuretic peptide release is myocardial stretch. From animal studies, myocardial induction and secretion of B-type natriuretic peptides in such situations is rapid, with detectable levels in the blood soon thereafter, making it a candidate tool for the recognition of CHF. (7–9)

Although derived from a common precursor, BNP and NT-proBNP are considerably different in many ways.As a biologically active compound, BNP is actively cleared from the circulation via natriuretic peptide receptors, as well as by degradation by neutral endopeptidases in the blood stream. Accordingly, the half-life of BNP is only 18 minutes.Additionally, once drawn, BNP levels are not stable in vitro for long periods, dropping significantly over the first 24 hours following collection.10 Also, if blood is collected into glass tubes, BNP levels may fall, due to activation of the kallikrein system. NT-proBNP is not biologically active, and as such does not have active clearance mechanisms. Therefore, the half-life of NT-proBNP is approximately 60–120 minutes. In humans, a renal route of clearance is suspected as a partial mechanism for NT-proBNP metabolism. NTproBNP is dramatically more stable than BNP, with very little variation in the level of the marker after collection for at least 72 hours, and probably longer. In addition, NT-proBNP may be collected into glass tubes without any issues. As noted above, sensitive assays now exist for both markers, though the NT-proBNP assay may be more sensitive than BNP in certain scenarios. Recent data has grown demonstrating the value of NT-proBNP testing for a wide variety of uses for patients with CHF.