Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent

Abstract

B-type natriuretic peptide (BNP) is a member of the natriuretic peptide family, a group of widely distributed, but evolutionarily conserved, polypeptide mediators that exert myriad cardiovascular effects. BNP is a potent vasodilator with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. Circulating levels of BNP correlate with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH). Elevated plasma BNP levels are associated with increased mortality in patients with PAH and a fall in BNP levels after therapy is associated with improved survival. These findings have important clinical implications in that a noninvasive blood test may be used to identify PAH patients at high-risk of decompensation and to guide pulmonary vasodilator therapy. BNP also has several biologic effects that could be beneficial to patients with PAH. However, lack of a convenient method for achieving sustained increases in circulating BNP levels has impeded the development of BNP as a therapy for treating pulmonary hypertension. New technologies that allow transdermal or oral administration of the natriuretic peptides have the potential to greatly accelerate research into therapeutic use of BNP for cor pulmonale and pulmonary vascular diseases. This review will examine the basic science and clinical research that has led to our understanding of the role of BNP in cardiovascular physiology, its use as a biomarker of right ventricular function and its therapeutic potential for managing patients with pulmonary vascular disease.

Keywords: biomarker; brain natriuretic peptide; pulmonary artery hypertension; therapeutic agent.

Figure 1

Structure of the gene and the biosynthetic pathway of human brain natriuretic peptide (BNP). The major storage form of BNP in the heart is the cleaved mature peptide, although in atrial tissue also prohormones may be stored. Reproduced with permission from Barr CS, Rhodes P, Struthers AD. C-type natriuretic peptide. Peptides. 1996;17(7):1243–1251. Copyright © 1996 Elsevier.

Figure 2

Amino acid structure of the 3 natriuretic peptides, atrial, brain and c-type natriuretic peptide (ANP, BNP, CNP). All 3 peptides share a similar 17 amino acid loop. Shaded circles represent amino acid sequence that is identical in each peptide. Reproduced with permission from Barr CS, Rhodes P, Struthers AD. C-type natriuretic peptide. Peptides. 1996;17(7):1243–1251. Copyright © 1996 Elsevier.

Figure 3

A) and B) Correlation between plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) and New York Heart Association (NYHA) functional class in patients with pulmonary arterial hypertension. C) Effect of plasma BNP levels at time of diagnosis on survival in patients with pulmonary arterial hypertension. D) Effect of plasma BNP levels after treatment on survival in the same patients. Reproduced with permission from Nagaya N, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102(8): 865–870. Copyright © 2002 Elsevier.

Figure 4

Effect of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels on survival in patients with pulmonary arterial hypertension. Reproduced with permission from Andreassen AK, Wergeland R, Simonsen S, Geiran O, Guevara C, Ueland T. N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension. Am J Cardiol. 2006;98:528–529. Copyright © 2002 Elsevier.

Figure 5

Vasodilator effect of atrial and brain natriuretic peptide (ANP, BNP) on pulmonary arterial rings isolated from normoxic A) and hypoxia-adapted rats B) and preconstricted with phenylephrine. C) Vasodilator effect of ANP and BNP on acute hypoxic pulmonary vasoconstriction in isolated rat lungs. D) Distribution of change in pulmonary vascular resistance following administration of ANP and BNP in isolated rat lungs exposed to acute hypoxia. Pressure in the pulmonary arteries, veins, and capillaries were assessed by occluding the pulmonary artery catheter (P_AO), pulmonary venous catheter (P_VO) and both catheters (double occlusion, P_DO), respectively. Abbreviations: PA, pulmonary artery; TA, thoracic aorta.

Figure 6

Upper panel: Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR ) in patients with pulmonary arterial hypertension during a 3-hour infusion of human BNP (nesiritide) and 6 hours after infusion was completed. Lower panel: Effect of BNP infusion on PAP and PVR when given 1 hour after sildenafil.