Brain natriuretic peptide (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume.[5] BNP is one of the three natriuretic peptides, in addition to atrial natriuretic peptide (ANP) and C-type natriuretic peptide ( CNP).[6] BNP was first discovered in porcine brain tissue in 1988, which led to its initial naming as "brain natriuretic peptide", although subsequent research revealed that BNP is primarily produced and secreted by the ventricular myocardium (heart muscle) in response to increased ventricular blood volume and stretching. To reflect its true source, BNP is now often referred to as "B-type natriuretic peptide" while retaining the same acronym. [7]
The 32-amino acid polypeptide BNP-32 is secreted attached to a 76–amino acid N-terminal fragment in the prohormone called NT-proBNP (BNPT), which is biologically inactive. Once released, BNP binds to and activates the atrial natriuretic factor receptor NPRA, and to a lesser extent NPRB, in a fashion similar to atrial natriuretic peptide (ANP) but with 10-fold lower affinity. The biological half-life of BNP, however, is twice as long as that of ANP, and that of NT-proBNP is even longer, making these peptides better targets than ANP for diagnostic blood testing.
The physiologic actions of BNP are similar to those of ANP and include decrease in systemicvascular resistance and central venous pressure as well as an increase in natriuresis. The net effect of these peptides is a decrease in blood pressure due to the decrease in systemic vascular resistance and, thus, afterload. Additionally, the actions of both BNP and ANP result in a decrease in cardiac output due to an overall decrease in central venous pressure and preload as a result of the reduction in blood volume that follows natriuresis and diuresis.[8]
Biosynthesis
BNP is synthesized as a 134-amino acid preprohormone (preproBNP), encoded by the human gene NPPB. Removal of the 26-residue N-terminal signal peptide generates the prohormone, proBNP, which is stored intracellularly as an O-linked glycoprotein; proBNP is subsequently cleaved between arginine-102 and serine-103 by a specific convertase (probably furin or corin) into NT-proBNP and the biologically active 32-amino acid polypeptide BNP-32, which are secreted into the blood in equimolar amounts.[9][10] Cleavage at other sites produces shorter BNP peptides with unknown biological activity.[11] Processing of proBNP may be regulated by O-glycosylation of residues near the cleavage sites.[12] The synthesis of BNP in cardiomyocytes is stimulated by pro-inflammatory cell factors, such as interleukin-1β, interleukin-6 and tumor necrosis factor-α.[13]
Physiologic effects
Renal
Dilates the afferent glomerular arteriole, constricts the efferent glomerular arteriole, and relaxes the mesangial cells. This increases pressure in the glomerular capillaries, thus increasing the glomerular filtration rate (GFR), resulting in greater filter load of sodium and water.
Increases blood flow through the vasa recta, which will wash the solutes (NaCl and urea) out of the medullary interstitium.[14] The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
Reduces aldosterone secretion by the zona glomerulosa of the adrenal cortex.
Vascular
Relaxes vascular smooth muscle in arterioles and venules by:
Membrane Receptor-mediated elevation of vascular smooth muscle cGMP
Inhibition of the effects of catecholamines
Promotes uterine spiral artery remodeling, which is important for preventing pregnancy-induced hypertension.[16]
Cardiac
Inhibits maladaptive cardiac hypertrophy
Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly[17]
Re-expression of NPRA rescues the phenotype.
Adipose tissue
Increases the release of free fatty acids from adipose tissue. Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans.
Activates adipocyte plasma membrane type A guanylyl cyclase receptors NPR-A
Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of a cGMP-dependent protein kinase-I (cGK-I)
The main clinical utility of either BNP or NT-proBNP is that a normal level helps to rule out chronic heart failure in the emergency setting. An elevated BNP or NT-proBNP should never be used exclusively to "rule in" acute or chronic heart failure in the emergency setting due to lack of specificity [dubious – discuss].[19]
Either BNP or NT-proBNP can also be used for screening and prognosis of heart failure.[20]
Increased NT-proBNP adjusted for age and sex and annual increase of NT-proBNP above 50% are associated with increased event rate in patients with non-severe aortic valve stenosis.[21]
BNP and NT-proBNP are also typically increased in patients with left ventricular dysfunction, with or without symptoms (BNP accurately reflects current ventricular status, as its half-life is 20 minutes, as opposed to 1–2 hours for NT-proBNP).[22]
BNP is cleared by binding to natriuretic peptide receptors (NPRs) and neutral endopeptidase (NEP). Less than 5% of BNP is cleared renally. NT-proBNP is the inactive molecule resulting from cleavage of the prohormone Pro-BNP and is reliant solely on the kidney for excretion. The achilles heel of the NT-proBNP molecule is the overlap in kidney disease in the heart failure patient population.[24][25]
Some laboratories report in units ng per Litre (ng/L), which is equivalent to pg/mL
There is a diagnostic 'gray area', often defined as between 100 and 500 pg/mL, for which the test is considered inconclusive, but, in general, levels above 500 pg/ml are considered to be an indicator of heart failure. This so-called gray zone has been addressed in several studies, and using clinical history or other available simple tools can help make the diagnosis.[26][27]
BNP has been suggested as a predictor for a variety of medical states, including cardiovascular mortality in diabetics[28] and cardiac impairment in cancer patients.[29][30]
BNP was found to have an important role in prognostication of heart surgery patients[31] and in the emergency department.[32] It has been shown that combining BNP with other tools like impedance cardiography (ICG) can improve early diagnosis of heart failure and advance prevention strategies.[33][34] Utility of BNP has also been explored in various settings like preeclampsia, intensive care, shock and end-stage renal disease (ESRD).[35][36][37]
The effect or race and gender on value of BNP and its utility in that context has been studied extensively.[38][39]
NT-proBNP levels (in pg/mL) by New York Heart Association Functional Classification (NYHA functional class)[40]
NYHA I
NYHA II
NYHA III
NYHA IV
5th Percentile
33
103
126
148
Mean
1015
1666
3029
3465
95th Percentile
3410
6567
10,449
12,188
The BNP test is used as an aid in the diagnosis and assessment of severity of heart failure. A recent meta-analysis concerning effects of BNP testing on clinical outcomes of patients presenting to the emergency department with acute dyspnea revealed that BNP testing led to a decrease in admission rates and decrease in mean length of stay, although neither was statistically significant. Effects on all cause hospital mortality was inconclusive.[41] The BNP test is also used for the risk stratification of patients with acute coronary syndromes.[42][43]
When interpreting an elevated BNP level, values may be elevated due to factors other than heart failure. Lower levels are often seen in obese patients.[44] Higher levels are seen in those with renal disease, in the absence of heart failure.
Therapeutic application
Recombinant BNP, nesiritide, has been suggested as a treatment for decompensated heart failure. However, a clinical trial failed to show a benefit of nesiritide in patients with acute decompensated heart failure.[45] Blockade of neprilysin, a protease known to degrade members of the natriuretic peptide family, has also been suggested as a possible treatment for heart failure. Dual administration of neprilysin inhibitors and angiotensin receptor blockers has been shown to be advantageous to ACE inhibitors, the current first-line therapy, in multiple settings.[46][47]
^Schellenberger U, O'Rear J, Guzzetta A, Jue RA, Protter AA, Pollitt NS (July 2006). "The precursor to B-type natriuretic peptide is an O-linked glycoprotein". Archives of Biochemistry and Biophysics. 451 (2): 160–6. doi:10.1016/j.abb.2006.03.028. PMID16750161.
^Kiberd BA, Larson TS, Robertson CR, Jamison RL (June 1987). "Effect of atrial natriuretic peptide on vasa recta blood flow in the rat". The American Journal of Physiology. 252 (6 Pt 2): F1112-7. doi:10.1152/ajprenal.1987.252.6.F1112. PMID2954471.
^Clerico A, Zaninotto M, Prontera C, Giovannini S, Ndreu R, Franzini M, et al. (December 2012). "State of the art of BNP and NT-proBNP immunoassays: the CardioOrmoCheck study". Clinica Chimica Acta; International Journal of Clinical Chemistry. 414: 112–9. doi:10.1016/j.cca.2012.07.017. hdl:11382/365432. PMID22910582.
^Atisha D, Bhalla MA, Morrison LK, Felicio L, Clopton P, Gardetto N, et al. (September 2004). "A prospective study in search of an optimal B-natriuretic peptide level to screen patients for cardiac dysfunction". American Heart Journal. 148 (3): 518–23. doi:10.1016/j.ahj.2004.03.014. PMID15389242.
^Daniels LB, Clopton P, Bhalla V, Krishnaswamy P, Nowak RM, McCord J, et al. (May 2006). "How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study". American Heart Journal. 151 (5): 999–1005. doi:10.1016/j.ahj.2005.10.011. PMID16644321.
^Brenden CK, Hollander JE, Guss D, McCullough PA, Nowak R, Green G, et al. (May 2006). "Gray zone BNP levels in heart failure patients in the emergency department: results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study". American Heart Journal. 151 (5): 1006–11. doi:10.1016/j.ahj.2005.10.017. PMID16644322.
^Palumbo I, Palumbo B, Fravolino M, et al. (2016). "Brain natriuretic peptide as a cardiac marker of transient radiotherapy-related damage in left-sided breast cancer patients: A prospective study". The Breast. 25: 45–50. doi:10.1016/j.breast.2015.10.004. PMID26547836.
^Castellanos LR, Bhalla V, Isakson S, Daniels LB, Bhalla MA, Lin JP, et al. (February 2009). "B-type natriuretic peptide and impedance cardiography at the time of routine echocardiography predict subsequent heart failure events". Journal of Cardiac Failure. 15 (1): 41–7. doi:10.1016/j.cardfail.2008.09.003. PMID19181293.
^Resnik JL, Hong C, Resnik R, Kazanegra R, Beede J, Bhalla V, et al. (August 2005). "Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women". American Journal of Obstetrics and Gynecology. 193 (2): 450–4. doi:10.1016/j.ajog.2004.12.006. PMID16098869.
^Bhalla V, Bhalla MA, Maisel AS (August 2004). "Evolution of B-type natriuretic peptide in evaluation of intensive care unit shock". Critical Care Medicine. 32 (8): 1787–9. doi:10.1097/01.CCM.0000135748.75590.54. PMID15286561.
^Sheen V, Bhalla V, Tulua-Tata A, Bhalla MA, Weiss D, Chiu A, et al. (February 2007). "The use of B-type natriuretic peptide to assess volume status in patients with end-stage renal disease". American Heart Journal. 153 (2): 244.e1–5. doi:10.1016/j.ahj.2006.10.041. PMID17239684.
^Maisel AS, Clopton P, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, et al. (June 2004). "Impact of age, race, and sex on the ability of B-type natriuretic peptide to aid in the emergency diagnosis of heart failure: results from the Breathing Not Properly (BNP) multinational study". American Heart Journal. 147 (6): 1078–84. doi:10.1016/j.ahj.2004.01.013. PMID15199359.
^Daniels LB, Bhalla V, Clopton P, Hollander JE, Guss D, McCullough PA, et al. (May 2006). "B-type natriuretic peptide (BNP) levels and ethnic disparities in perceived severity of heart failure: results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study of BNP levels and emergency department decision making in patients presenting with shortness of breath". Journal of Cardiac Failure. 12 (4): 281–5. doi:10.1016/j.cardfail.2006.01.008. PMID16679261.
^"N-terminal-pro-BNP". LABORATORY SERVICES HANDBOOK. The University of Iowa (UIHC), Department of Pathology. 28 May 2020. Archived from the original on 2008-10-11. Showing 95th percentiles. Epic Lab Code: LAB649.
^Lam LL, Cameron PA, Schneider HG, Abramson MJ, Müller C, Krum H (December 2010). "Meta-analysis: effect of B-type natriuretic peptide testing on clinical outcomes in patients with acute dyspnea in the emergency setting". Annals of Internal Medicine. 153 (11): 728–35. doi:10.7326/0003-4819-153-11-201012070-00006. PMID21135296. S2CID27272593.
^Fitzgerald RL, Cremo R, Gardetto N, Chiu A, Clopton P, Bhalla V, et al. (September 2005). "Effect of nesiritide in combination with standard therapy on serum concentrations of natriuretic peptides in patients admitted for decompensated congestive heart failure". American Heart Journal. 150 (3): 471–7. doi:10.1016/j.ahj.2004.11.021. PMID16169326.
Cosson S (September 2004). "Usefulness of B-type natriuretic peptide (BNP) as a screen for left ventricular abnormalities in diabetes mellitus". Diabetes & Metabolism. 30 (4): 381–6. doi:10.1016/S1262-3636(07)70132-5. PMID15525883.
Cauliez B, Berthe MC, Lavoinne A (2005). "[Brain natriuretic peptide: physiological, biological and clinical aspects]". Annales de Biologie Clinique. 63 (1): 15–25. PMID15689309.
Buchner S, Riegger G, Luchner A (2005). "[Clinical utility of the cardiac markers BNP and NT-proBNP]". Acta Medica Austriaca. 31 (4): 144–51. PMID15732251.
Hino J, Tateyama H, Minamino N, Kangawa K, Matsuo H (March 1990). "Isolation and identification of human brain natriuretic peptides in cardiac atrium". Biochemical and Biophysical Research Communications. 167 (2): 693–700. doi:10.1016/0006-291X(90)92081-A. PMID2138890.
Sudoh T, Maekawa K, Kojima M, Minamino N, Kangawa K, Matsuo H (March 1989). "Cloning and sequence analysis of cDNA encoding a precursor for human brain natriuretic peptide". Biochemical and Biophysical Research Communications. 159 (3): 1427–34. doi:10.1016/0006-291X(89)92269-9. PMID2522777.
Seilhamer JJ, Arfsten A, Miller JA, Lundquist P, Scarborough RM, Lewicki JA, et al. (December 1989). "Human and canine gene homologs of porcine brain natriuretic peptide". Biochemical and Biophysical Research Communications. 165 (2): 650–8. doi:10.1016/S0006-291X(89)80015-4. PMID2597152.
Arden KC, Viars CS, Weiss S, Argentin S, Nemer M (March 1995). "Localization of the human B-type natriuretic peptide precursor (NPPB) gene to chromosome 1p36". Genomics. 26 (2): 385–9. doi:10.1016/0888-7543(95)80225-B. PMID7601467.
Weir ML, Pang SC, Flynn TG (September 1993). "Characterization of binding sites in rat for A, B and C-type natriuretic peptides". Regulatory Peptides. 47 (3): 291–305. doi:10.1016/0167-0115(93)90396-P. PMID7901875. S2CID23098254.
Totsune K, Takahashi K, Satoh F, Sone M, Ohneda M, Satoh C, et al. (July 1996). "Urinary immunoreactive brain natriuretic peptide in patients with renal disease". Regulatory Peptides. 63 (2–3): 141–7. doi:10.1016/0167-0115(96)00035-3. PMID8837222. S2CID23508808.
Totsune K, Takahashi K, Murakami O, Satoh F, Sone M, Ohneda M, et al. (September 1996). "Immunoreactive brain natriuretic peptide in human adrenal glands and adrenal tumors". European Journal of Endocrinology. 135 (3): 352–6. doi:10.1530/eje.0.1350352. PMID8890728. S2CID8706854.
Shimizu H, Masuta K, Aono K, Asada H, Sasakura K, Tamaki M, et al. (February 2002). "Molecular forms of human brain natriuretic peptide in plasma". Clinica Chimica Acta; International Journal of Clinical Chemistry. 316 (1–2): 129–35. doi:10.1016/S0009-8981(01)00745-8. PMID11750283.
Asakawa H, Fukui T, Tokunaga K, Kawakami F (2002). "Plasma brain natriuretic peptide levels in normotensive Type 2 diabetic patients without cardiac disease and macroalbuminuria". Journal of Diabetes and Its Complications. 16 (3): 209–13. doi:10.1016/S1056-8727(01)00173-8. PMID12015190.
Bordenave L, Georges A, Bareille R, Conrad V, Villars F, Amédée J (May 2002). "Human bone marrow endothelial cells: a new identified source of B-type natriuretic peptide". Peptides. 23 (5): 935–40. doi:10.1016/S0196-9781(02)00004-9. PMID12084525. S2CID43543051.
