Medicine:Brain natriuretic peptide

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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. BNP is named as such because it was originally identified in extracts of pig brain.

The 32-amino acid polypeptide BNP 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 systemic vascular 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.[1]

Biosynthesis

BNP is synthesized as a 134-amino acid preprohormone (preproBNP), encoded by the human gene NPPB. Removal of the 25-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.[2] Cleavage at other sites produces shorter BNP peptides with unknown biological activity.[3] Processing of proBNP may be regulated by O-glycosylation of residues near the cleavage sites.[4]

Physiologic effects

Since the actions of BNP are mediated via the ANP receptors, the physiologic effects of BNP are identical to those of ANP. Those will be reviewed here.

Receptor-agonist binding causes a reduction in renal sodium reabsorption, which results in a decreased blood volume. Secondary effects may be an improvement in cardiac ejection fraction and reduction of systemic blood pressure. Lipolysis is also increased.

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.[5] The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
  • Decreases sodium reabsorption in the distal convoluted tubule (interaction with NCC)[6] and cortical collecting duct of the nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC.
  • Its natriuretic effect is affected by dopamine and dopamine receptor D1 activity in vivo [7]
  • Inhibits renin secretion, thereby inhibiting the renin–angiotensin–aldosterone system.

Adrenal

  • 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.[8]

Cardiac

  • Inhibits maladaptive cardiac hypertrophy
  • Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly[9]
  • 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)
  • Does not modulate cAMP production or PKA activity

Measurement

BNP and NT-proBNP are measured by immunoassay.[10]

Interpretation of BNP

  • 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].[11]
  • Either BNP or NT-proBNP can also be used for screening and prognosis of heart failure.[12]
  • 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).[13]

A preoperative BNP can be predictive of a risk of an acute cardiac events during cardiac surgeries. A cutoff of 100 pg/ml has a sensitivity of approximately 100%, a negative predictive value of approximately 100%, a specificity of 90%, and a positive predictive value of 78% according to data from the United Kingdom .[14]

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.[15][16]

Low BNP was found to be a predictor of survival to age 90 in men.[17]

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.[18][19]

BNP may be a reliable predictor of cardiovascular mortality in diabetics.[20]

BNP was found to have an important role in prognostication of heart surgery patients[21] and in the emergency department.[22] Bhalla et al. showed that combining BNP with other tools like ICG can improve early diagnosis of heart failure and advance prevention strategies.[23][24] Utility of BNP has also been explored in various settings like preeclampsia, ICU and shock and ESRD.[25][26][27]

The effect or race and gender on value of BNP and its utility in that context has been studied extensively.[28][29]

NT-proBNP levels (in pg/mL) by NYHA functional class [30]
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.[31] The BNP test is also used for the risk stratification of patients with acute coronary syndromes.[32][33]

When interpreting an elevated BNP level, it is useful to remember that values may be elevated due to factors other than heart failure. Lower levels are often seen in obese patients.[34] Higher levels are seen in those with renal disease, in the absence of heart failure.

Therapeutic application

Recombinant BNP, nesiritide, is used to treat decompensated heart failure. However, a recent clinical trial[35] failed to show a benefit of nesiritide in patients with acute decompensated heart failure, and the authors could not recommend its use.

Synonyms

Other terms for BNP include B-type natriuretic peptide, ventricular natriuretic peptide and natriuretic peptide B')

See also

  • C-type natriuretic peptide

References

  1. ↑ "CV Pharmacology - Natriuretic Peptides". Archived from the original on 21 October 2017. https://web.archive.org/web/20171021200256/http://cvpharmacology.com/diuretic/natriuretics. Retrieved 29 April 2018. 
  2. ↑ "The precursor to B-type natriuretic peptide is an O-linked glycoprotein". Arch. Biochem. Biophys. 451 (2): 160–6. July 2006. doi:10.1016/j.abb.2006.03.028. PMID 16750161. 
  3. ↑ "Detection of endogenous B-type natriuretic peptide at very low concentrations in patients with heart failure". Circ Heart Fail 1 (4): 258–64. November 2008. doi:10.1161/CIRCHEARTFAILURE.108.790774. PMID 19808300. 
  4. ↑ "Processing of pro-brain natriuretic peptide is suppressed by O-glycosylation in the region close to the cleavage site". Clin. Chem. 55 (3): 489–98. March 2009. doi:10.1373/clinchem.2008.113373. PMID 19168558. 
  5. ↑ "Effect of atrial natriuretic peptide on vasa recta blood flow in the rat". The American Journal of Physiology 252 (6 Pt 2): F1112–7. Jun 1987. PMID 2954471. Archived from the original on 2009-01-08. https://web.archive.org/web/20090108133007/http://ajprenal.physiology.org/cgi/content/abstract/252/6/F1112. 
  6. ↑ "Chapter 31 – Sodium Chloride Transport in the Loop of Henle, Distal Convoluted Tubule, and Collecting Duct". Seldin and Giebisch's the kidney: physiology and pathophysiology. Amsterdam: Elsevier/Academic Press. 2008. doi:10.1016/B978-012088488-9.50034-6. ISBN 0-12-088488-7. 
  7. ↑ "Concerted action of ANP and dopamine D1-receptor to regulate sodium homeostasis in nephrotic syndrome". BioMed Research International 2013: 397391. 2013. doi:10.1155/2013/397391. PMID 23956981. 
  8. ↑ "Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy". Nature 484 (7393): 246–50. Apr 2012. doi:10.1038/nature10897. PMID 22437503. Bibcode: 2012Natur.484..246C. 
  9. ↑ "Mice Deficient in Atrial Natriuretic Peptide Receptor A (NPRA) Exhibit Decreased Lung Inflammation: Implication of NPRA Signaling in Asthma Pathogenesis". The Journal of Allergy and Clinical Immunology 119 (1): S127. 2007. doi:10.1016/j.jaci.2006.11.482. 
  10. ↑ "State of the art of BNP and NT-proBNP immunoassays: the CardioOrmoCheck study". Clin. Chim. Acta 414: 112–9. December 2012. doi:10.1016/j.cca.2012.07.017. PMID 22910582. 
  11. ↑ "Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure". N Engl J Med 347 (3): 161–7. 2002. doi:10.1056/NEJMoa020233. PMID 12124404. 
  12. ↑ "B-type natriuretic peptide: the level and the drug--partners in the diagnosis of heart failure". Congest Heart Fail 10 (1 Suppl 1): 3–27. 2004. doi:10.1111/j.1527-5299.2004.03310.x. PMID 14872150. 
  13. ↑ "A prospective study in search of an optimal B-natriuretic peptide level to screen patients for cardiac dysfunction". Am. Heart J. 148 (3): 518–23. September 2004. doi:10.1016/j.ahj.2004.03.014. PMID 15389242. 
  14. ↑ Berry, C (2005). "Predictive value of plasma brain natriuretic peptide for cardiac outcome after vascular surgery". Heart 92 (3): 401–402. doi:10.1136/hrt.2005.060988. ISSN 1355-6037. 
  15. ↑ "Correlation and prognostic utility of B-type natriuretic peptide and its amino-terminal fragment in patients with chronic kidney disease". Am. J. Clin. Pathol. 126 (4): 506–12. October 2006. doi:10.1309/M7AAXA0J1THMNCDF. PMID 16938661. 
  16. ↑ "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". Am. Heart J. 151 (5): 999–1005. May 2006. doi:10.1016/j.ahj.2005.10.011. PMID 16644321. 
  17. ↑ Nilsson, G; Hedberg P; Ohrvik J (2014). "How to live until 90 – Factors predicting survival in 75-year-olds from the general population". Healthy Aging Research 3 (5): 1–10. doi:10.12715/har.2014.3.5. 
  18. ↑ "Impact of the history of congestive heart failure on the utility of B-type natriuretic peptide in the emergency diagnosis of heart failure: results from the Breathing Not Properly Multinational Study". Am. J. Med. 119 (1): 69.e1–11. January 2006. doi:10.1016/j.amjmed.2005.04.029. PMID 16431187. 
  19. ↑ "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". Am. Heart J. 151 (5): 1006–11. May 2006. doi:10.1016/j.ahj.2005.10.017. PMID 16644322. 
  20. ↑ "Prognostic role of B-type natriuretic peptide levels in patients with type 2 diabetes mellitus". J. Am. Coll. Cardiol. 44 (5): 1047–52. September 2004. doi:10.1016/j.jacc.2004.05.071. PMID 15337217. 
  21. ↑ "Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery". J. Am. Coll. Cardiol. 43 (10): 1873–9. May 2004. doi:10.1016/j.jacc.2003.12.048. PMID 15145114. 
  22. ↑ "Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath". J. Am. Coll. Cardiol. 44 (6): 1328–33. September 2004. doi:10.1016/j.jacc.2004.06.015. PMID 15364340. 
  23. ↑ "Diagnostic ability of B-type natriuretic peptide and impedance cardiography: testing to identify left ventricular dysfunction in hypertensive patients". Am. J. Hypertens. 18 (2 Pt 2): 73S–81S. February 2005. doi:10.1016/j.amjhyper.2004.11.044. PMID 15752936. 
  24. ↑ "B-type natriuretic peptide and impedance cardiography at the time of routine echocardiography predict subsequent heart failure events". J. Card. Fail. 15 (1): 41–7. February 2009. doi:10.1016/j.cardfail.2008.09.003. PMID 19181293. 
  25. ↑ "Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women". Am. J. Obstet. Gynecol. 193 (2): 450–4. August 2005. doi:10.1016/j.ajog.2004.12.006. PMID 16098869. 
  26. ↑ "Evolution of B-type natriuretic peptide in evaluation of intensive care unit shock". Crit. Care Med. 32 (8): 1787–9. August 2004. doi:10.1097/01.CCM.0000135748.75590.54. PMID 15286561. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=32&issue=8&spage=1787. 
  27. ↑ "The use of B-type natriuretic peptide to assess volume status in patients with end-stage renal disease". Am. Heart J. 153 (2): 244.e1–5. February 2007. doi:10.1016/j.ahj.2006.10.041. PMID 17239684. 
  28. ↑ "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". Am. Heart J. 147 (6): 1078–84. June 2004. doi:10.1016/j.ahj.2004.01.013. PMID 15199359. 
  29. ↑ "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". J. Card. Fail. 12 (4): 281–5. May 2006. doi:10.1016/j.cardfail.2006.01.008. PMID 16679261. 
  30. ↑ "N-terminal pro-BNP". Archived from the original on 2008-10-11. https://web.archive.org/web/20081011225930/http://www.medicine.uiowa.edu/Path_Handbook/handbook/test2621.html. 
  31. ↑ "Meta-analysis: effect of B-type natriuretic peptide testing on clinical outcomes in patients with acute dyspnea in the emergency setting". Ann. Intern. Med. 153 (11): 728–35. December 2010. doi:10.7326/0003-4819-153-11-201012070-00006. PMID 21135296. 
  32. ↑ "N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary heart disease". JAMA 297 (2): 169–76. January 2007. doi:10.1001/jama.297.2.169. PMID 17213400. 
  33. ↑ "Effect of nesiritide in combination with standard therapy on serum concentrations of natriuretic peptides in patients admitted for decompensated congestive heart failure". Am. Heart J. 150 (3): 471–7. September 2005. doi:10.1016/j.ahj.2004.11.021. PMID 16169326. 
  34. ↑ "Impact of obesity on plasma natriuretic peptide levels". Circulation 109 (5): 594–600. 2004. doi:10.1161/01.CIR.0000112582.16683.EA. PMID 14769680. 
  35. ↑ "Effect of nesiritide in patients with acute decompensated heart failure". N. Engl. J. Med. 365 (1): 32–43. July 2011. doi:10.1056/NEJMoa1100171. PMID 21732835. 

Further reading

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