Plasma Concentrations of Aminoterminal Pro Atrial Natriuretic Peptide and Aminoterminal Pro Brain Natriuretic Peptide in Healthy Neonates: Marked and Rapid Increase After Birth
* Klinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Kinderkardiologie, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany
Abteilung Neonatologie, Allgemeines Krankenhaus Barmbek, Hamburg, Germany
Klinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Neonatologie und Paediatrische Intensivmedizin, Universitätsklinik Eppendorf, Hamburg, Germany
|| Institut für Experimentelle und Klinische Pharmakologie, Abteilung für Allgemeine Pharmakologie, Universitätsklinik Eppendorf, Hamburg, Germany
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Objective. The purpose of the study was to examine the possible age dependency of plasma N-terminal pro atrial natriuretic peptide (N-ANP) and N-terminal pro brain natriuretic peptide (N-BNP) levels in healthy term neonates to establish normal ranges for the neonatal period.
Methods. N-ANP and N-BNP plasma concentrations were measured in peripheral venous (n = 116) and umbilical cord blood (n = 37) in 153 healthy term neonates (mean: 5.1; range: 0–30 days) using an enzyme immunoassay. The neonates were classified into 8 groups according to their age (day of delivery and 1, 2, 3, 4, 5–7, 8–14, and 14–30 days of age).
Results. The plasma N-ANP and N-BNP concentration were the highest at the first day of age (96 700; 6912–436 000 and 641; 254-1272 fmol/mL) and were found significantly higher compared with the day of delivery (5680; 1005–16 900 and 221; 58–478 fmol/mL; P < 0,0001). After this marked increase, N-ANP and N-BNP levels decreased steadily and became stable at the fifth (5232; 2691–7353 fmol/mL) and third (246; 110–430 fmol/mL) day of life, respectively.
Conclusions. The N-ANP and N-BNP plasma concentrations in healthy neonates showed a marked increase during the first days of age, suggesting that ANP and BNP have physiologic roles in the perinatal circulatory change from fetus to neonate.
Key Words: Nt pro ANP • Nt pro BNP • neonates • natriuretic peptides
Abbreviations: ANP, atrial natriuretic peptide • BNP, brain natriuretic peptide • N-ANP, N-terminal pro atrial natriuretic peptide • N-BNP, N-terminal pro brain natriuretic peptide
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) represent a family of circulating cardiac peptides with a wide range of biological effects1–7 that play an important role in the regulation of extracellular fluid volume and blood pressure. They induce natriuresis, diuresis, and vasodilation and specifically act to counter the effects of the renin-angiotensin-aldosterone system. ANP is primarily synthesized and secreted from the cardiac atria, although several studies have shown that it is also synthesized and secreted from the ventricles in patients with congestive heart failure.8,9 BNP is a more recently identified cardiac peptide with a strong sequence homology to ANP and is primarily produced in the ventricles.2,6,10 Plasma levels of ANP and BNP are known to be increased in patients with heart failure,11 essential hypertension,12 pulmonary hypertension,13 and renal failure14 and after cardiac transplantation.15 Hunt et al16,17 and Daggubati11 were the first to demonstrate that the biologically inactive N-terminal portion of pro ANP (N-ANP) and pro BNP (N-BNP) also circulate when the plasma levels of the biologically active portions are elevated in heart failure. Additional investigations showed that the biologically inactive portions of ANP and BNP are more sensitive and more specific as markers of ventricular dysfunction than either the biologically active ANP or BNP,11,16 and from the viewpoint of stability in blood samples, the N-terminal portion of the natriuretic peptides seems to be the best.18 The N-terminal portion of pro BNP is stable in whole blood for >24 hours at 20°C and is not significantly influenced by exercise or position of the patient.19 Normal circulating levels of N-ANP and N-BNP in adults14,16,20 and children beyond the perinatal period21 have been established. Levels of N-ANP and N-BNP in the plasma of neonates have not been reported. The purpose of the study was to investigate the course of N-ANP and N-BNP plasma concentrations in healthy term neonates. These data could serve as a reference pool for future N-ANP and N-BNP measurements in neonates and children with heart diseases or vascular diseases.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Plasma N-BNP in Neonates
Plasma N-ANP and N-BNP concentrations were determined in 153 healthy neonates from birth to 30 days of age. The 153 patients were classified into the following 8 groups according to their age: day of delivery (day 0; total = 51; peripheral venous [n = 14], umbilical blood [n = 37]), 1 day of age (day 1; n = 18), 2 days of age (day 2; n = 12), 3 days of age (day 3; n = 16), 4 days of age (day 4; n = 18), 5 to 7 days of age (days 5–7; n = 16), 8 to 14 days of age (day 8–14; n = 10), and 15 to 30 days of age (days 15–30; n = 12). The neonates were born after uncomplicated pregnancy and normal vaginal full-term delivery after early clamping of the cord. The Apgar score 1 minute after birth was higher than 7 points in all neonates. In 37 neonates, umbilical venous blood was obtained at delivery. In the other 116 neonates, 0.5 mL of peripheral venous blood was obtained from the samples drawn at the occasion of a routine blood analysis. Only patients without cardiac, hepatic, and renal diseases and normal water and electrolyte status were included in the study. Informed consent for the blood sampling was obtained from the parents of each neonate. Approval was given by the local ethical committee of our institution.
Measurement of Plasma N-ANP and N-BNP
Blood samples were collected to chilled plastic tubes containing aprotinin and ethylenediaminetetraacetic acid and then immediately placed on ice and promptly centrifuged. An aliquot of plasma was frozen immediately at –80°C and thawed only once at the time of assay, which was performed within 4 weeks after the sampling. For each determination, a minimum of 0.15 mL of plasma was needed. N-ANP and N-BNP plasma concentrations were assayed with a competitive Enzyme Immuno Assay (Biomedica, Vienna, Austria). The kit incorporates an immunoaffinity purified sheep antibody specific for Nt pro ANP (amino acids 1–30) and Nt pro BNP (amino acids 8–29). The intra- and interassay variation coefficient is 6% and 8%, respectively.
Statistical Analysis
All data were presented as mean with standard deviation. Wilcoxon’s test for unpaired observations was used to compare the means of 2 sets of data. The null hypothesis was rejected at the 95% confidence interval, considering a P < .05 as significant.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Figure 1 shows the plasma N-ANP and N-BNP concentrations throughout the neonatal period. There was no significant difference in plasma N-ANP and N-BNP concentrations between umbilical venous cord blood and peripheral venous blood on the day of delivery. In neonates during the first 4 days of life (N-ANP) and during the first 2 days of life (N-BNP), levels of plasma N-ANP and N-BNP were significantly higher (P < .0001) compared with the day of delivery (Fig 1).
|
N-ANP plasma levels on day 1 of life (mean: 96 700; range: 6912–436 000 fmol/mL) were 17 times higher compared with the day of delivery (5680; 1005–16900 fmol/mL). N-BNP plasma levels on the first day of life (641; 254-1272 fmol/mL) were only 3 times higher compared with the day of delivery (222; 58–779 fmol/mL; Table 1).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
A number of studies have reported plasma levels of N-ANP and N-BNP in normal adults.14,16,20 Recently, we reported our investigations on N-BNP levels in children beyond the perinatal period.21 To our knowledge, no other studies have been published on plasma N-ANP and N-BNP levels in the human perinatal period. The transition from fetal to neonatal circulation is accompanied by an increase of pulmonary blood flow as a result of lung expansion and an elevation of systemic vascular resistance. Because of these circulatory changes after birth, normal plasma levels of N-ANP and N-BNP need to be establish for this age group. A possible reaction of the natriuretic peptides on these circulatory changes after birth is expected. The questions are at what day of life plasma levels of N-ANP and N-BNP return to normal levels and how extensive the expected increase of the plasma N-ANP and N-BNP levels after birth is.
In the present study, N-ANP and N-BNP plasma levels of 153 healthy term neonates were measured. We were able to prove that the plasma N-ANP and N-BNP concentrations in healthy neonates show a marked and rapid increase after birth. The N-ANP and N-BNP levels descend, then remain almost constant after the first 4 (N-ANP) and 2 (N-BNP) days of life, respectively.
These results are consistent with previous observations with pro ANP and pro BNP in healthy neonates.22–24 This rapid and marked increase of plasma N-ANP and N-BNP immediately after birth is an important finding.
The perinatal circulatory changes lead to an increase in ventricular volume and pressure load, and this may stimulate the ANP and BNP synthesis and secretion in the left and right atrium and ventricle after birth. The increased levels of plasma ANP and BNP may act to alleviate the increased ventricular load after birth and may also support the heart function with a decreased preload in the first days of life.
Another important finding in this study is the different reaction of N-ANP and N-BNP on the cardiopulmonary changes after birth. The course of the N-ANP and the N-BNP plasma levels were different after birth. N-ANP plasma levels return to almost constant levels at the fourth day of life, whereas N-BNP plasma levels need 2 days only for returning to normal levels (Fig 1). There is a variable increase of N-ANP and N-BNP plasma levels after birth. N-ANP plasma levels at day 1 of life were approximately 17 times higher compared with baseline at day of delivery, whereas N-BNP plasma levels at day 1 of life were only 3 times higher compared with the day of delivery (Table 1).
These results indicate that ANP and BNP respond differently to the hemodynamic changes after birth, and these results again suggest a dual natriuretic peptide system of ANP and BNP with distinct physiologic or pathophysiologic roles in the hemodynamic control.10 The increase in left and right ventricular volume and pressure load at birth seems to stimulate a variable ANP and BNP synthesis and secretion. A report in hemodialysis patients also showed a different response of ANP and BNP to hemodynamic changes, ie, plasma levels of BNP were lowered less efficiently by the dialysis procedure than those of ANP.25
Our findings extend previous studies and investigations with pro ANP and pro BNP in normal children and adults.1,2,21–24 Recently, we presented the normal levels of N-BNP beyond the perinatal period.21 Neonates show N-BNP plasma concentrations beyond the normal range at the first day of life. There is a normal range of the plasma concentrations of N-BNP in neonates at the day of delivery and beyond the first day of life (Fig 1).21
A number of studies have suggested that the measurement of N-ANP and N-BNP levels in plasma may serve as a noninvasive indicator of heart disease, especially in heart failure.11,14,16,18,19 To date, BNP and its aminoterminal portion N-BNP are independent markers of cardiac status and prognosis in cardiac disease, including heart failure.26 Therefore, the results of the present study may serve as a useful baseline for comparing levels of N-ANP and N-BNP in plasma of neonates and children with heart diseases, vascular diseases, or water and electrolyte disturbances.
|
ACKNOWLEDGMENTS |
|---|
This study was supported in part by a grant of the Herz Kinder Hilfe Hamburg e.V. We gratefully acknowledge the technical assistance of Marianne Flato in the pharmacologic laboratory. We are grateful to all the doctors, nurses, and midwives of the Neonatology, AK Barmbek and University Hospital Eppendorf, Hamburg, for excellent support of this study.
|
FOOTNOTES |
|---|
Received for publication Dec 12, 2002; Accepted Apr 8, 2003.
Reprint requests to (T.S.M.) Klinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Kinderkardiologie, Universitätsklinik Eppendorf, 20246 Hamburg, Martinistrasse 52, Germany. E-mail: mir{at}uke.uni-hamburg.de
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Ationu A, Sorensen K, Whitehead B, Singer D, Burch M, Carter ND. Ventricular expression of brain natriuretic peptide gene following orthotopic cardiac transplantation in children. A three year follow up. Cardiovasc Res.1993; 27 :2135 –2139
2. Ationu A, Singer DR, Smith A, Elliott M, Burch M, Carter ND. Studies of cardiopulmonary bypass in children: implications for the regulation of brain natriuretic peptide.
Cardiovasc Res.1993; 27
:1538
–1541
3. Yoshimura M, Yasue H, Morita E. Hemodynamic, renal and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure.
Circulation.1991; 84
:1581
–1588
4. Molina CR, Fowler MB, McCrory S. Hemodynamic, renal and endocrine effects of atrial natriuretic peptide infusion in severe heart failure. J Am Coll Cardiol.1988; 12 :175 –186[Abstract]
5. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature.1988; 332 :78 –81[CrossRef][Medline]
6. Saito Y, Nakao K, Itoh H. Brain natriuretic peptide is a novel cardiac hormone. Biochem Biophys Res Commun.1989; 158 :360 –368[CrossRef][Web of Science][Medline]
7. Sugawara A, Nakao K, Mori N. Alpha human atrial natriuretic polypeptide is released from the heart and circulates in the body. Biochem Biophys Res Commun.1985; 129 :439 –446[CrossRef][Web of Science][Medline]
8. Saito Y, Nakao K, Arai H. Augmented expression of atrial natriuretic peptide in ventricle of human failing heart. J Clin Invest.1989; 83 :298 –305
9. Yasue HK, Obata K, Okumura K. Increased secretion of atrial natriuretic peptide from the left ventricle in patients with dilated cardiomyopathy. J Clin Invest.1989; 83 :46 –51
10. Mokuyama M, Nakao K, Nosada K. Brain natriuretic peptide as a novel cardiac hormone in humans: evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest.1991; 87 :1402 –1412
11. Daggubati S, Parks JR, Overton RM, Cintron G, Schocken DD, Vesell DL. Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators.
Cardiovasc Res.1997; 36
:246
–255
12. Kohno M, Horio T, Yoshiyama M, Takeda T. Accelerated secretion of brain natriuretic peptide from the hypertrophied ventricles in experimental malignant hypertension.
Hypertension.1992; 19
:206
–211
13. Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.
Circulation.2000; 102
:865
–870
14. Buckley MG, Markandu ND, Sagnella GA, MacGregor GA. Plasma concentration and comparison of brain natriuretic peptide in normal subjects and patients with essential hypertension. Clin Sci.1992; 82 :29
15. Ationu A, Burch M, Singer DRJ. Cardiac transplantation affects ventricular expression of brain natriuretic peptide.
Cardiovasc Res.1993; 27
:188
–191
16. Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol Oxf.1997; 47 :287 –296[CrossRef][Medline]
17. Hunt PJ, Yandle TG, Nichols MG, Richards AM, Espiner EA. The amino-terminal portion of pro-brain natriuretic peptide (pro-BNP) circulates in human plasma. Biochem Biophys Res Commun.1995; 214 :1175 –1183[CrossRef][Web of Science][Medline]
18. Downie PF, Talwar S, Squire IB, Davies JE, Barnett DB, Ng LL. Assessment of the stability of N-terminal pro-brain natriuretic peptide in vitro: implications for assessment of left ventricular dysfunction. Clin Sci Colch.1999; 97 :255 –258[Medline]
19. Wijbenga JAM, Balk AHMM, Boosma F, Man in’t Veld AJ, Hall C. Cardiac peptides differ in their response to exercise. Implications for patients with heart failure.
Eur Heart J.1999; 20
:1424
–1428
20. Karl J, Borgya A, Gallusser A, et al Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection limit. Scand J Clin Lab Invest.1999; 230 :177 –181
21. Mir TS, Marohn S, Läer S, Eiselt M, Grollmus O, Weil J. Plasma concentrations of N-terminal pro brain natriuretic peptide (N-BNP) in control children from the neonatal to adolescent period and in children with congestive heart failure. Pediatrics.2002; 110(6) . Available at: http://pediatrics.org/cgi/content/full/110/6/e76
22. Ationu A, Carter ND. Brain and atrial natriuretic peptide plasma concentration in normal children. Br J Biomed Sci.1993; 50 :92 –95[Web of Science][Medline]
23. Yoshibayashi M, Saito Y, Nakao K. Brain natriuretic peptide versus atrial natriuretic peptide-physiological and pathophysiological significance in children and adults: a review.
Eur J Endocrinol.1996; 135
:265
–268
24. Weil J, Bidlingmaier F, Doehlemann C, Kuhnle U, Strom T, Lang RE. Comparison of plasma atrial natriuretic peptide levels in healthy children from birth to adolescence and in children with cardiac diseases. Pediatr Res.1986; 20 :1328 –1331[Web of Science][Medline]
25. Kohse KP, Feifel K, Mayer W. Differential regulation of brain and atrial natriuretic peptides in hemodialysis patients. Clin Nephrol.1993; 40 :83 –90[Web of Science][Medline]
26. Troughton RW, Frampton C, Yandle T, Espiner EA, Nicholls M, Richards A. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet.2000; 355 :1126 –1130[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. M. Law, A. W. Hoyer, M. D. Reller, and M. Silberbach Accuracy of Plasma B-Type Natriuretic Peptide to Diagnose Significant Cardiovascular Disease in Children: The Better Not Pout Children! Study J. Am. Coll. Cardiol., October 6, 2009; 54(15): 1467 - 1475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Walsh, C. Boyer, J. LaCorte, V. Parnell, C. Sison, D. Chowdhury, and K. Ojamaa N-terminal B-type natriuretic peptide levels in pediatric patients with congestive heart failure undergoing cardiac surgery J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 98 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. El-Khuffash and E. J Molloy Are B-type natriuretic peptide (BNP) and N-terminal-pro-BNP useful in neonates? Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F320 - F324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cannesson, C. Bionda, B. Gostoli, O. Raisky, S. di Filippo, D. Bompard, C. Vedrinne, R. Rousson, J. Ninet, J. Neidecker, et al. Time Course and Prognostic Value of Plasma B-type Natriuretic Peptide Concentration in Neonates Undergoing the Arterial Switch Operation Anesth. Analg., May 1, 2007; 104(5): 1059 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Dodge-Khatami, E. V. Buchel, W. Knirsch, A. Kadner, V. Rousson, H. H. Dave, U. Bauersfeld, and R. Pretre Brain natriuretic peptide and magnetic resonance imaging in tetralogy with right ventricular dilatation. Ann. Thorac. Surg., September 1, 2006; 82(3): 983 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. da Graca, D. C. Hassinger, P. A. Flynn, C. P. Sison, M. Nesin, and P. A.M. Auld Longitudinal changes of brain-type natriuretic Peptide in preterm neonates. Pediatrics, June 1, 2006; 117(6): 2183 - 2189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hammerer-Lercher, J. Mair, G. Tews, B. Puschendorf, and R. Sommer N-Terminal Pro-B-Type Natriuretic Peptide Concentrations Are Markedly Higher in the Umbilical Cord Blood of Newborns than in Their Mothers Clin. Chem., May 1, 2005; 51(5): 913 - 915. [Full Text] [PDF]
|
|
|
|
|
|
B. Bar-Oz, A. Lev-Sagie, I. Arad, L. Salpeter, and A. Nir N-Terminal pro-B-Type Natriuretic Peptide Concentrations in Mothers just before Delivery, in Cord Blood, and in Newborns Clin. Chem., May 1, 2005; 51(5): 926 - 927. [Full Text] [PDF]
|
|
|
|
|
|
S. Cohen, C. Springer, A. Avital, Z. Perles, A. J. J. T. Rein, Z. Argaman, and A. Nir Amino-Terminal Pro-Brain-Type Natriuretic Peptide: Heart or Lung Disease in Pediatric Respiratory Distress? Pediatrics, May 1, 2005; 115(5): 1347 - 1350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bakker, I. Gies, B. Slavenburg, O. Bekers, T. Delhaas, and M. van Dieijen-Visser Reference Values for N-Terminal Pro-B-Type Natriuretic Peptide in Umbilical Cord Blood Clin. Chem., December 1, 2004; 50(12): 2465 - 2465. [Full Text] [PDF]
|
|
|
|
|
|
E. W. Reynolds, J. G. Ellington, M. Vranicar, and H. S. Bada Brain-Type Natriuretic Peptide in the Diagnosis and Management of Persistent Pulmonary Hypertension of the Newborn Pediatrics, November 1, 2004; 114(5): 1297 - 1304. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
