European Heart Journal

European Heart Journal Advance Access originally published online on February 8, 2006
European Heart Journal 2006 27(7):861-866; doi:10.1093/eurheartj/ehi773

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B-type natriuretic peptide in paediatric patients with congenital heart disease

Andreas Koch^*, Stefan Zink and Helmut Singer

Paediatric Cardiology, Department of Paediatrics and Adolescent Medicine, University of Erlangen-Nürnberg, Loschgestr. 15, D-91054 Erlangen, Germany

Received 24 June 2005; revised 13 December 2005; accepted 19 January 2006; online publish-ahead-of-print 8 February 2006.

^* Corresponding author. Tel: +49 9131 8533118; fax: +49 9131 8535987. E-mail address: andreas.koch{at}kinder.imed.uni-erlangen.de

	Abstract

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Aims To examine the diagnostic value of B-type natriuretic peptide (BNP) plasma concentration in congenital heart disease.

Methods and results BNP was measured in 288 consecutive patients (mean age 6.0±6.4 years) with left-to-right shunt, left or right heart obstruction, tetralogy of Fallot, functionally univentricular heart, or impaired left ventricular function and compared with age- and gender-specific normal values, and to haemodynamic and echocardiographic data. BNP increased with decreasing left ventricular shortening fraction (r=–0.80; P<0.001). In patients with left-to-right shunt, BNP was increased (mean SDS +1.64; P<0.001) and positively correlated (P<0.001) to shunt volume (r=0.66), systolic right ventricular pressure (r=0.69), mean pressure of the pulmonary artery (r=0.66), and pulmonary resistance (r=0.59). There was no correlation between BNP and invasive pressure gradient or extent of ventricular hypertrophy in patients with left or right heart obstruction. In patients with tetralogy of Fallot, BNP was not significantly increased. Patients with functionally univentricular heart had elevated BNP plasma levels (mean SDS +1.39; P<0.001) without decrease after volume unloading by cavopulmonary connection.

Conclusion In children with congenital heart defects, plasma BNP correlates closely to ventricular function. BNP plasma levels do not reflect directly the extent of ventricular pressure or volume work, but mirror the impairment of the loaded ventricles. Normal BNP cannot exclude pathology, but reflects a compensated status of the heart.

Key Words: BNP • Congenital heart disease • Ventricular function • Volume • Pressure • Resistance

	Introduction

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B-type natriuretic peptide (BNP) is a cardiac hormone with diuretic, natriuretic, and vasodilatory properties secreted mainly by the ventricles in response to volume expansion and pressure load.^1,2 Within the myocyte, the active hormone is cleaved from the C-terminus of the precursor protein proBNP.^1,2 Measurement of plasma BNP levels or the concentration of the N-terminal fragment of proBNP (NT-proBNP) is increasingly used to aid diagnosis, assess prognosis, and tailor therapy in adults with congestive heart failure.^2,3 BNP may be useful in various other conditions such as hypertrophic cardiomyopathy,⁴ left ventricular remodelling after myocardial infarction,⁵ arrhythmogenic right ventricular dysplasia,⁶ or congenital heart disease.^7–9 The few data dealing with BNP and NT-proBNP in children suggest that these peptides are useful in paediatric patients too.^10–15 However, the groups of investigated paediatric patients with congenital heart disease were small or heterogeneous,^10–13 and the results were not compared with age- and gender-specific normal values.^14,15 Recently, we have reported normal concentrations of both parameters from infancy to adolescence.^16,17 The purpose of this study was to investigate systematically the diagnostic validity of plasma BNP on paediatric patients with congenital heart defects.

	Methods

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Venous samples were collected into tubes containing potassium ethylene diamine tetra acetic acid and BNP was measured immediately by a sandwich immunoassay (Triage BNP assay, Biosite^® Diagnostics Inc., San Diego, California).

The assay uses murine polyclonal, fluorescent-tagged BNP antibodies to label the BNP molecules and immobilized murine monoclonal antibody against the ring structure of BNP to bind the BNP-fluorescent antibody complex. Performance of the assay takes 15 min.

Plasma BNP levels of the patients were compared with 152 healthy subjects.¹⁶

Owing to significant different BNP plasma levels in healthy girls and boys from infancy to adolescence, BNP plasma concentrations were expressed as standard deviation scores calculated according to the following formulas. Boys and girls aged 2 weeks to 10 years: SDS=(natural logarithm of BNP plasma level–2.05)/0.56; female patients older than 10 years: SDS=(lnBNP–2.32)/0.67; male patients older than 10 years: SDS=(lnBNP–1.80)/0.31.

The BNP values were compared with haemodynamic data from cardiac catheterization (e.g. pressure data, invasive pressure gradients, pulmonary and systemic flow, and resistance using Fick's principle) and to echocardiographic data.

The study was approved by the local Ethics Committee.

Subjects
Patients
From 2002 to 2004, we measured BNP in all consecutive patients with congenital heart disease who were admitted for cardiac catheterization. In general, blood sampling was performed at the beginning of catheterization procedure from the vena cava inferior. Propofol was used to obtain conscious sedation during cardiac catheterization. Intubation was performed only in newborns, very small infants (body weight <4–5 kg), or severe cyanotic patients. In addition, we measured BNP in patients with cardiac disease admitted for minor operations, outpatient visits, or diagnostic work-up including a venous puncture. These patients were in supine position during blood sampling, and venous puncture was typically performed at a cubital vene between 8:30 and 11:00 a.m. after 10 min of rest.

None of the parents refused to include their child into the study. BNP was measured in 691 patients. A total of 346 patients complied with one of the following requirements: left ventricular shortening fraction currently <30% or in the normal range but a myocardial disease in the medical history, a cardiac defect causing any left-to-right shunt, left or right heart obstruction, tetralogy of Fallot without surgical therapy, or functionally univentricular heart.

A total of 58 out of 346 patients were deemed ineligible for inclusion because of one of the following causes: reduced left ventricular function in combination with another inclusion criteria (n=9); considerable valve insufficiency in addition to an outflow obstruction (n=11); additional heart defects (n=17); incomplete haemodynamic data (n=21).

The present analysis used the data of 288 patients (217 patients with, 71 without cardiac catherization; 132 females, 156 males; aged 0–29.2 years, mean age 6.0±6.4 years, median age 3.7 years). Left ventricular shortening fraction currently <30% or in the normal range but a myocardial disease or damage with reduced left ventricular shortening fraction in the medical history: n=30; a cardiac defect causing any left-to-right shunt (ventricular septal defect, atrial septal defect, persistent ductus arteriosus, or coronary fistula without any signs of ischaemia): n=74; isolated outflow obstruction (aortic valve stenosis, isthmic coarctation, or pulmonary valve stenosis): n=70; tetralogy of Fallot before corrective or palliative surgery: n=33; functionally univentricular heart: n=81 (Table 1).

View this table: [in this window] [in a new window]   Table 1 Clinical characteristics of the study population

 
Cardiac catheterization was performed in all patients with tetralogy of Fallot to exclude anomalies of the coronary arteries and to evaluate pulmonary arterial anatomy, in patients with aortic or pulmonary valve stenosis or isthmic coarctation to measure invasive pressure gradients or to perform balloon dilatation, in some selected patients with ventricular septal defect to evaluate invasively pulmonary artery pressure and resistance, in patients with atrial septal defect or persistent ductus arteriosus to close the defect with devices, in asymptomatic patients with coronary fistula to evaluate the coronary arterial anatomy and perfusion by angiography, and in patients with univentricular heart to evaluate the pulmonary resistance and the pulmonary arterial anatomy before bidirectional or total cavopulmonary anastomosis.

With scattered exceptions (single patients with very large left-to-right shunts or markedly reduced ventricular function), all patients were in good clinical condition. Naturally, patients with tetralogy of Fallot and patients with functionally univentricular heart before complete separation of systemic and pulmonary venous return were cyanotic in a variable degree. All patients with bidirectional or complete cavopulmonary anastomosis were taking antithrombotic drugs (acetylsalicylic acid 2–5 mg/kg/day, dipyridamole 2–3 mg/kg/day), almost half of the patients with tetralogy of Fallot propranolol (1–2 mg/kg/day) to prevent hypoxic spells, and some patients with large VSD or PDA diuretics (furosemide/spironolactone 1–2 mg/kg/day) and digoxin (5–10 µg/kg/day).

Controls
The 152 infants, children, and adolescents from 2 weeks to 17.6 years of age (mean age 8.7±5.0 years, median age 9.1 years; age >2 weeks to <10 years: n=43 males/42 females; age 10 years: n=31 males/36 females) were admitted for minor operations (e.g. hernia repair, tonsillectomy) or diagnostic work-up (e.g. for short stature, headache, neonatal screening). Physical examination and laboratory testing (e.g. electrolytes, kidney function, blood count) did not give any indication for acute illness (fever, infections, water and electrolyte imbalance, neoplastic disease, liver disease, renal disease) and the subjects had no history of heart disease or another serious disease. Blood sampling was typically done between 8:30 and 11:00 h in the supine position after 10 min of rest. They were not on drug treatment, they were not receiving intravenous infusions, and their diet was appropriate for their age.

Statistics
Statistical analyses were performed with SPSS 12.0 for Windows^®.

Statistical differences between patient groups and healthy subjects were evaluated using Student's t-test.

In patients with functionally univentricular heart, statistical differences between patients with complete, partial, or without separation of systemic and pulmonary venous return were evaluated using one-way analysis of variance.

Correlations were performed by Pearson's correlation method.

Statistical significance was accepted with a P-value below 0.05. The significance level was adjusted by use of Dunnett's test to compare patient groups with controls (see Figure 1). Bonferroni adjustment was used to account for the inflation of the overall Type I error rate in case of multiple testing in patients with functionally univentricular heart.

View larger version (29K): [in this window] [in a new window]   Figure 1 Correlation of BNP plasma concentration to left ventricular shortening fraction in 35 patients with dilated cardiomyopathy (solid dots), left ventricular non-compaction (open dots), myocarditis (triangles), Bland–White–Garland syndrome (rhombs), or congenital heart defect before (open squares; 1, patient with isthmic coarctation and hypoplasia of the left coronary artery; 2, patient with congenital mitral regurgitation) and after surgery (solid squares; 3, patient with Shone complex 1 year after aortic and mitral valve replacement; 4 and 5, patients with tetralogy of Fallot 3 and 5 years after corrective surgery; 6, patient 4 years after closure of a muscular VSD and resection of an isthmic coarctation; 7, patient 0.6 year after closure of a large perimembranous VSD). Individual z-scores (standard deviation score) and normal range (SDS –2 to +2, dotted lines) are shown.

 
Sample size calculations indicated that groups comprising 16 patients were sufficient to detect a difference in plasma BNP concentration of 1 SDS with 80% power at the 5% significance level.

The total coefficient of variation was between 4.0 and 12.4%.

	Results

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Plasma BNP concentration increased significantly (r=–0.80, P<0.001) with decreasing left ventricular shortening fraction (Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 2 Plasma concentration of BNP in controls and in patients with isthmic coarctation (IST), aortic valve stenosis (AST), pulmonary valve stenosis (PST), tetralogy of Fallot (TOF), left-to-right shunt defects (LRS), univentricular heart before separation of pulmonary and systemic venous return (SV), after superior bidirectional cavopulmonary connection (Glenn), and after total cavopulmonary connection (TCPC). Individual z-scores (standard deviation score) and normal range (SDS –2 to +2, dotted lines) are shown. Additionally, median (horizontal line), interquartile range (box), mean (bold horizontal line), and significant differences (*) to normal individuals are shown.

 
In patients with left-to-right shunt, plasma BNP was increased (mean SDS +1.63±2.41; P<0.001) (Figure 1). Plasma BNP was positively correlated to shunt volume (r=0.66; P<0.001), to systolic right ventricular pressure (r=0.69; P<0.001), to mean pressure of the pulmonary artery (0.66; P<0.001), and to increasing pulmonary resistance (r=0.59; P<0.001) (Figure 3).

View larger version (24K): [in this window] [in a new window]   Figure 3 (A) Correlation of BNP plasma concentration to shunt volume, (B) ratio of systolic right ventricular to systemic pressure, (C) mean pressure in the pulmonary artery, and (D) ratio of pulmonary to systemic resistance in 74 patients with left-to-right shunt because of a ventricular septal defect (solid dots), atrial septal defect (open dots), persistent ductus arteriosus (solid squares), or coronary fistula (open squares). Individual z-scores (standard deviation score) and normal range (dotted lines) are shown.

 
Plasma BNP levels in patients with aortic valve stenosis was slightly increased with significance (mean SDS +1.23±1.92; P=0.003) (Figure 1). In patients with pulmonary valve stenosis (mean SDS +0.58±1.65) or isthmic coarctation (mean SDS +1.01±2.00), there was no significant difference to healthy subjects (P>0.1) (Figure 1). There was no correlation between BNP and invasive pressure gradient (Figure 4).

View larger version (14K): [in this window] [in a new window]   Figure 4 BNP plasma concentration according to invasive peak-to-peak gradient in 66 patients with aortic valve stenosis (squares), isthmic coarctation (dots), or pulmonary valve stenosis (rhombs). Individual z-scores (standard deviation score) and normal range (dotted lines) are shown.

 
In patients with tetralogy of Fallot, plasma BNP was not significantly increased (mean SDS +0.57±1.84; P=0.43) (Figure 1).

Patients with functionally univentricular heart had higher plasma BNP levels than normal subjects (mean SDS +1.39±1.95; P<0.001). There was no difference between plasma BNP in patients before separation of systemic and pulmonary venous return (mean SDS +1.28±1.62), after bidirectional Glenn operation (mean SDS +1.04±2.04), or after complete cavopulmonary connection (mean SDS +1.70±2.12) (Figure 1).

	Discussion

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There is an increasing interest in BNP and its N-terminal pro-peptide not only in patients with congestive heart failure, but also in patients with congenital heart disease. According to the rapid and accurate measurement, the Triage test system allows a widespread clinical use of BNP determination and recent studies reported usefulness of BNP and NT-proBNP in predominantly adult patients with variable congenital heart disease.^7–10 However, it has to be taken into account that normal values of BNP plasma concentration are totally different in paediatric and adult patients. Healthy newborns, for example, have very high plasma concentration of BNP and NT-proBNP.^16–18 In contrast, in infants and children, BNP plasma levels are much lower than in adults, with significant differences in girls and boys after puberty.¹⁶ Accordingly, in adults, a 10-year increase in age is associated with a 1.4-fold increase in plasma BNP.¹⁹ Therefore, the results of studies on BNP in patients with congenital heart disease have to be compared with age- and gender-specific normal values. The need for adequate normal values is underlined by reports indicating a more discreet increase of natriuretic peptides in patients with congenital heart disease compared with adults with acquired left ventricular dysfunction.^8–10

In our patients, there was a very strong negative correlation between left ventricular systolic function and BNP plasma concentration. This finding is in line with the very few reports in the literature dealing with BNP and NT-proBNP values in children. We found increasing plasma BNP concentration with decreasing left ventricular shortening fraction, and Mir et al.¹³ described a significant relationship between NT-proBNP and left ventricular ejection fraction. Law et al.¹⁰ found significantly higher BNP plasma concentrations in children with reduced shortening or ejection fraction.

In children with left-to-right shunt, we found an increase of plasma BNP correlated to shunt volume, systolic right ventricular pressure, mean pressure in the pulmonary artery, and pulmonary resistance. These data are very consistent to the current conception of BNP released by the ventricular myocytes in response to volume and pressure load. The results are in line with one other report on natriuretic peptides in children with ventricular septal defect.¹⁵ Although their data were not compared with BNP concentrations in healthy children, the authors found BNP plasma levels positively correlated to shunt size, mean pulmonary artery pressure, ratio of pulmonary to systemic pressure, and pulmonary resistance.¹⁵ In addition, elevated NT-proBNP plasma levels have been described in small groups of children with cardiac defects causing a left-to-right shunt.^12,13

Although we found a slightly increased BNP concentration in our patients with aortic valve stenosis, most of the BNP plasma levels were in the normal range. In addition, BNP plasma levels did not correlate to the invasive pressure gradient. In contrast, in adult patients with aortic stenosis, elevated plasma levels of BNP and NT-proBNP have been reported with a correlation to severity,^20–23 particularly to transvalvular pressure gradient.^23–25 The differences between paediatric and adult patients with aortic stenosis may be explained by the greater possibility for compensation of left ventricular function in younger than in elderly patients. Some details of our data support this suspicion. The two neonates with critical aortic stenosis characterized by a reduced left ventricular function had very high BNP levels of >1300 pg/mL, however, because of high BNP plasma levels even in healthy newborns, the elevation with regard to normative data was cut down (SDS +2.44 and +2.86). One of the two patients with the proportionally highest BNP level (SDS +5.76) was a 2-month old girl with slightly reduced left ventricular shortening fraction and increased left ventricular diameter. In addition, in children with preserved left ventricular function, normal BNP levels were found, despite an invasive pressure gradient of up to 105 mmHg, a left ventricular systolic pressure of up to 220 mmHg, and a markedly increased left ventricular hypertrophy.²⁶ Cowley et al.¹⁴ reported a correlation of plasma BNP with the degree of left ventricular outflow obstruction. However, looking at their data in detail, the results are less conflicting to our findings: 18/21 patients had very similar plasma BNP levels with gradients between 10–90 mmHg. The positive correlation was based on 3/21 patients with high plasma BNP levels of 379–1060 pg/mL. However, the data were not compared with age specific normal values. The age of the three decisive patients was 3 days, 4 days, and 2 months and high BNP concentrations are normal in healthy newborns, in particular, in the first week of life.¹⁶

In patients with isolated right-heart obstruction because of a pulmonary valve stenosis, we could not find any increase of plasma BNP concentration, even in patients with invasive pressure gradients of more than 100 mmHg. Moreover, patients with tetralogy of Fallot featuring systemic pressure in the right ventricle and increased right ventricular mass again had normal BNP levels. In contrast, a positive correlation between right ventricular pressure and plasma BNP has been described in patients with tetralogy of Fallot after surgical correction.²⁷ At the first glance, this seems to be inconsistent with our findings of normal plasma BNP in patients with tetralogy of Fallot before surgical repair. However, corrective surgery of tetralogy of Fallot includes resection of the infundibulum obstruction and often incision of the right ventricle. Possibly, the changes in the myocardial architecture of the right ventricle reduce the ability to compensate and determine the different reaction to pressure load.

Experimental data indicate that hypertrophy itself may activate BNP expression in mice.²⁸ In man, a correlation between BNP levels to left ventricular mass in hypertensive patients has been reported.^29,30 In contrast, in athletes, increased ventricular mass was not associated with an increase of BNP plasma concentration,²⁹ probably because physiological hypertrophy is not associated with increased wall stress.³¹ Although increased BNP levels were described in patients with right ventricular pressure load, BNP levels were not correlated to right ventricular pressure, but inversely to the right ventricular ejection fraction.⁹ In one study on a large but very heterogeneous group of paediatric patients with different congenital heart diseases, no correlation was found between plasma BNP and right ventricular systolic pressure or right ventricular outflow tract obstruction.¹⁴

These data together with our findings of normal BNP levels in children with left or right ventricular hypertrophy and good ventricular function support the hypothesis that an increase in ventricular mass does not cause directly an increase of BNP plasma level.

Our patients with functional univentricular heart had on average higher plasma BNP levels than normal subjects. Unexpectedly, reduction of volume load according stepwise separation of systemic and pulmonary venous return did not decrease plasma BNP levels. In accordance, Hjortdal et al.³² found significantly higher, almost doubled BNP levels in 12 patients after total cavopulmonary connection and slightly, not significantly increased BNP plasma levels in eight patients after Glenn anastomosis compared with controls. Therefore, other factors than volume load have to cause the BNP increase in these patients.

In fact, there are a lot of data indicating a much more complex role for BNP than only to be the myocardial answer of pressure or volume load. For example, BNP exerts potent actions on cell growth and proliferation of fibroblasts, vascular smooth muscle cells, and cardiac myocytes.^28,33–35 Moreover, in the rat heart, experimental ischaemia leads to an increase of BNP messenger RNA in the ventricular myocardium and exogenously administered BNP limited infarct size in a concentration dependant matter,^36,37 and in humans, elevated concentrations of plasma BNP are detected following unstable angina.³⁸ All these reports suggest that BNP is a pleiotropic peptide with additional effects beyond its natriuretic and cardiac unloading properties.³⁹

BNP is a firmly established marker of ventricular dysfunction, but taking BNP as direct marker of volume and pressure load seems to be an oversimplification. Our data on different effects of pressure and volume on BNP plasma level in children with distinct congenital heart defects suggest that there are additional factors modulating the release of BNP apart from myocyte stretch alone. The role of BNP in patients with congenital heart disease is obviously much more complex.

Some limitations to this study have to be considered. Although focusing on patients with circumscribed haemodynamic problems, standardization is limited in paediatric patients with congenital heart disease. For example, there were some differences between the patients regarding arterial saturation or oral medication. However, from our own experience, we have no evidence that cyanosis or any of the given drugs influence BNP plasma levels. Next, we have investigated a relative large number of consecutive paediatric patients, but we do not have longitudinal data. Particularly in patients with functionally univentricular heart, data on the same subjects before and after separation of the systemic and pulmonary venous blood would be much more favourable than cross-sectional data.

In summary, BNP correlates well with systolic ventricular function and with increasing pulmonary pressure and pulmonary resistance in patients with left-to-right shunt. However, the data on patients with severe left and right heart obstruction demonstrated that not every kind of increasing ventricular pressure cause directly an increase of plasma BNP. In addition, the reduction of volume load in patients with functional univentricular hearts could not decrease the elevated BNP levels. There was not a simple, straight correlation between plasma BNP and pressure or volume load regardless of the underlying cardiac defect. Therefore, we have to conclude, that in children with congenital heart defects, plasma BNP levels do not reflect directly the extent of ventricular pressure or volume load, but reflect more likely the degree of impairment of the ventricles because of the increased volume and pressure work. A normal BNP value cannot preclude any pathology, but reflects a compensated status of the heart.

In future, BNP may change the current strategies for clinical management of congenital heart disease. However, data on adult patients cannot be directly transferred to children ⁴⁰ and the clinical impact of measuring BNP plasma levels has to be evaluated separately for each entity, before we can use this marker in clinical routine.

Conflict of interest: none declared.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339:321–328.[Free Full Text]
2. Cowie MR, Mendez GF. BNP and congestive heart failure. Prog Cardiovasc Dis 2002;44:293–321.[CrossRef][Web of Science][Medline]
3. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AHB, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–167.[Abstract/Free Full Text]
4. Nakamura T, Sakamoto K, Yamano T, Kikkawa M, Zen K, Hikosaka T, Kubota T, Azuma A, Nishimura T. Increased plasma brain natriuretic peptide levels as a guide for silent myocardial ischemia in patients with non-obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:1657–1663.[Abstract/Free Full Text]
5. Crilley JG, Farrer M. Left ventricular remodelling and brain natriuretic peptide after the first myocardial infarction. Heart 2001;86:638–642.[Abstract/Free Full Text]
6. Matsuo K, Nishikimi T, Yutani C, Kurita T, Shimizu W, Taguchi A, Suyama K, Aihara N, Kamakura S, Kangawa K, Takamiya M, Shimomura K. Diagnostic value of plasma levels of brain natriuretic peptide in arrhythmogenic right ventricular dysplasia. Circulation 1998;98:2433–2440.[Abstract/Free Full Text]
7. Bolger AP, Sharma R, Li W, Leenarts M, Kalra PR, Kemp M, Coats AJS, Anker SD, Gatzoulis MA. Neurohumoral activation and the congenital heart failure syndrome in adults with congenital heart disease. Circulation 2002;106:92–99.[Abstract/Free Full Text]
8. Book WM, Hott BJ, McConnel M. B-type natriuretic peptide levels in adults with congenital heart disease and right ventricular failure. Am J Cardiol 2005;95:545–546.[CrossRef][Web of Science][Medline]
9. Tulevski II, Groenink M, van der Wall EE, van Veldhuisen DJ, Boomsma F, Stoker J, Hirsch A, Lemkes JS, Mulder BJM. Increased brain and atrial natriuretic peptides in patients with chronic right ventricular pressure overload: correlation between plasma neurohormones and right ventricular dysfunction. Heart 2001;86:27–30.[Abstract/Free Full Text]
10. Law YM, Keller BB, Feingold BM, Boyle GJ. Usefulness of plasma B-type natriuretic peptide to identify ventricular dysfunction in pediatric and adult patients with congenital heart disease. Am J Cardiol 2005;95:474–478.[CrossRef][Web of Science][Medline]
11. Westerlind A, Wahlander H, Lindstedt G, Lundberg PA, Holmgren D. Clinical signs of heart failure are associated with increased levels of natriuretic peptide types B and A in children with congenital heart defects or cardiomyopathy. Acta Paediatr 2004;93:340–345.[CrossRef][Web of Science][Medline]
12. Nir A, Bar-Oz B, Perles Z, Korach A, Rein AJJT. N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence. Elevated levels at birth and in infants and children with heart diseases. Acta Paediatr 2004;93:603–607.[CrossRef][Web of Science][Medline]
13. Mir TS, Marohn S, Laer S, Eiselt M, Grollmus O, Weil J. Plasma concentrations of N-terminal pro-brain natriuretic peptide in control children from the neonatal to adolescent period and in children with congestive heart failure. Pediatrics 2002;110:e76.[Abstract/Free Full Text]
14. Cowley CG, Bradley JD, Shaddy RE. B-type natriuretic peptide levels in congenital heart disease. Pediatr Cardiol 2004;25:336–340.[Web of Science][Medline]
15. Suda K, Matsumura M, Matsumoto M. Clinical implication of plasma natriuretic peptides in children with ventricular septal defect. Pediatr Int 2003;45:249–254.[CrossRef][Web of Science][Medline]
16. Koch A, Singer H. Normal values of B-type natriuretic peptide in infants, children, and adolescents. Heart 2003;89:875–878.[Abstract/Free Full Text]
17. Rauh M, Koch A. Plasma N-terminal pro B-type natriuretic peptide concentrations in a control population of infants and children. Clin Chem 2003;49:1563–1564.[Free Full Text]
18. Schwachtgen L, Herrmann M, Georg T, Schwarz P, Marx N, Lindinger A. Reference values of NT-proBNP serum concentrations in the umbilical cord blood and in healthy neonates and children. Z Kardiol 2005;94:399–404.[CrossRef][Web of Science][Medline]
19. Wang TJ, Larson MG, Levy D, Leip EP, Benjamin EJ, Wilson PW, Sutherland P, Omland T, Vasan RS. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 2002;90:254–258.[CrossRef][Web of Science][Medline]
20. Ikeda T, Matsuda K, Ito H, Shirakami G, Miyamato Y, Yoshimasa K, Nakao K, Ban T. Plasma levels of brain and atrial natriuretic peptides elevated in proportion to left ventricular end-systolic wall stress in patients with aortic stenosis. Am Heart J 1997;133:307–314.[CrossRef][Web of Science][Medline]
21. Qi W, Mathisen P, Kjekshus J, Simonsen S, Bjornerheim R, Endresen K, Hall C. Natriuretic peptides in patients with aortic stenosis. Am Heart J 2001;142:725–732.[CrossRef][Web of Science][Medline]
22. Gerber IL, Stewart RA, Legget ME, West TM, French RL, Sutton TM, Yandle TG, French JK, Richards AM, White HD. Increased plasma natriuretic peptide levels reflect symptom onset in aortic stenosis. Circulation 2003;107:1884–1890.[Abstract/Free Full Text]
23. Weber M, Arnold R, Rau M, Maikowski C, Keil E, Mitrovic V, Brandt R, Hamm C. N-terminal pro braintype natriuretic peptide (NT-proBNP) is a highly sensitive biochemical marker for surgical therapy in patients with aortic stenosis. Circulation 2003;108(Suppl. 17):IV513.
24. Prasad N, Bridges AB, Lang CC, Clarkson PBM, MacLeod C, Pringle TH, Struthers AD, MacDonald TM. Brain natriuretic peptide concentrations in patients with aortic stenosis. Am Heart J 1997;133:477–479.[CrossRef][Web of Science][Medline]
25. Talwar S, Downie PF, Squire IB, Davies JE, Barnett DB, Ng LL. Plasma N-terminal proBNP and cardiotrophin-1 are elevated in aortic stenosis. Eur J Heart Fail 2001;3:15–19.[CrossRef][Web of Science][Medline]
26. Koch A, Singer H. Plasma levels of B-type natriuretic peptide in children and adolescents with aortic valve stenosis. Eur Heart J 2005;doi:10.1093/eurheartj/ehi369.
27. Mir TS, Falkenberg J, Friedrich B, Gottschalk U, Le TP, Laer S, Weil J. Levels of brain natriuretic peptide in children with right ventricular overload due to congenital cardiac disease. Cardiol Young 2005;15:396–401.[CrossRef][Web of Science][Medline]
28. Rosenkranz AC, Woods RL, Dusting GJ, Ritchie RH. Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: importance of cyclic GMP. Cardiovasc Res 2003;57:515–522.[Abstract/Free Full Text]
29. Almeida SS, Azevedo A, Castro A, Frioes F, Freitas J, Ferreira A, Bettencourt P. B-type natriuretic peptide is related to left ventricular mass in hypertensive patients but not in athletes. Cardiology 2002;98:113–115.[CrossRef][Web of Science][Medline]
30. Yamamoto K, Burnett JC Jr, Jougasaki M, Nishimura RA, Bailey KR, Saito Y, Nakao K, Redfield MM. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28:988–994.[Abstract/Free Full Text]
31. Pluim BM, Chin JC, De Roos A, Doornbos J, Siebelink HM, Van der Laarse A, Vliegen HW, Lamerichs RM, Bruschke AV, Van der Wall EE. Cardiac anatomy, function and metabolism in elite cyclists assessed by magnetic resonance imaging and spectroscopy. Eur Heart J 1996;17:1271–1278.[Abstract/Free Full Text]
32. Hjortdal VE, Stenbog EV, Ravn HB, Emmertsen K, Jensen KT, Pedersen EB, Olsen KH, Hansen OK, Sorensen KE. Neurohormonal activation late after cavopulmonary connection. Heart 2000;83:439–443.[Abstract/Free Full Text]
33. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 2001;107:975–984.[Web of Science][Medline]
34. Cao L, Gardner D. Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. Hypertension 1995;25:227–234.[Abstract/Free Full Text]
35. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H, Katsuki M, Nakao K. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci USA 2000;97:4239–4244.[Abstract/Free Full Text]
36. D'Souza SP, Yellon DM, Martin C, Schulz R, Heusch G, Onady A, Ferdinandy P, Baxter GF. B-type natriuretic peptide (BNP) limits infarct size in rat isolated heart via K-ATP channel opening. Am J Physiol Heart Circ Physiol 2003;284:H1592–H1600.[Abstract/Free Full Text]
37. Hama N, Itoh H, Shirakami G, Nakagawa O, Suga S, Ogawa Y, Masuda I, Nakanishi K, Yoshimasa T, Hashimoto Y, Yamaguchi M, Hori R, Yasue H, Nakao K. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995;92:1558–1564.[Abstract/Free Full Text]
38. Talwar S, Squire IB, Downie PF, Davies JE, Ng LL. Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina. Heart 2000;84:421–424.[Abstract/Free Full Text]
39. D'Souza SP, Baxter GF. B-type natriuretic peptide: a good omen in myocardial ischemia. Heart 2003;89:707–709.[Free Full Text]
40. Jefferies JL, Chang AC. The neurohormonal axis and biochemical markers of heart failure. Cardiol Young 2005;15:333–344.[Medline]

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