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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 42  |  Issue : 2  |  Page : 53-57

Serum levels of amino terminal of probrain natriuretic peptide (NT-Pro BNP) as a diagnostic and prognostic biomarker in children with dilated cardiomyopathy


1 Department of Pediatric, Faculty of Medicine, Tanta University Hospital, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University Hospital, Tanta, Egypt

Date of Submission11-Apr-2014
Date of Acceptance17-Apr-2014
Date of Web Publication31-Jul-2014

Correspondence Address:
Wegdan H Mawlana
Department of Pediatric, Faculty of Medicine, Tanta University Hospital, Tanta
Egypt
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DOI: 10.4103/1110-1415.137800

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  Abstract 

Background
The amino terminal fragment of proB-type natriuretic peptide (NT-proBNP) has become commonly utilized as a sensitive marker for cardiac dysfunction in adults. However, its value in children with dilated cardiomyopathy (DCM) has not been widely investigated. We aimed to evaluate the serum levels of NT-proBNP as a diagnostic and prognostic biomarker of left ventricular dysfunction in children with DCM.
Patients and methods
The level of NT-proBNP was measured in 20 critically ill children with DCM and in 20 age-matched control children.
Results
There was highly significant increase in serum NT-proBNP level in patients with DCM as compared with the control group. At cutoff level of 1500 pg/ml, the sensitivity of NT-proBNP as a diagnostic biomarker in children with DCM was 85% and the specificity was 100%. There were significant positive correlations between serum NT-proBNP level and left ventricular systolic and diastolic diameters, whereas significant negative correlations were present between serum NT-proBNP level and ejection fraction and fraction shortening in children with DCM.
Conclusion
Serum NT-proBNP levels could play a role as a diagnostic and prognostic biomarker (with high sensitivity and specificity) of left ventricular systolic dysfunction in children with DCM.

Keywords: children, dilated cardiomyopathy, proBNP


How to cite this article:
Zoair AM, Mawlana WH, El-Bendary AS, Nada EA. Serum levels of amino terminal of probrain natriuretic peptide (NT-Pro BNP) as a diagnostic and prognostic biomarker in children with dilated cardiomyopathy. Tanta Med J 2014;42:53-7

How to cite this URL:
Zoair AM, Mawlana WH, El-Bendary AS, Nada EA. Serum levels of amino terminal of probrain natriuretic peptide (NT-Pro BNP) as a diagnostic and prognostic biomarker in children with dilated cardiomyopathy. Tanta Med J [serial online] 2014 [cited 2017 Oct 18];42:53-7. Available from: http://www.tdj.eg.net/text.asp?2014/42/2/53/137800


  Introduction Top


Dilated cardiomyopathy (DCM), the most common type of heart muscle disease in children, is characterized by impaired systolic function of one or both ventricles with ventricular dilation [1]. The idiopathic type of DCM accounts for 50% of all patients [2]. Brain natriuretic peptide (BNP) is one of the cardiac markers of heart failure. It correlates with symptoms of heart failure and may indicate left ventricular (LV) volume and pressure overload in the presence of shunt [3].

The N-terminal fragment of proB-type natriuretic peptide (NT-proBNP) is secreted from cardiac myocytes together with BNP. Both BNP and NT-proBNP have been used to identify the presence and to determine the severity of heart failure in children [4-6]. Most of the pediatric studies demonstrate an increase in natriuretic peptide levels in proportion to the symptomatic severity and the degree of remodeling in diverse pediatric cardiac diseases [7-9]. Few studies focused on heart failure due to DCM [10]. In this study, we hypothesize that changes in NT-proBNP serum levels are associated with changes in echocardiographic indices of LV systolic function in children or young adults with DCM.


  Patients and methods Top


Twenty children with DCM were enrolled in this study. They were chosen from critically ill patients admitted at the Pediatric Intensive Cardiac Care Unit, Pediatric Department, Tanta University Hospital during the period from November 2011 to February 2013. Their ages ranged from 4 to 48 months, and there were eight boys and 12 girls. Twenty healthy children, matched for age and sex, were enrolled as a control group. Their ages ranged from 4 to 46 months, and there were 10 boys and 10 girls.

The exclusion criteria

Other types of cardiomyopathy (hypertrophic or restrictive), myocarditis, congenital heart disease, rheumatic heart disease, respiratory illness, renal disease or failure, cerebral disease, sepsis, shock, anemia, or any chronic disease were excluded to exclude the effect on natriuretic peptide levels.

Written informed consent was obtained from all patients' parents or guardians. The study was approved by the local Ethics Committee.

All children in this study were subjected to complete history taking to exclude any other illness and to thorough clinical examination, including signs of congestive heart failure and complete local cardiac examination. Echocardiographic study was performed in all patients within the first day of admission using Ultrasound Machine, Vivid7 (GE medical system, Horten, Norway). Echocardiographic examination included LV dimensions, including LV end-diastolic dimension (LVEDD) and LV end-systolic dimension (LVESD), and LV systolic function, including LV ejection fraction (EF%) using M-mode echocardiography, two-dimensional echocardiography, and color Doppler echocardiography.

Blood for NT-proBNP assay was taken from peripheral venous puncture and collected in tubes containing EDTA. Plasma was separated and stored at −20°C until the time of analysis. All reagents were brought to room temperature before use. NT-proBNP was analyzed using a commercial NT-proBNP ELISA Kit (Biomedica, Vienna, Ausria).

Statistical analysis was performed using the statistical package for the social science base IBM SPSS statistics (V. 21.0, IBM Corp., USA, 2012) for mean, SD, and the χ2 -test. Correlations were calculated using the Pearson correlation test.


  Results Top


The demographic characters of our cohort study are presented in [Table 1]. The mean age of the DCM group was 14.63 ± 1.25 months, whereas the mean age of the control group was 13.52 ± 1.63 months, with no statistically significant difference between the two studied groups. With respect to sex, the patient group comprised eight boys (40%) and 12 girls (60%), whereas the control group comprised 10 boys (50%) and 10 girls (50%), with no significant difference between both groups. Half of the patients in the DCM group presented with failure to thrive, whereas heart murmur and gallop were present in 30% of the patients [Table 2]. The echocardiographic parameters of our cohort are presented in [Table 3]. There was significant decrease in fractional shortening (FS%), EF%, LVEDD, and LVESD in the patient group as compared with the control group (P < 0.005).

NT-proBNP mean plasma level of the DCM group was 2583.2 ± 4253 pg/ml (range 300-6100), and it was 48.05 ± 8.45 pg/ml (range 0-130) in the control group, with highly significant increase in NT-proBNP plasma level in the patient group with dilated cardiomyopathy (DMC) as compared with the control group (P < 0.005) [Table 4]. At serum NT-proBNP cutoff level of 1500 pg/ml, the sensitivity of NT-proBNP in children with DCM was 85% (17/20) and the specificity was 100% (20/20) [Table 5].
Table 1 Demographic data of the studied group

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Table 2 Clinical data of patients with DCM

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Table 3 Echocardiographic fi ndings of the studied groups

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Table 4 Serum levels of probrain natriuretic peptide in the studied groups

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Table 5 Sensitivity and specifi city of serum NT-proBNP (at a specific cutoff point) as a diagnostic biomarker in children with DCM

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[Table 6] and [Figure 1] and [Figure 2] show the correlation between plasma NT-proBNP level and echocardiographic assessment of these patients. There was significant positive correlation between plasma NT-proBNP level and LVEDD and LVESD, whereas negative correlation was found between plasma NT-proBNP level and FS% and EF% in the patient group as compared with the control group.
Figure 1: Correlation between plasma NT-proBNP level and EF% of the studied patients with DMC. EF, ejection fraction; NT-proBNP, proB-type natriuretic peptide.

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Figure 2: Correlation between plasma NT-proBNP level and FS% of the studied patients with DMC. FS, fractional shortening; NT-proBNP, proB-type natriuretic peptide.

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Table 6 Correlation between plasma NT-proBNP level at a cutoff point of 1500 pg/ml and echocardiographic fi ndings of the studied patients with DMC

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  Discussion Top


DCM is a heterogeneous group of myocardial diseases characterized by cardiac dilatation and impaired myocardial contractility [11]. The epidemiology and clinical course of DCM in children are not well established, and most children have an undiagnosed cause of DCM, which limits the potential for disease-specific therapies [1].

In the present study, the mean age of our cohort was 14.6 months, with 50% of them presenting younger than age 1 year and about 70% presenting before their second birthday, which is consistent with most published data. In a nationwide Finnish study carried out by Arola et al. [12] it was found that 52% of DCM occurs in the first year of life with a median age of 13 months. In addition, Towbin et al. [1] reported a higher incidence in infants (<1 year) than in children. Similarly, Venugopalan et al. [13] stated that 50% of patients with new onset DCM were younger than age 2 years.

With respect to sex distribution, 60% of our patients were girls. This is in agreement with the study by Holmgren et al. [14] and Nugent et al. [15]. The annual incidence in the USA is reported to be higher in boys than in girls (0.66 vs. 0.47 patients per 100 000; P < 0.001) [1]. Others have reported no sex predilection in patients with DCM. These differences may be attributable to racial basis [13].

With respect to the echocardiographic parameters in our study, there was LV systolic dysfunction in patients with DCM, as there was significant decrease in EF% and FS % as compared with the control group. In addition, there was significant increase in LVEDD and LVESD in the patient group as compared with the control group. These results were in agreement with the results of Salah-Eldin et al. [16] who reported significant increase in the mean indexed values of left atrial and ventricular dimensions and great arteries diameters in studied patients with DCM than in control individuals, with decreased EF% and FS% due to LV systolic impairment.

BNP, a member of the natriuretic peptide family, is produced in cardiac myocytes and secreted into the circulation in response to cardiac volume load, causing diuresis, natriuresis, and vasodilatation, as well as inhibition of the renin-aldosterone system and sympathetic activity [17]. BNP has emerged as a very sensitive biochemical marker for cardiac dysfunction in adults [18]. Limited data suggest similar properties in infants and children [19].

The amino terminal of NT-proBNP has been found to be elevated in adults and children with congestive heart failure [5]. NT-proBNP has been reported to be a better marker than BNP for the detection and evaluation of chronic heart failure; this is because it is more stable and is a better predictor of cardiac dysfunction. A single measurement of the NT-proBNP level in patients with advanced dilated cardiomyopathy (CHF) can help to identify those at highest risk of death, and it is also a better prognostic marker than the LVEF [20].

In the present study, there was highly significant increase in serum NT-proBNP level in the patient group with DCM as compared with the control group (with high sensitivity and specificity). This is in agreement with the study conducted by Nasser and colleagues who found that NT-proBNP proved to be a good marker for LV systolic dysfunction in children with DCM. Its levels were significantly elevated in patients with persistent LV dysfunction, and it correlated with echocardiographic parameters [21]. In addition, Niebroj-Dobosz and colleagues reported that NT-proBNP and NT-proANP are used as screening tests for heart failure. BNP is indicated as the best marker to detect patients with impaired LVEF, and NT-proBNP might be an alternative marker of deteriorated cardiac function in patients with DCM. They stated that elevated NT-proBNP better predicted the risk of adverse events in long-term systolic dysfunction [22].

However, it needs to be kept in mind that increased BNP/NT-proBNP levels are not strictly specific for heart diseases and that BNP and NT-proBNP are influenced by extracardiac factors such as sex, age, glomerular filtration, and obesity, which must be kept as exclusion criteria [22].

In the present study, there was significant negative correlation between serum NT-proBNP level and the echocardiographic parameters of LV systolic function (EF% and FS%), whereas significant positive correlation was found between serum NT-proBNP level and LVEDD and LVESD in children with DCM as compared with the control group. Similarly, Rusconi et al. [23] found that, in 36 children with DCM, a 10-fold increase in NT-proBNP serum levels was associated with decrease in LVEF and increase in LVEDD and LVESD.

There is moderate-to-strong relationship of NT-proBNP levels with several echocardiographic variables and with functional status, which potentially makes possible a test that quickly and objectively indicates the patient's clinical condition and corroborates the clinical assessment of functional status and echocardiographic indices of ventricular size and function. The potential clinical applications of this biomarker include tracking the progression of the disease and assessing the response to therapy. It can be speculated that a patient with progressive increases in NT-proBNP may need more aggressive treatment or that one with decreasing NT-proBNP levels after an increase in medication indicates improvement in heart failure (HF) [23].

The results of the present study showed that, using a cutoff point of NT-proBNP as 1500 pg/ml, the sensitivity of NT-proBNP as a diagnostic biomarker in children with DCM was 85% and the specificity was 100%. This is in agreement with the study by Kim and colleagues, who found that the optimal NT-proBNP cutoff level for predicting cardiac events was 1500 pg/ml, with a sensitivity and specificity of 80 and 92%, respectively; patients with levels above this threshold had a 22.9 hazard ratio for cardiac events compared with those with levels below this threshold [20].

However, Rusconi et al. [23] found that NT-proBNP level above 1000 pg/ml clearly identified the sickest patients. NT-proBNP levels between 450 and 1000 pg/ml did not distinguish between symptomatic and asymptomatic patients.

Limitation of the study

Further studies are recommended to include large number of children with DCM to confirm NT-proBNP as a diagnostic biomarker for LV dysfunction in these patients. We would suggest long-term follow-up of these patients to study whether NT-proBNP could be used as a prognostic marker as well strongly correlated with the echocardiographic parameters of LV systolic function in these patients suggesting its role as a diagnostic biomarker with high sensitivity and specificity.


  Acknowledgements Top


 
  References Top

1.Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav J, et al. Incidence, causes and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296:1867-1876.  Back to cited text no. 1
    
2.Olson TM, Chan DP. Dilated congestive cardiomyopathy. J Am Coll Cardiol 2001; 18:152-156.  Back to cited text no. 2
    
3.Nir A, Nasser N. Clinical value of NT-ProBNP and BNP in pediatric cardiology. J Card Fail 2005; 11:76-80.  Back to cited text no. 3
    
4.Mangat J, Carter C, Riley G, Foo Y, Burch M. The clinical utility of brain natriuretic peptide in paediatric left ventricular failure. Eur J Heart Fail 2009; 11:48-52.  Back to cited text no. 4
    
5.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.  Back to cited text no. 5
    
6.Geiger R, Hammerer-Lercher A, Url C, et al. NT-proBNP concentrations indicate cardiac disease in pediatric patients. Int J Cardiol 2007; 123:63-65.  Back to cited text no. 6
[PUBMED]    
7.Nir A, Bar-Oz B, Perles Z, Brooks R, Korach A, Rein AJ. 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.  Back to cited text no. 7
    
8.Wong DT, George K, Wilson J, Manlhiot C, McCrindle BW, Adeli K, Kantor PF. Effectiveness of serial increases in amino-terminal pro-B-type natriuretic peptide levels to indicate the need for mechanical circulatory support in children with acute decompensated heart failure. Am J Cardiol 2011; 107:573-578.  Back to cited text no. 8
    
9.Abassi Z, Karram T, Ellaham S, et al. Implications of the natriuretic peptide system in the pathogenesis of heart failure: diagnostic and therapeutic importance. Pharmacol Ther 2004; 102:223-241.  Back to cited text no. 9
    
10.Kantor F, Rusconi P, Lipshultz S, Mital S, Wilkinson JD, Michael Burch M. Current applications and future needs for biomarkers in pediatric cardiomyopathy and heart failure: summary from the Second International Conference On Pediatric Cardiomyopathy. Prog Pediatr Cardiol 2011; 32:11-14.  Back to cited text no. 10
    
11.Wynne J, Branuwald E. The cardiomyopathies. Eur Heart J 2005; 16:46-49.  Back to cited text no. 11
    
12.Arola A, Tuominen J, Ruuskanen O, et al. Idiopathic dilated cardiomyopathy in children: prognostic indicators and outcome. Pediatrics 1998; 101:369-376.  Back to cited text no. 12
    
13.Venugopalan P, Agarwal AK, Worthing EA. Chronic cardiac failure in children due to dilated cardiomyopathy: diagnostic approach, pathophysiology and management. Eur J Pediatr 2006; 159:803-810.  Back to cited text no. 13
    
14.Holmgren D, Wahlander H, Eriksson BO, et al. Cardiomyopathy in children with mitochondrial disease: clinical course and cardiological findings. Eur Heart J 2002; 24:280-288.  Back to cited text no. 14
    
15.Nugent AW, Daubeney PEF, Carlin JB, et al. The National Australian Childhood Cardiomyopathy Study: the epidemiology of childhood cardiomyopathy in Australia. Circulation 2003; 17:1639-1646.  Back to cited text no. 15
    
16.Salah-Eldin A, El-Saied MM, Mohammed A, et al. Clinical, Virological and Echocardiographic Study in children with dilated cardiomyopathy. Alex J Pediatrics 2005; 19:343-347.  Back to cited text no. 16
    
17.Espiner EA, Richards AM, Yandle TG, Nicholls MG. Natriuretic hormones. Endocrinol Metab Clin North Am 1995; 24:481-509.  Back to cited text no. 17
    
18.Baughman KL. B-type natriuretic peptide - a window to the heart. N Engl J Med 2002; 347:158-159.  Back to cited text no. 18
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19.Suda K, Matsumura M, Matsumoto M. Clinical implication of plasma natriuretic peptides in children with ventricular septal defect. Pediatr Int 2003; 45:249-254.  Back to cited text no. 19
    
20.Kim HJ, Jeon E, Choi J, et al. Discharged patients with idiopathic dilated cardiomyopathy. Korean Circ J 2007; 37:202-207.  Back to cited text no. 20
    
21.Nasser N, Perlez Z, Rein AJ, et al. NT-proBNP as a marker for persistent cardiac disease in children with dilated cardiomyopathy. Pediatr Cardiol 2006; 27:87-90.  Back to cited text no. 21
    
22.Niebroj-Dobosz C, Soko³owska B, Madej-Pilarczyk A, et al. Natriuretic peptides assessment in dilated cardiomyopathy in patients with Emery-Dreifuss muscular dystrophy. J Clin Exp Cardiol 2012; 3:8-12.  Back to cited text no. 22
    
23.Rusconi PG, Ludwig DA, Ratnasamy A, et al. Serial measurements of serum NT-proBNP as markers of left ventricular systolic function and remodeling in children with heart failure. Pediatr Cardiol 2010; 160:776-783.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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