Prognostic value of B-type natriuretic peptide in children with pulmonary hypertension
Introduction
Severe pulmonary vascular disease leads to right heart failure and death. The prognosis was extremely poor until specific therapies were introduced a few years ago. These therapies have improved quality of life and survival. Monitoring progress, assessing the need for modification and escalation of therapy and determining the time to transplantation remain a challenge, particularly in children where non-invasive assessment is desirable. In adult populations B-type natriuretic peptide has been shown to be a valuable diagnostic tool in patients with respiratory or cardiac disease [1]. BNP is helpful in predicting both left and right ventricular dysfunction [1], [2], [3]. It correlates closely with New York Heart Association functional class [1], [4], [5] and haemodynamic parameters [6], [7]. In adult patients with idiopathic pulmonary hypertension (IPAH), BNP correlated with the mean pulmonary artery pressure (PAP), total pulmonary vascular resistance (PVR) [5], right atrial pressure and right ventricular end-diastolic pressure [8]. BNP has also been shown to be predictive of survival in adults with IPAH [9]. No comparable studies have been carried out in children with pulmonary hypertension (PH) but elevated levels have been described in children with congenital heart disease [10], [11], [12], [13], Kawasaki disease [14], cardiomyopathy [15] and congestive heart failure [16].
B-type natriuretic peptide (BNP) is synthesized as a prehormone, proBNP, predominantly by ventricular cardiomyocytes. It is cleaved in equal proportions into the biologically active BNP, which represents the C-terminal fragment and the biologically inactive N-terminal fragment (NT-proBNP). Both NT-proBNP and active BNP have been used as biomarkers for diagnosis and risk stratification in several cardiovascular cohorts, and their diagnostic significance is comparable [17], [18]. BNP is synthesized and secreted by the ventricular myocardium, little is stored and rapid gene expression with de novo synthesis regulates secretion. BNP-production is stimulated by an increase in pressure and/or volume overload [2], but the main stimulus for secretion is wall stress [8], [19], [20]. Synthesis of BNP can also be augmented by tachycardia, glucocorticoids, thyroid hormones and vasoactive peptides [2], such as endothelin-1 and angiotensin II [19], both of which are thought to play a role in the pathobiology of pulmonary vascular disease.
The purpose of this study was to evaluate the significance of the plasma BNP level in children with PH by assessing the relationship between BNP and WHO Functional Class, and the echocardiographic and haemodynamic features of right ventricular dysfunction. Whether or not the plasma BNP level can predict death or the need for transplantation was also considered.
Section snippets
Methods
Fifty patients from the UK Pulmonary Hypertension Service for Children seen between January 2004 and September 2006 were studied (Table 1). Informed parental consent was obtained and the study was carried out with the permission of the local ethics committee. The mean age of the group was 8.4 ± 5.1 years (range 0.3–18.4) and the male:female ratio was 1.8:1. Twenty-seven children (male:female ratio, 1.02:1) had IPAH. Twenty-three children with APH had congenital cardiac disease (n = 17), lung
Results
The mean BNP level in all the children with PH was 143.5 ± 236.2 pg/ml (range < 5–1250) significantly greater than the normal mean value described by Koch [13] (p < 0.01). There was no significant difference between those patients with IPAH and those with APH (mean 119.9 ± 168.9 pg/ml, range < 5–644.0, versus 171.1 ± 298.4 pg/ml, range < 5–1250, respectively; p = 0.60). Considering the children individually and taking 32.7 pg/ml [13] as the upper limit of normal, 56% of all children with PH had an
Discussion
The present study showed that the BNP level in children with pulmonary hypertension correlated with functional status (WHO Functional Class). The level was higher in those ill enough to need epoprostenol rather than oral therapies. These findings are similar to those found in adults, BNP being higher in those with greater physical disability [27]. The BNP level correlated positively with echocardiographic measures of right ventricular dysfunction and in those with IPAH, with haemodynamic
Conclusion
The BNP level in groups of children with IPAH and APH showed a positive correlation with the WHO Functional Class and echocardiographic measures of right ventricular dysfunction and in those with IPAH, with the haemodynamic findings. In the individual child however, the BNP level could not be used as a marker of clinical status based on the evidence presented in this paper.
Acknowledgements
We wish to thank all the UK pediatric cardiologists and pediatricians who referred and helped care for these children as part of the UK Pulmonary Hypertension Service for Children.
We also would like to acknowledge Jane Bettany, Senior Clinical Biochemist for measuring the plasma BNP level in our patients.
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