In this single center retrospective cohort study, we sought to investigate and compare the characteristics between BNP and NTproBNP in pediatric PH patients with variations in disease severity. We found that BNP and NTproBNP levels had a strong correlation with each other and there were significant age and gender related differences in both peptides. Additionally, both peptides significantly, but moderately correlated with TR velocity and hemodynamics such as mRAP, when considered in a cross sectional analysis. NTproBNP correlated better with variables not collected on the same day, such as 6MWD and echocardiographic data, moreover, the difference in the correlation estimates lessened with the constraint that the measurements be taken on the same day. In contrast, BNP tended to correlate better with the catheterization variables such as mPAP and PVRI as the blood samples were collected during catheterization. Therefore, NTproBNP may have advantages if the time between collection and measurements are greater owing to a longer half-life. However, mPAP and PVRI were significantly associated with both peptides when evaluated longitudinally. The longitudinal associations yielded similar results. None of the associations with the clinical variables were statistically different between BNP and NTproBNP. Our studies suggested both markers may be equally useful for making decisions in a clinical setting. This study is interesting because this is the first report to evaluate both BNP and NTproBNP in a relatively large pediatric PAH population.
Previous studies in PAH have shown that each peptide significantly correlated with hemodynamics. A circulating BNP was significantly correlated with mPAP (r = 0.73
), total pulmonary resistance (r = 0.79
), and mean RAP (r = 0.79
) in 26 patients with idiopathic or thromboembolic pulmonary hypertension,19
but the number of patients in this study was small and the population was more clearly defined compared the population used here. In addition, elevated BNP level was a significant prognostic factor.13,20
Likewise, the elevation of serum NTproBNP level was useful in identifying the poor long-term prognosis in idiopathic PAH.13,16,17
Both peptides can be easily and non-invasively measured, therefore, they are widely used as reliable biomarkers in patients with PAH. However, there are few data comparing BNP and NTproBNP. The elimination of BNP in plasma is shorter compared with NTproBNP.21
For this reason, the plasma BNP level may be more useful for assessing more real-time hemodynamic changes in pediatric patients with PAH. In contrast, NTproBNP is eliminated only via the kidneys, resulting in a significantly longer half-life 22,23
and higher concentrations compared to BNP. A previous report showed that such different clearance mechanisms might contribute to the superiority of NTproBNP as a mortality marker.24
In our present study, we were unable to determine whether BNP and NTproBNP is a more sensitive predictor of outcome. However, our results performed on the concentrations collected serially over time, indicate the increased stability of NTproBNP concentrations compared to BNP and would corroborate this finding.
BNP and NTproBNP concentrations at 0 days of age were higher (20-fold for NTroBNP and 18-fold for BNP) compared to adult levels in a prior study 25
and both peptides immediately decrease after birth.26,27
Koch et al. reported that plasma concentration of BNP had sex related differences in the second decade of life,28
and even in adult studies, both peptides were related with age and gender.29–32
Likewise, we found concentrations in both BNP and NTproBNP levels decreased until age 12, after which they began to increase at slightly different rates between males and females. The associations with the clinical variables were however robust after adjusting for these potential confounding effects. In addition, a recent report showed that the decreasing trend of NTproBNP was different from BNP.33
This result was replicated in the presented work as well. Therefore, interpretation of NPs in the clinical setting should include consideration of age- and gender-related differences.
Several limitations should be mentioned. First, as previously described, of the 88 patients, all patients survived, and did not receive lung transplantation. Therefore, we could not evaluate the predictive value of both peptides due to the low number of events. The present study was an observational cohort study from a single center, therefore, clinical findings regarding the prognostic impact of these NPs remain to be confirmed in a larger multi-site study. Second, there was heterogeneity in the study population because our patients included a variety of associated forms of PAH. Third, the patients were individually treated with various vasodilator therapies according to their conditions. Despite these limitations, we found that both biomarkers can be noninvasively assessed as promising tools for the evaluation of pediatric patients with PAH.