Plasma Level of NT-Pro-BNP In Children with Sickle Cell Disease Is Associated with Degree of Anemia and Left Ventricular Measures: The PUSH Study

Amino-terminal pro-brain type natriuretic peptide (NT-proBNP) is a widely used clinical laboratory marker of left ventricular stress, although it is also known to be elevated in adults with right ventricular stress due to pulmonary hypertension associated with sickle cell disease (SCD) and other disorders. NT-proBNP is associated with early mortality in adults with SCD.

Using a standard clinical laboratory assay, we measured NT-proBNP in 346 children (median age 12; IQR 7–16 years) with SCD enrolled in the Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH) study, an ongoing, longitudinal and observational multicenter study of children with sickle cell disease. In order to adjust for age, a known confounding factor of NT-proBNP in young children, we compared the characteristics of children with the top quartile of NT-proBNP for each 3-year increment of age with those of children in the remaining three quartiles for that age increment. We examined several factors alone and as part of a logistic regression model.

In univariate analyses, high expression of NT-proBNP was associated with lower hemoglobin levels (median 83 vs. 87 gm/L, p=0.0006). The high NT-proBNP group also had a higher hemolytic component, a principal component-derived index of the common properties of the hemolytic markers reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and bilirubin (median 0.5 vs. 0.7 relative units, p=0.021). The high NT-proBNP group had a higher prevalence of high left ventricular filling pressure, as indicated by the mitral inflow E wave to tissue Doppler E wave (E/Etdi) above 9.22 (13.1% vs. 2.9%, p<0.001) and left ventricular dilatation (median internal diastolic diameter z-score 2.1 vs. 1.5, p=0.013). There was a trend toward higher prevalence of elevated estimated pulmonary artery pressures as indicated by tricuspid regurgitant velocity of 2.6 m/s or higher (17.1% vs. 10.8%, p=0.14), and higher ferritin (median 339 vs. 199, p=0.15). Children on hydroxyurea treatment had lower median NTproBNP levels (77 vs. 121 pg/mL, p=0.005). In a logistic regression model, hemoglobin (odds ratio 0.7, 95% confidence interval 0.6–0.9, p=0.001) and E/ETdi>9.22 were independently associated with high NT-proBNP levels.

After adjustment for age in children with SCD, upper quartile NTproBNP is independently associated with severity of anemia and echocardiographic markers of left ventricular size and diastolic filling pressure. At this age, they have not yet developed the association observed prominently in SCD adults between NT-proBNP and elevated pulmonary arterial pressures. Our data lends support to childhood being considered as a pre-symptomatic phase of pulmonary hypertension; which could be targeted for clinical trials of preventative strategies to prevent adult onset of pulmonary vascular changes associated with higher NT-proBNP and higher TRV. Hydroxyurea therapy is associated in our results from children with SCD with lower NT-proBNP, making it an attractive candidate for a trial in children with SCD to prevent pulmonary hypertension in adulthood. NT-proBNP in childhood SCD remains a marker of left ventricular measures, identifying this additional feature of cardiopulmonary risk.

No relevant conflicts of interest to declare.