Exploring N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) in Children with Sickle Cell Disease (SCD) and Vaso-Occlusive Pain Episodes (VOE)

Background: Cardiovascular dysfunction is the leading cause of mortality in adults with SCD. High-risk groups are identified by elevated NT-proBNP ≥160 pg/ml, increased pulmonary artery pressure by tricuspid regurgitation velocity (TRV) on Doppler echocardiography, and chronic kidney disease. TRV, a non-invasive surrogate for pulmonary hypertension risk, and NT-proBNP, a biomarker of cardiac stress and heart failure signaling a strained heart unable to pump blood, both predict early mortality in adults with SCD. While well-documented in adults, cardiovascular risk in children with SCD is less explored. Onalo and colleagues found elevated TRV in over 60% of children presenting with SCD-VOE in Nigeria, along with abnormal NT-proBNP levels. They also reported improvements in these markers with oral arginine supplementation compared to placebo, highlighting its potential therapeutic benefit. Arginine is the obligate substrate for nitric oxide (NO) production, which plays a pivotal role in vascular function. Evaluating cardiac dysfunction and the response to arginine in children with SCD is key for early detection and management of cardiac complications.

Objective: To assess NT-proBNP levels in hospitalized children with SCD-VOE and its association with chest pain and the arginine-NO pathway.

Methods: This is a secondary analysis of samples collected as part of clinical trials evaluating the impact of L-arginine therapy in children with SCD-VOE. Samples were part of a pharmacokinetics/pharmacodynamics and a phase II randomized control trial of intravenous (IV) arginine in children 3-21 years old with SCD hospitalized for pain. NT-proBNP levels were analyzed using enzyme linked immunosorbent assay (ELISA) at ED presentation and at discharge from the hospital. NT-proBNP ≥125pg/ml was considered elevated based on prior studies. Plasma global arginine bioavailability ratio (GABR;arginine/[ornithine+citrulline]) was determined via mass spectrometry.

Results: A total of 105 children (12.7±3.7 years, 48% male, 66% hemoglobin SS disease, and 70% on Hydroxyurea) were included. NT-proBNP at ED presentation was 123±217 pg/ml vs 116±211 pg/ml at discharge (p=0.69). In this VOE cohort, 28% had NT-proBNP ≥125 pg/ml and 23% had values ≥160 pg/ml; 20% remained ≥125 pg/ml and 19% remained ≥160 pg/ml at discharge. There were no significant differences in patient demographics, blood pressure, laboratory assessments or clinical characteristics including chest pain and acute chest syndrome (ACS) in patients with elevated NT-proBNP vs those with values <125 pg/ml at presentation. Children with NT-proBNP ≥125 had a higher frequency of requiring blood transfusion during their inpatient stay (29% vs 18%) compared to children with levels <125 pg/ml, that was not statistically significant. There were no statistically significant differences in absolute or % change between presentation and discharge NT-proBNP levels in patients who received arginine compared to placebo. However, within the 28 patients with elevated NT-proBNP, there was a non-significant trend towards greater improvement in NT-proBNP by discharge in patients with the greatest increase in their arginine concentration (r=-0.35, p=0.11). NT-proBNP correlated positively with GABR at ED presentation (r=0.22, p=0.02) and negatively with systolic blood pressure (r=-0.22, p=0.03). In the patients with highest NT-proBNP ≥160 pg/ml (n=24) at presentation, NT-proBNP correlated with retic count (r=0.45, p=0.03) and NO metabolites (NO_x; r=0.49, p=0.02).

Conclusion: In this cohort of patients with SCD-VOE, more than one in four children with SCD-VOE had elevated NT-proBNP indicating notable cardiac stress during acute SCD-VOE not associated with chest pain or ACS that is currently unaddressed. The significant positive correlation between NT-proBNP and plasma GABR in our young cohort differs from reports in adults with SCD at risk for pulmonary hypertension, however in the presence of normal kidney function, this may reflect an increase in arginine synthesis as a compensatory mechanism to increase the production of nitric oxide and maintain vascular health. While the clinical consequences of this observation remain to be determined, these findings highlight that children with SCD experience cardiac stress during VOE that doesn’t resolve by discharge, warranting further investigation and cardiovascular monitoring.