Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease

Abstract

Background: Pulmonary hypertension and left ventricular diastolic dysfunction are complications of sickle cell disease. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well.

Design and methods: Plasma concentrations of three angiogenic markers (fibroblast growth factor, platelet derived growth factor-BB [PDGF-BB], vascular endothelial growth factor [VEGF]) and seven inflammatory markers implicated in pulmonary hypertension in other settings were determined by Bio-Plex suspension array in 237 children and adolescents with sickle cell disease at steady state and 43 controls. Tricuspid regurgitation velocity (which reflects systolic pulmonary artery pressure), mitral valve E/Edti ratio (which reflects left ventricular diastolic dysfunction), and a hemolytic component derived from four markers of hemolysis and hemoglobin oxygen saturation were also determined.

Results: Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P<or=0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi.

Conclusions: Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated.

Figure 1. Bivariate relationships of VEGF with PDGF-BB and interleukin-6 in patients with sickle cell disease.

Figure 2. Adjusted mean values VEGF, PDGF-BB, interleukin-6 and hemolytic component according to tricuspid regurgitation velocity category.

Presented are least square mean (±standard error) values from ANOVA with adjustment for the other variables depicted. TRV indicates tricuspid regurgitation velocity.

Figure 3. Pathway analysis of tricuspid regurgitation velocity in sickle cell disease patients.

The numbers shown are standardized betas. Each of the arrows depicts a significant relationship (P<0.05). According to this analysis, higher hemolytic component was a direct predictor of increasing tricuspid regurgitation velocity and it also was associated with lower hemoglobin concentration and higher interleukin-6 concentration. Lower hemoglobin concentration was not a direct predictor of higher regurgitation velocity, but it was associated with higher VEGF concentration. Higher interleukin-6 concentration was a direct predictor of increasing tricuspid regurgitation velocity and it also was associated with higher VEGF and PDGF-BB concentrations. Higher PDGF-BB concentration was a direct predictor of increasing regurgitation velocity while higher VEGF concentration was a direct predictor of lower regurgitation velocity.