Abstract
BackgroundPulmonary 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 MethodsPlasma 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.ResultsPlasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P≤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.ConclusionsCirculating 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.
Highlights
Pulmonary hypertension and left ventricular diastolic dysfunction are found in up to 32% and 18% of adults with sickle cell disease, respectively, and are associated with reduced exercise tolerance and high mortality [1,2,3]
Greater values for platelet-derived growth factor (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 vascular endothelial growth factor (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
Summary
Pulmonary hypertension and left ventricular diastolic dysfunction are found in up to 32% and 18% of adults with sickle cell disease, respectively, and are associated with reduced exercise tolerance and high mortality [1,2,3]. Elevated estimated systolic pulmonary artery pressures [4,5,6] and left ventricular stiffness [7] are recognized to develop in children with sickle cell disease but the clinical importance is not clear [7,8]. A functional deficit was not found in the children with elevated tricuspid regurgitation velocity as measured by the six-minute walk test, there was a statistically significant decrease in oxygenation during the test. This observation indicates that the children with elevation of tricuspid regurgitation velocity are biologically different with respect to pulmonary vascular function compared to those with lower velocities. Pulmonary hypertension is associated with hemolysis and hypoxia, but other unidentified factors are likely involved in pathogenesis as well
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