Abstract
Abstract 2570
Poster Board II-547
Introduction:
Ascorbate is vital for endothelial homeostasis because it is responsible for regeneration of tetrahydrobiopterin (BH4) from dihydrobiopterin (BH2). BH4 is essential for proper electron transport from oxygen to arginine in the synthesis of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS). When BH4 is deficient, eNOS becomes uncoupled from arginine and synthesizes superoxide, producing a vasoconstrictive rather than a vasodilatory phenotype. Low BH4/BH2 ratios are correlated with decreased flow-mediated dilation, a known marker of nitric oxide-dependent endothelial function. Dietary supplementation with ascorbate has been show to acutely improve NO-mediated vasodilation in smokers and patients with coronary artery disease. Since patients with sickle cell disease (SCD) are known to have low levels of NO and impaired vascular reactivity, we examined the correlates of ascorbate deficiency in our chronically transfused SCD patients.
Methods:
We recently studied micronutrient levels in convenience sample of our chronically transfused SCD patients. In that study, 56.7% of SCD patients had ascorbate levels below the lower limit of normal (0.2–1.9 mg/dl). We screened the following parameters as predictors of abnormal ascorbate: LDH, cell-free Hb, total bilirubin, liver iron concentration (LIC), pancreas iron, cardiac iron, ferritin, transferrin saturation, insulin, glucose, brain natriuretic peptide (BNP) and high sensitivity C reactive peptide( hs-CRP). A total of 28 patients (21 females, 7 males), ranging in age from 1.4 to 31.4 years old, who had low ascorbate levels at the time of micronutrient measurements were studied. All patients had chelating drugs held for 24 hours prior to being evaluated.
Results:
None of the above predictors demonstrated significant linear relationships with ascorbate levels. However, low or undetectable ascorbate levels were observed with extremes of a number of parameters including LIC > 30 mg/g, BNP > 40 pg/ml, LDH > 1500 U/Lcell-free hemoglobin > 30 mg/dl,hs-CRP > 7mg/L,and homocysteine > 10 μM/L. LDH, cell-free hemoglobin and hs-CRP exhibited the best specificity for prediction of ascorbate levels and were the only variables to achieve statistical significance by Fischer's Exact test (Table 1). More importantly, there was sufficient independence among these predictors that having and extreme value for one of the above parameters identified 14/15 patients with low ascorbate, with only 1/13 false positives.
Discussion:
These observations suggest that low ascorbate levels in SCD patients result from a combination of chronic inflammation, hemolysis, and hyperhomocysteinemia. Since ascorbate is vital for proper endothelial function, these observations are consistent with known associations of inflammation and hemolysis with sickle vasculopathy. Although hyperhomocysteinemia is a known vascular stressor in other diseases, its contribution in SCD is less clear because treatment with pyridoxine and folate, which reduce homocysteine levels, do not affect other markers of SCD vascular dysfunction. Taken together, these data suggest that comprehensive treatment of sickle vasculopathy may require multiple interventions, including decreasing hemolysis and inflammation as well as B vitamin supplementation. Ascorbate replacement alone is unlikely to be effective without correction of upstream stressors, similar to its use in other complex vascular disorders.
Disclosures:
No relevant conflicts of interest to declare.
Spatiotemporal Dysfunction of the Vascular Permeability Barrier in Transgenic Mice with Sickle Cell Disease