Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study

The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated.

In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography.

FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet.

This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.