Vitamin D deficiency is emerging as an independent risk factor for subclinical vascular dysfunction, metabolic syndrome, and later cardiovascular disease (CVD) in children. Obese children (BMI 95th percentile) and overweight children (BMI 85th-94th percentile) exhibit CVD risk factors and a relatively high prevalence of hypovitaminosis D, and their atherogenic risks track from childhood to adulthood. Therefore, vitamin D replenishment in vitamin D-deficient obese and overweight children has the potential to improve their cardiometabolic health and reduce their risk of CVD later in life. In this proposa, we will test the central hypothesis that enhancement of vitamin D status in such children will improve their vascular health and their CVD and metabolic syndrome risk profile. Our primary objective is to determine, in obese and overweight children aged 10 to 18 years with vitamin D deficiency (defined as serum 25-hydroxyvitamin D <20 ng/mL), the efficacy of enhanced vitamin D3 supplementation in improving vascular endothelial function, arterial stiffness, insulin sensitivity, and metabolic syndrome risk status;and to assess whether these effects are dose- dependent. As a secondary objective, we will examine the vitamin D supplementation-induced effect on adipokines and inflammatory markers relevant to CVD risk. In a double-masked, controlled trial, we will randomize 252 eligible children to receive either 600 IU (conventional supplementation), or 1000 IU or 2000 IU (enhanced supplementation) of vitamin D3 daily for 6 months. Study outcome measures, assessed at baseline, 3 and 6 months, will include (1) brachial artery flow-mediated dilation (FMD) as a measure of vascular endothelial function;(2) pulse wave velocity as a measure of arterial stiffness;(3) surrogate estimates of insulin sensitivity (fasting glucose/fasting insulin ratio or Homeostasis Model of Assessment - Insulin Resistance [HOMA-IR]);(4) metabolic syndrome risk factors (blood pressure, waist circumference, HDL cholesterol, triglycerides, and fasting blood glucose);(5) inflammatory markers (e.g. CRP, IL-6, TNF-alpha);(6) adipokines (leptin and adiponectin);and (7) nitric oxide metabolites. Brachial FMD at 6 months will be the primary outcome measure. We will assess the safety of enhanced vitamin D3 supplementation by measuring serum calcium at the 3- and 6-month-follow-ups. Total body fat will be ascertained by Dual-energy X-ray Absorptiometry to examine the confounding effects of adiposity on outcome measures. Innovative aspects of this proposal include (1) characterizing the temporal changes in vascular health and cardiometabolic risk outcomes in response to enhancement of vitamin D status in a population of children at high-risk for vascular dysfunction and cardiometabolic risks;and (2) delineating the vitamin D effects on inflammatory markers and adipokines relevant to CVD risk. Establishing the protective benefits of vitamin D would have major public health importance, since optimization of vitamin D status would be an inexpensive primary prevention strategy for improving cardiometabolic health during childhood and for reducing CVD risk during adulthood.
This proposal is relevant to public health because demonstrating the cardiovascular and metabolic benefits of vitamin D status enhancement could have significant public health impact - as vitamin D status optimization could be implemented as an inexpensive primary prevention strategy for improving cardiovascular health.