Grant Abstract: Vitamin D and Vascular Function in Obese Children

Grant Number: 5R01HL112985-03
PI Name: Rajakumar
Project Title: Vitamin D and Vascular Function in Obese Children

Abstract: 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 proposal, 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-a); (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.
The above referenced NHLBI-funded R01 clinical trial is ongoing, and a total of 117 children have been randomized so far. Blood samples collected in PAXgene RNA tubes in the randomized children have been banked for secondary analyses. We are now proposing an ancillary study to examine the gene expression profile in a subset of subjects at baseline and after 3 months of vitamin D supplementation.

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