The Role of the Intraplaque Vitamin D System in Atherogenesis

Table 4

Interventional studies investigating the relationship between vitamin D deficiency and atherosclerosis.

Author	Year	Study design; (sample size)	Country; (ethnicity); Age	Intervention; (follow-up)	Findings
Coronary artery calcification
Manson et al. [72]	2010	Prospective randomized double-blind placebo-controlled trial; (750 postmenopausal women from the WHI-CACS)	U.S.; (Caucasian, Africa Americans, Hispanic, and Asian); 50–59 years	Calcium 500 mg ×2/day or calcium 500 mg + 25(OH)D 5 𝜇g twice daily or placebo; (7 years)	After follow-up, CAC measurements were similar in both groups also at multivariate analysis.
Raggi et al. [73]	2011	Prospective randomized double-blind controlled trial; (360 patients in haemodialysis from the ADVANCE trial)	U.S.; (Caucasian, Africa Americans, Hispanic, and Asian); Mean 61 years	Cinecalcet (30–180 mg/day) + active vitamin D or vitamin D alone; (20 weeks for titration and after 32 weeks of follow-up)	After 52 weeks, treatment with cinecalcet significantly slowed vascular calcification (𝑃=0.009)
Endothelial dysfunction
Sudgen et al. [74]	2008	Prospective randomized double-blind controlled trial; (34 TDM2 patients)	U.K.; (not provided); Mean 64 years	Ergocalciferol loading dose 100.000 U or placebo; (8 weeks)	Vitamin D supplementation improves FMD (𝑃=0.04), in addition to reducing systolic BP (𝑃=0.001) and increasing serum levels of 25(OH)D (𝑃=0.02)
Tarcin et al. [75]	2009	Longitudinal interventional; (23 subjects with 25(OH)D < 75 nmol/L)	Turkey; (not provided); Stratified	Ergocalciferol loading dose 300.000 U/monthly ×3 doses; (3 months)	Treatment significantly improved FMD (𝑃=0.002)
Witham et al. [76]	2010	Prospective randomized double-blind placebo-controlled trial; (61 TDM2 patients)	U.K.; (not provided); Stratified	Ergocalciferol loading dose 100.000 U or 200.000 U or placebo; (8 and 16 weeks)	Supplementation significantly raised serum 25(OH)D levels but failed to improve FMD.
Shab-Bidar et al. [77]	2011	Prospective randomized double-blind controlled trial; (100 TDM2 patients)	Iran; (not provided); 29–67 years	Fortified diet with Ca^++ 170 mg/or Ca^++ 170 mg + 25(OH)D 12.5 𝜇g twice a day; (12 weeks)	Supplementation improved endothelial function evaluated through adjusted endothelin-1 (𝑃=0.009) and MMP-9 (𝑃=0.005) assay.
Witham et al. [78]	2012	Prospective randomized double-blind placebo-controlled trial; (34 TDM2 patients)	U.K.; (not provided); Stratified	Ergocalciferol loading dose 100.000 or placebo; (8 and 16 weeks)	Supplementation significantly improves FMD at 8 weeks (𝑃=0.007) but not at 16 weeks.
Stricker et al. [79]	2012	Prospective randomized double-blind placebo-controlled trial; (76 patients with PAD)	Swiss; (Caucasian); Stratified	Ergocalciferol loading dose 100.000 or placebo; (1 months)	Supplementation significantly raised serum 25(OH)D levels but failed to improve arterial stiffness.
Yiu et al. [80]	2013	Prospective randomized double-blind placebo-controlled trial; (100 TDM2 patients with 25(OH)D < 75 nmol/L)	Hong Kong; (not provided); Mean 65 years	25(OH)D 125 μg/day or placebo; (12 weeks)	Supplementation significantly raised serum 25(OH)D and Ca^++ concentration in addition to decreasing PTH. However, the study failed to improve vascular function assessed by FMD circulating EPCs and PWV.

WHI-CACS: Women’s Health Initiative Coronary Artery Calcium Study; CAC: coronary artery calcification; ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis; TDM2: type 2 diabetes mellitus; FMD: flow mediated dilatation; PAD: peripheral artery disease; EPCs: endothelial progenitor cells; and PWV: pulse wave velocity.