Vitamin D Repletion in Coronary Artery Disease

The Effects of Vitamin D Repletion on Endothelial Function and Inflammation in Patients With Coronary Artery Disease

American Heart Association, Jacobi Medical Center, Albert Einstein College of Medicine, Yale University, Montefiore Medical Center

Vitamin D (Vit D) status is an emerging risk marker of great interest in cardiovascular disease (CVD). Lower serum levels of Vit D are associated with both cardiac risk factors and prevalent cardiovascular disease. Vit D insufficiency remains very prevalent in free living populations in the United States especially in urban, and multi-ethnic low income Northern cities.To date, prospective randomized trials using Vit D supplementation to modify CVD risk and evaluate outcomes have not been performed. The investigators propose a double-blind, randomized wait-list control trial in subjects with Coronary Artery Disease (CAD) and Vit D deficiency with two specific aims. Specific aim 1 is to measure endothelial function using reactive hyperemia peripheral arterial tonometry (RH-PAT) before and after treatment with Vit D replacement therapy. Specific Aim 2 is to measure levels of inflammation before and after treatment with Vit D replacement therapy. These aims will test the hypotheses that Vit D repletion will improve endothelial function and reduce the levels of detectable inflammation in the plasma of these subjects.

100 subjects with angiographically documented CAD and Vit D deficiency will be randomized to 50,000 IU oral ergocalciferol (active treatment group) or placebo (delayed intervention group) once a week for 12 weeks. The investigators will measure endothelial function at randomization and week 12 using RH-PAT and serologically measured adhesion molecules (s-VCAM, s-ICAM, soluble e-selectin). Changes in levels of plasma cytokines and chemokines representing a T-cell activation pathway (IL-12, IFN-g and CXCL-10 - "IFN-g axis") the investigators have linked to coronary atherogenesis (independent of CRP) and poor CV outcomes, will be measured over the 12 week study period. Given published evidence showing that Vit D can influence this T- cell pathway, specific aim 2 will add mechanistic insights to this proposal. High sensitivity C-reactive protein (hs-CRP) will be measured as it is a well established traditional marker of inflammation in CAD and has also been linked to Vit D status.

vitamin D,, vitamin D deficiency, coronary artery disease, ergocalciferol, endothelial function, adhesion molecules, inflammation, IL-12, interferon-gamma, CXCL-10, reactive hyperemia peripheral arterial tonometry, endothelial dysfunction, cytokines, chemokines

Endothelial function was measured using peripheral arterial tonometry expressed as the reactive hyperemia index. The index is derived from the ratio of the post-to-pre occlusion peripheral arterial tonometry signal amplitude of the tested arm, divided by the post -to-pre occlusion ratio of the control arm. Median within subject change in endothelial function as measured by reactive hyperemia peripheral arterial tonometry index in each group is presented.

Median within subject change in hs-CRP levels between baseline and week 12 in active and placebo groups

Median within subject change in interferon-gamma levels between baseline and week 12 in active and placebo groups

Median within subject change in cxcl-10 .levels between baseline and week 12 in active and placebo groups

Median within subject change in IL-12 levels between baseline and week 12 in active and placebo groups

Inclusion Criteria: Male and nonpregnant females greater than 18 years of age ≥ 50% angiographic stenosis of at least 1 coronary artery or documented previous revascularization Serum 25-hydroxyvitamin D < 20 ng/ml Exclusion Criteria: confinement to a nursing facility, institution or home GFR < 60 ml/min (by MDRD equation) presence of liver disease hypercalcemia NYHA class III or IV heart failure cardiogenic shock at time of presentation current planned or emergent CABG prior gastric or small bowel surgery pancreatitis malabsorption inflammatory bowel disease autoimmune disease active malignancy current use of > 800 IU/day of vitamin D Current use of dilantin, phenobarbitol, immunosuppressant, or immunostimulant therapy

Sokol SI, Srinivas V, Crandall JP, Kim M, Tellides G, Lebastchi AH, Yu Y, Gupta AK, Alderman MH. The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease. Vasc Med. 2012 Dec;17(6):394-404. doi: 10.1177/1358863X12466709. Erratum In: Vasc Med. 2013 Feb;18(1):51. Lebastchi, Amir [corrected to Lebastchi, Amir H].