Coronary Artery Disease, Endothelial Dysfunction, Inflammation, Vitamin D Deficiency
Conditions
Keywords
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
Brief summary
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.
Detailed description
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.
Interventions
OTHERSugar pill
Oral capsule, once a week, 12 weeks
DRUGErgocalciferol
Oral capsule, 50,000 units, once a week, 12 weeks
Sponsors
American Heart Association
Jacobi Medical Center
Albert Einstein College of Medicine
Yale University
Montefiore Medical Center
Seth I. Sokol, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function | Baseline and 12 weeks | 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. |
| Inflammation - | Baseline and 12 weeks | Median within subject change in hs-CRP levels between baseline and week 12 in active and placebo groups |
| Inflammation | Baseline to 12 weeks | Median within subject change in interferon-gamma levels between baseline and week 12 in active and placebo groups |
Countries
United States
Participant flow
Recruitment details
Recruitment from October 2008 through December 2010 from the cardiac catheterization laboratories and outpatient clinics of the Jacobi Medical Center and Montefiore Medical Center in the Northeastern section of the Bronx, NY. Additional recruitment occurred at Crystal Run Health in Orange County, NY.
Pre-assignment details
Subjects with ≥ 50% angiographic stenosis of at least 1 coronary artery or documented previous revascularization, were screened for vitamin D deficiency by measurement of serum 25-hydroxyvitamin D (25-vitamin D).Eligible subjects with a 25-vitamin D level \< 20 ng/ml were randomly assigned 1:1 to active or placebo treatment
Participants by arm
| Arm | Count |
|---|---|
| Ergocalciferol 50,000 units of ergocalciferol once a week for 12 weeks | 48 |
| Sugar Pill Matching placebo | 48 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Sugar Pill | Ergocalciferol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 13 Participants | 5 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 43 Participants | 78 Participants |
| Age Continuous | 56.5 years STANDARD_DEVIATION 11.7 | 54.6 years STANDARD_DEVIATION 9.5 | 55.6 years STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 48 participants | 48 participants | 96 participants |
| Sex: Female, Male Female | 15 Participants | 9 Participants | 24 Participants |
| Sex: Female, Male Male | 33 Participants | 39 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 45 | 4 / 45 |
| serious Total, serious adverse events | 10 / 45 | 9 / 45 |
Outcome results
Primary
Endothelial Function
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.
Time frame: Baseline and 12 weeks
Population: Assuming a standard deviation of 0.6 in the change in RH-PAT score from baseline to 12 weeks, we estimated that the study would need a sample size of 45 patients per treatment group to have 80% power at a two tailed alpha=0.05 level to detect a minimum difference in change in RH-PAT score of 0.36 between treatment groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ergocalciferol | Endothelial Function | 0.13 reactive hypermia index |
| Sugar Pill | Endothelial Function | -0.04 reactive hypermia index |
Primary
Inflammation
Median within subject change in interferon-gamma levels between baseline and week 12 in active and placebo groups
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ergocalciferol | Inflammation | -2.29 pg/ml |
| Sugar Pill | Inflammation | -2.8 pg/ml |
Primary
Inflammation
Median within subject change in cxcl-10 .levels between baseline and week 12 in active and placebo groups
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ergocalciferol | Inflammation | -7.45 pg/ml |
| Sugar Pill | Inflammation | -2.72 pg/ml |
Primary
Inflammation
Median within subject change in IL-12 levels between baseline and week 12 in active and placebo groups
Time frame: Baseline to week 12
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ergocalciferol | Inflammation | -10.96 pg/ml |
| Sugar Pill | Inflammation | -2.33 pg/ml |
Primary
Inflammation -
Median within subject change in hs-CRP levels between baseline and week 12 in active and placebo groups
Time frame: Baseline and 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ergocalciferol | Inflammation - | -0.17 mg/dl |
| Sugar Pill | Inflammation - | -0.05 mg/dl |