Effect of Vitamin D3 on Vascular Function

Cardiovascular Disease (CVD) and related disorders remain the leading cause of death in the nation. Hypovitaminosis D has been linked not only to several cardiovascular (CV) risk factors including hypertension, diabetes, obesity but also to increased rates of CVD. Thus,hypovitaminosis D presents a common pathway for a select subgroup with a clustering of CV risk factors in a profile that is predominant among ethnic minorities. Indeed, hypovitaminosis D is highly prevalent with an estimated 55% of the US adult population having levels at or below 30 ng/ml, and over 80% of African Americans having suboptimal values. Thus, we propose a twelve week randomized double-blind, placebo controlled pilot trial to assess the effect on vascular function and CV risk factors of 100,000 IU Vitamin D3 given every 4 weeks to overweight, hypertensive African-Americans with hypovitaminosis D. To our knowledge, the proposed project is the first to assess the effect of 'high-dose' Vitamin D3 administration on vascular function.We believe this study is also the first to examine the impact at a molecular level of Vitamin D3 repletion on the key mediators of cardio-metabolic pathways in humans. If our study results support our working hypothesis, we will be positioned to propose a larger scale study to detect a therapeutic effect on more definitive, clinical cardiovascular endpoints across a more diverse population.

Objectives:

• Assess the role of Vitamin D3 treatment on vascular function in high risk subjects.

Primary Outcome: The primary outcome variable is pulse wave velocity (PWV, unit - m/s) for vascular stiffness assessed by radial artery tonometry (via SphygmoCor). The hypothesis for the primary analysis is that a greater increase in the PWV will occur in the Vitamin D3 treatment group than in the placebo group.

Secondary Outcome: Vascular/endothelial function as determined by measuring non-invasive vascular finger plethysmography (via EndoPat). Additional surrogates to be assessed as secondary markers of vascular/endothelial function include sitting and 24 hour ambulatory blood pressure measurements and spot urine protein/creatinine ratio.

Inclusion criteria

• Males or females, 18-70 years of age and self-identified as African-American or Black
• Hypertension
• If a potential study patient is not on treatment, their systolic blood pressure (SBP) must be > 130 mmHg, or diastolic blood pressure (DBP) > 85 mmHg, and SBP must be <160 mmHg and DBP must be < 105 mmHg.
• If a potential study patient is on treatment then the SBP must be <160 mmHg and DBP must be < 105 mmHg
• Screening Vitamin D (D2 and D3 level) between 10 and 25 ng/ml (normal level > 30 ng/ml)
• Body mass index (BMI) > 25 kg/m2

Exclusion criteria

• Poorly controlled high blood pressure (SBP >160 mmHg or DBP > 105 mmHg)
• Diabetes (fasting blood sugar > 125 mg/dl, or HbA1c > 6.5%)
• Screening Vitamin D (D2 and D3 level) < 10 ng/ml or > 25 ng/ml
• Estimated glomerular filtration rate (eGFR) < 45 ml/min
• Evidence of disease resulting in hypercalcemia
• History of kidney stones
• History of drug, alcohol, or illicit substance abuse within the past 6 months
• History of another chronic disease which the investigator feels should preclude the subject from entering the study
• Liver function tests (LFTs) greater than twice the upper limit of normal
• Subjects requiring chronic use of nonsteroidal anti-inflammatory drugs, aspirin, or other drugs that may affect the measurement of reactive oxidative species
• Subjects requiring treatment with other vitamin D preparations containing more than 400 IU of vitamin D
• Subjects requiring chronic use of immunosuppressive therapy or corticosteroids
• Recent (< 6 months) myocardial infarction, stroke, or hospitalization for congestive heart failure
• Allergy/intolerance: known allergy to oral vitamin D or microcrystalline cellulose