Steroid hormone vitamin D: Implications for cardiovascular disease Circulation research. 2018; 122:

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1 Steroid hormone vitamin D: Implications for cardiovascular disease Circulation research. 2018; 122: November 20, 2010: Canadian and US government request the Institute of Medicine to provide a report on conflicting information on the conflicting information surrounding vitamin D Over 1000 studies and reports + testimony were considered regarding Vitamin D and bone and CV health, cancer, diabetes, inflammation, neuropsychological function, physical performance, preeclampsia, and reproduction Conclusion: o A MAJORITY of Americans and Canadians are receiving adequate amounts of both calcium and vitamin D o Too much of either of these nutrients may be harmful

2 o Most info on the health benefits were from studies with mixed/inconclusive results (i.e. unreliable) o There is currently NO EVIDENCE from randomized clinical trials showing cardiovascular benefits of vitamin D supplementation Physicians widely recommend routine vitamin D testing and supplementation Forms of vitamin D Vitamin D is not a true vitamin (the human body can synthesize its own D (cholecalciferol) Formal definition/nomenclature: steroid or secosteroid (9,10-secocholesta-5,8,10(19)- trien-3beta-ol) SIX different steroid hormones go by the name vitamin D o Cholecalciferol (D3) o Calcidiol (this is used to diagnose deficiency!) o Calcitriol (active form!) o Ergocalciferol (plant derived form) Sources of vitamin D Exposure to UV rays (sunlight) Certain foods (liver, cheese, egg yolks, salmon, oysters) Dietary supplements Endogenous (synthesized in the body) vitamin D transport and activation UV light exposure within the skin results in synthesis of D3 from 7-dehydrocholesterol D3 is carried by vitamin D binding protein (DBP) in the blood 15 minutes per week (in light skinned individuals) may produce tens of thousands of units of D3! Endogenous production has been the main source of D3 for most humans for centuries Exogenous sources and delivery Diet (eggs, fish, liver, marine mammal fat) Supplements 1 cup of milk provides ~100 IU of vitamin D 1 serving of salmon contains ~400 IU of D3 Vitamin D supplements typically contain the plant derived form (ergocalciferol; D2) MAIN DIFFERENCE between dietary/supplemental sources vs. endogenous is the transport o Oral vitamin D3 is transported via chylomicrons from the intestine into the circulation

3 o ~35% of this is carried in lipoproteins (HDL/LDL) rather than vitamin D binding protein Activation In the liver, both endogenous/exogenous sources of D3 converted to 25(OH)D3 this is the metabolite measured to assess vitamin D levels 25(OH)D3 is further converted in the capillaries in the kidney to 1,25(OH)D3 (ACTIVE FORM) The enzyme responsible for this conversion is also found in vascular cells and monocytes Guidelines for assessment and supplementation Conservative definitions (refers to levels of 25(OH)D) o < 20 ng/ml = deficiency o ng/ml = insufficiency Institute of medicine values o <12 ng/ml = deficiency o > 50 ng/ml = excess Recommendation for individuals 1-70 years of age are 600 IU daily For individuals 71 and older, 800 IU/day is recommended This can ALL be obtained through ordinary sun exposure Safe upper limit is 4000 IU/day (risk of toxicity increases above this level) **Recommendations may give a false impression that a day without sunshine requires a dose of supplement We may not require daily replacement of Vitamin D Half life of vitamin D is 2 weeks 3 months, and is stored in adipose (fat) tissue and liver Stores vitamin D is available for release into body Additionally, vitamin D recycles in circulation Hormones may not require daily, weekly, or even monthly replenishment Summer sun exposure may provide enough for the winter! **It may be more correct to refer to monthly requirements for vitamin D, which may vary by age and season (i.e. summer or winter) Personalized approach Supplementation should be personalized because body composition, environment, and differences in DBP and vitamin D receptor (VDR) influence levels High body fat increases availability of fat-soluble vitamin D (storage in adipose tissue) High skeletal muscle content also increases uptake/retention of vitamin D

4 Elderly may have lower levels (less outdoor activity/sun exposure) Vitamin D and cardiovascular health Evidence for a protection against CVD all comes from observational studies (inferred) Supplementation became a guideline based on these studies w/out adequate control trials U shaped relationship for vitamin D levels and CVD risk (*Framingham Heart Study) Minimum CVD risk shows to be the least at <20 ng/ml (the level considered deficient in many recommendations) Deficiency and excess may promote CVD risk Few RCT s have shown a benefit to supplementation Individuals with chronic kidney disease (CKD) shown to benefit (they have a reduced capacity to produce active vitamin D) Accumulation and Activation of LDL-associated vitamin D in the arteries In atherosclerosis, vitamin D from the diet may accompany LDL into the artery wall where lesions form Active vitamin D may be produced locally in the arteries and possibly plaque

5 Effects of vitamin D in the vasculature Vitamin D in the artery wall may accelerate atherosclerosis and calcification Stimulation of smooth muscle cell proliferation, growth factor expression Increased bone density (benefit) may come at the cost of increased CVD risk o Calcification of vasculature High dose vitamin D used experimentally have been shown to induce calcification of the aorta Toxicity and benefits Overuse may result in hypercalcemia (increased blood calcium) o Fatigue o Weakness o Altered mental status o Irritability o Coma o GI upset o Nausea o Vomiting o Constipation o Polyuria o Polydipsia o Kidney injury, kidney stones Daily intake up to 4000 IU deemed upper limit of safety Universal upper limit may not necessarily be accurate (individual variation) For health reasons, many Americans pay extra for bread free of preservatives (such as antioxidants) and meats that are free of steroid hormones. In the next aisle of the store, they buy bottles of antioxidant and preservatives and steroid hormones in pill form, labeled as nutritional supplements, including D3 hormones.