Vitamin D and Cardiovascular Disease: Is the Evidence Solid?
The following are 10 points to remember about vitamin D and cardiovascular disease (CVD):
1. Vitamin D is a group of fat-soluble molecules similar to steroids. Several forms of vitamin D exist; cholecalciferol (or vitamin D3) is synthesized in response to ultraviolet (UV) irradiation of the skin. A second form of vitamin D, ergocalciferol (or vitamin D2), is produced by irradiation of ergosterol, a membrane sterol found in the Ergot fungus. Dietary sources of vitamin D include fish oils (D3), egg yolks (D3), and mushrooms (D2), as well as artificially fortified cereals and dairy products (D2 or D3). Following chronic, severe vitamin D deficiency, frank hypocalcemia ensues, but patients rarely present with acute symptoms (e.g., tingling or tetany), as this usually develops over an extended period of time. Rather, the most common presenting symptoms of vitamin D deficiency include vague, local, or diffuse musculoskeletal aches and pains.
2. Biologic effects of vitamin D result largely from its binding to the nuclear steroid hormone vitamin D receptor (VDR), which is found in virtually all tissues and is also closely related to the thyroid, retinoid, and peroxisome proliferator-activator receptors. Although all vitamin D metabolites bind the VDR, most biological effects are likely mediated by calcitriol because of its greater receptor affinity. Both VDR and 1-a-hydroxylase that convert vitamin D into the hormonal 1, 25-OH D2 (calcitriol) form are actively expressed in CV tissues, including cardiomyocytes, endothelial, and vascular smooth muscle cells.
3. Several areas of research suggest an active role for vitamin D in the pathogenesis of CV disorders and parallel results from clinical investigations. Endothelial cells express VDR and its activation affects the development of immature cells, partly by modulating response elements in the vascular endothelial growth factor promoter. While VDR is up-regulated under stress in endothelial cells, active vitamin D analogues decrease cytokine-induced expression of adhesion molecules and protect against advanced glycation products. Vitamin D metabolites reduced endothelium-dependent vascular smooth muscle contractions and vascular tone in hypertensive models, an effect mediated by affecting calcium influx across endothelial cells. Renin expression was shown to be highly deregulated in VDR knockout murine models, despite maintenance of a normal electrolyte balance.
4. Vitamin D and blood pressure have been studied extensively. Studies in normotensive and hypertensive subjects reveal an inverse relationship between vitamin D metabolites and plasma renin activity, regardless of baseline renin levels or salt intake. Dietary salt loading results in blood pressure increases that are worse with vitamin deficiency, and are positively correlated with calcitriol synthesis. Cholecalciferol therapy (15,000 IU/day for 1 month) in obese, hypertensive patients increased renal plasma flow (RPF) and decreased mean arterial pressure. Moreover, infusion of angiotensin II following cholecalciferol therapy resulted in a greater RPF decline and higher aldosterone secretion when compared with pretreatment infusions.
5. The third National Health and Nutrition Examination Survey (NHANES III) looked at serum 25-OH D in relation to CVD risk factors in over 13,000 US adults. After multivariable adjustment, those with 25-OH D levels in the lowest quartile had a significantly higher prevalence of hypertension compared with those in the highest quartile, and sufficient levels attenuated the expected age-related increases in blood pressure. Other population studies, including the 1958 British Birth Cohort and the German National Health Survey and Examination, confirm this inverse relationship. In two prospective cohorts of health care professionals, the risk of incident hypertension was increased by three-fold in those with 25-OH D, 15 ng/ml compared with those with levels 0.30 ng/ml. In a study that estimated 25-OH D levels based on dietary surveys in over 110,000 health care professionals, those with low ‘‘predicted’’ 25-OH D levels had a higher incidence of hypertension during nearly 16 years of follow-up.
6. Trials reporting these measurements have either shown no blood pressure changes or small reductions in blood pressure; however, these were limited by small and heterogeneous study samples, widely variable dosing strategies, and a short duration of follow-up. Several meta-analyses and systematic reviews have also arrived at conflicting conclusions; while a net significant hypotensive effect of vitamin D replacement was reported by some, others found either no change or only reductions in systolic blood pressure, which may be apparent in specific subgroups such as those with vitamin D deficiency at baseline.
7. Vitamin D deficiency is associated with disorders of insulin synthesis, secretion, and sensitivity. Vitamin D may influence glycemic control via modulation of pancreatic renin-angiotensin system activity and regulation of calcium ion traffic across b-cells that directly affect insulin synthesis and secretion. Vitamin D deficiency results in aberrant immune responses that precipitate an inflammatory milieu and subsequent insulin resistance. Observational, case-control, and prospective evidence strongly suggests that supplementing infants with vitamin D may significantly reduce the future incidence of type 1 diabetes. The evidence for type 2 diabetes is weaker. Recent results from the Women’s Health Initiative demonstrated no primary prevention benefit of vitamin therapy. Several smaller and nonrandomized clinical trials show promising improvements in glycemic control with vitamin D therapy. However, a recent Endocrine Society statement emphasized the lack of solid evidence supporting benefits of vitamin therapy in diabetes mellitus.
8. Vitamin D deficiency has been implicated as an independent risk factor for incident CV events and all-cause mortality in several large prospective studies. A recent meta-analysis of prospective studies that assessed the relationship between vitamin D status and CVD risk from 1966 to 2012, revealed an inverse relationship between levels of 25-OH D and future risk of CVD endpoints, including coronary heart disease, stroke, and total CVD mortality. In contrast, the Women’s Health Initiative observed after 7 years of follow-up that rates of incident CVD events did not differ between the treatment and placebo groups. An ongoing trial will determine the effects of cholecalciferol (2000 IU/day), with or without omega-3 fatty acids supplementation, on the incidence of CVD, stroke, and cancer in 20,000 healthy, middle-aged US adults. The mean treatment period in the VITAL (VITamin D and Omega-3 triAL) study is projected at 5 years, with a similar follow-up period. Baseline 25-OH D levels will be measured in the majority of subjects at baseline, allowing for subgroup analysis in deficient subjects. This and other studies will provide much needed evidence for determining the relationship between vitamin D and CVD.
9. In healthy individuals, prevention of vitamin D deficiency can be achieved by a combination of casual sunlight exposure, consumption of fatty fish or fish oils, in addition to fortified foods and/or supplements. While the current recommended dietary allowance of vitamin D in the United States ranges between 400 and 800 IU/day, as much as 2000 IU/day may be needed to maintain sufficient 25-OH D levels (≥30 ng/ml) in at-risk adults. Most diets generally provide less than the recommended daily allowance of vitamin D; thus, pharmacological supplementation with vitamin D2 or D3 is often required.
10. For treatment of documented vitamin D deficiency, a recent practice guideline statement by the Endocrine Society recommends oral administration of 50,000 IU per week of either vitamin D2 or D3 for 8 weeks, followed by daily maintenance doses between 1500 and 2000 IU. Both loading and maintenance doses may be significantly higher in those with increasing risks for the development or recurrence of vitamin D deficiency. Concurrent calcium supplementation is a key component of effective therapy. In addition to maintaining sufficient serum 25-OH D levels, patients with end-stage renal and/or hepatic disease impairing vitamin D activation and resulting in hypocalcemia, in addition to those with secondary hyperparathyroidism or hypoparathyroidism require activated vitamin D therapy (e.g., 1, 25-OH D2; 0.25–0.5 mg/day).
As this excellent review points out, vitamin D deficiency is a highly prevalent condition. Given the evidence to date from experimental, cross-sectional, and prospective studies, the need for randomized trials of vitamin D therapy with CVD endpoints is warranted. Thus, we await the findings of the VITAL study.
Keywords: Transcription Factors, Peroxisome Proliferator-Activated Receptors, Sodium Chloride, Dietary, Vitamins, Calcium, Dietary, Vitamin D Deficiency, Dairy Products, Cardiovascular Diseases, Sterols, Calcitriol, Obesity, Hypocalcemia, Receptors, Calcitriol, Muscle, Smooth, Vascular, Myocytes, Cardiac, Hypertension, Claviceps, Vitamin D, Cholecalciferol, Ergocalciferols
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