Steroid Hormone Vitamin D: Implications for Cardiovascular Disease

Abstract

Understanding of vitamin D physiology is important because about half of the population is being diagnosed with deficiency and treated with supplements. Clinical guidelines were developed based on observational studies showing an association between low serum levels and increased cardiovascular risk. However, new randomized controlled trials have failed to confirm any cardiovascular benefit from supplementation in the general population. A major concern is that excess vitamin D is known to cause calcific vasculopathy and valvulopathy in animal models. For decades, administration of vitamin D has been used in rodents as a reliable experimental model of vascular calcification. Technically, vitamin D is a misnomer. It is not a true vitamin because it can be synthesized endogenously through ultraviolet exposure of the skin. It is a steroid hormone that comes in 3 forms that are sequential metabolites produced by hydroxylases. As a fat-soluble hormone, the vitamin D-hormone metabolites must have special mechanisms for delivery in the aqueous bloodstream. Importantly, endogenously synthesized forms are carried by a binding protein, whereas dietary forms are carried within lipoprotein particles. This may result in distinct biodistributions for sunlight-derived versus supplement-derived vitamin D hormones. Because the cardiovascular effects of vitamin D hormones are not straightforward, both toxic and beneficial effects may result from current recommendations.

Keywords: cardiovascular diseases; cholecalciferol; lipoproteins; vascular calcification; vitamin D.

Figure 1.. Vitamin D-hormone metabolism, carriers and distribution.

Due to its lipophilic nature, endogenously produced D3 is carried in the aqueous environment of blood by D-binding protein (DBP), whereas exogenous (dietary and supplemental) D3 and D2, absorbed from the intestines, are transported within chylomicrons, which are further processed to lipoproteins (e.g., VLDL and LDL), many of which continue to carry the exogenous D. The conventional sites of vitamin D-hormone metabolism are the liver and proximal tubules of the kidney, where hydroxylases convert it to its active form. But hydroxylase activity is also found in parenchymal and immune cells, including VSMC and monocytes, in other tissues. This raises the potential for accumulation of vitamin D-hormone within LDL in the subendothelial space, where it may undergo activation in atherosclerotic plaque and possibly influence ectopic differentiation and calcification. Abbreviations: LDL, low-density lipoprotein; VLDL, very low-density lipoprotein; VSMC, vascular smooth muscle cells; UV, ultraviolet.

Figure 2.

U-shape of the multivariable-adjusted relation between baseline serum 25(OH)D₃ levels and incident cardiovascular events reported by Wang et al. (from Circulation 117:503–511, with permission [pending]). Solid lines show the estimated relation of adjusted hazard ratios (with 95% confidence limits) and 25(OH)D₃ levels when time to cardiovascular event is modeled as a function of penalized regression splines of 25(OH)D₃ levels with adjustment for all other covariates. Hatched lines on the horizontal axis represent cardiovascular events (top axis) and individuals (bottom axis). This relationship suggests increased cardiovascular risk at both low and high levels.