Vitamin D and cardiovascular disease: potential role in health disparities

Abstract

Cardiovascular disease (CVD), which includes coronary artery disease and stroke, is the leading cause of mortality in the nation. Excess CVD morbidity and premature mortality in the African American community is one of the most striking examples of racial/ ethnic disparities in health outcomes. African Americans also suffer from increased rates of hypovitaminosis D, which has emerged as an independent risk factor for all-cause and cardiovascular mortality. This overview examines the potential role of hypovitaminosis D as a contributor to racial and ethnic disparities in cardiovascular disease (CVD). We review the epidemiology of vitamin D and CVD in African Americans and the emerging biological roles of vitamin D in key CVD signaling pathways that may contribute to the epidemiological findings and provide the foundation for future therapeutic strategies for reducing health disparities.

Figure 1

Vitamin D is a fat soluble pro-hormone obtained from dietary sources or produced from UV activation in the skin. In the liver vitamin D is converted by the vitamin 1,25D hydroxylase (25-OHase) to 25-D3 (25-hydroxivitamin D3). 25-D3 is biologically inactive and is converted primarily in the kidney by the 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) to its biologically active form 1,25-dihydroxyvitamin D (1,25-D3) or calcitriol.

Figure 2

Direct and indirect effects of vitamin D on Myocardium structure and function.

Figure 3

Vitamin D, lymphocyte, and macrophage involvement in atherosclerosis. Recent studies suggest that lymphocytes and macrophages play the initial role in the generation of atheromas. It is hypothesized that Th1 cells start producing excess IFNγ, which is a potent stimulator of macrophage activity. Activated macrophages secrete IL-1β, IL-6, and TNF-α. These cytokines recruit additional monocytes, increase LDL oxidation, and generate production of MMPs that can destabilize the plaque to cause rupture and thrombosis. In contrast, the TH2 lymphocyte subset is called the antiatherogenic phenotype, because these cells produce IL-10, an anti-inflamatory cytokine that suppresses macrophage activation and Th1 proliferation.

Figure 4

Vitamin D reverts the fibrotic process induced by 5′-azacytidine (AZCT) in mesenchymal multipotent cells. (A) In the absence of vitamin D, an injury triggers the inflammatory cascade, which can lead to a fibrotic process (progressive scarring). (B) 1,25D (the active form of vitamin D) induces a VDR-mediated antifibrotic signaling phenotype in multipotent mesenchymal cells.

Figure 5

Vitamin D and the renin-angiotensin system. Vitamin D or novel VDR activators have emerged as potential independent negative RAS regulators. AT-R = Angiotensin Receptor EP = Endopeptidases EC = Endothelial Cells

Figure 6

Impact of vitamin D receptor activators on cardiovascular endpoints and patient outcome. ANF = Atrial Natriuretic Factor ANP = Atrial Natriuretic Peptide BMP-2 = Bone Morphogenetic Protein-2 BNP = Brain Natriuretic Peptide IL-1β = Interleukin-1beta LV = Left Ventricular MGP = Matrix Gla Protein PAI-1 = Plasminogen Activator Inhibitor-1 TGF-β = Tumour Growth Factor-β TNF-α = Tumour Necrosis Factor-alpha VEGF = Vascular Endothelial Growth Factor