Vitamin D and Cardiovascular Disease: An Updated Narrative Review

Abstract

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

Keywords: atherosclerosis; calcium; cardiovascular; chronic kidney disease; epidemiology; heart; mortality; vitamin D; vitamin D receptor.

Figure 1

Major metabolic pathways of vitamin D in the human body. Previtamin D₃ is produced in the skin by solar UVB radiation (290–315 nm) from 7-dehydrocholesterol and isomerized by a thermal reaction into vitamin D₃ or reversely metabolized to vitamin D-inactive substances such as lumisterol and tachysterol. Vitamin D₃ (cholecalciferol) or vitamin D₂ (ergocalciferol) can also be ingested orally from native foods (fish, dairy, mushrooms), vitamin D-fortified foods, or supplements. Both cutaneously synthesized and orally ingested vitamin D are metabolized by hepatic 25-hydoxylases into 25-hydroxyvitamin D (25(OH)D), the main 25-hydroxylase being a microsomal enzyme (gene CYP2R1). A renal 1α-hydroxylation of 25(OH)D results in the formation of the physiologically active vitamin D hormone, 1,25-dihydroxyvitamin D (1,25(OH)₂D). After release into circulation, 1,25(OH)₂D can be taken up by various target tissues and exerts its effects by vitamin D receptor-mediated processes. Vitamin D binding protein (DBP) is the major transport protein for vitamin D and its metabolites. Inactivation of vitamin D is induced by 24-hydroxylase. Anabolic molecules are highlighted in red font, and catabolic molecules in blue font.

Figure 2

Proposed effects of vitamin D signaling in cardiomyocytes by rapid non-genomic and genomic effects via membrane-bound and cytosolic vitamin D receptors, respectively. Cytosolic binding of 1,25(OH)₂D leads to hetero-dimerization of the vitamin D receptor (black rectangle) with the retinoid X receptor (white rectangle), and ultimately to translocation of this complex into the nucleus, where it binds to vitamin D response elements (orange rectangle). Additionally, 1,25(OH)₂D may be produced locally by the internalization of 25(OH)D via diffusion or a vitamin D receptor (VDR)-independent, megalin–cubilin-mediated process (hypothetical). Non-genomic effects of 1,25(OH)₂D result in the rapid release of ionized calcium from intracellular stores, whereas genomic effects result in calcium-binding protein (CaBP) synthesis. Locally produced 1,25(OH)₂D may also exhibit paracrine actions. Yellow circle, 25(OH)D; blue circle, 1,25(OH)₂D.

Figure 3

Suggested effect of vitamin D deficiency on the risk of cardiovascular disease. Notes: 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; RAAS, renin–angiotensin–aldosterone system. White arrows indicate suppression or activation, where appropriate.