Vitamin D and Cardiovascular Diseases: From Physiology to Pathophysiology and Outcomes

Abstract

Vitamin D is rightly recognized as an essential key factor in the regulation of calcium and phosphate homeostasis, affecting primary adequate bone mineralization. In the last decades, a more complex and wider role of vitamin D has been postulated and demonstrated. Cardiovascular diseases have been found to be strongly related to vitamin D levels, especially to its deficiency. Pre-clinical studies have suggested a direct role of vitamin D in the regulation of several pathophysiological pathways, such as endothelial dysfunction and platelet aggregation; moreover, observational data have confirmed the relationship with different conditions, including coronary artery disease, heart failure, and hypertension. Despite the significant evidence available so far, most clinical trials have failed to prove any positive impact of vitamin D supplements on cardiovascular outcomes. This discrepancy indicates the need for further information and knowledge about vitamin D metabolism and its effect on the cardiovascular system, in order to identify those patients who would benefit from vitamin D supplementation.

Keywords: cardiovascular disease; cholecalciferol; outcome; pathophysiology; vitamin D.

Figure 1

Vitamin D synthesis pathway. The figure depicts the synthesis of vitamin D and its metabolites derived by ergosterol and cholesterol. CYP24A1 = cytochrome P450 family 24 subfamily A member 1, also named 25(OH)-D 24-hydroxylase; CYP27A1 = cytochrome P450 family 27 subfamily A member 1, also named sterol 27-hydroxylase; CYP27B1 = cytochrome P450 family 27 subfamily B member 1, also named 25(OH)-D 1α-hydroxylase; CYP2R1 = cytochrome P450 family 2 subfamily R member 1, also named vitamin D 25-hydroxylase; DBP = vitamin D binding protein; UVB = ultraviolet B; VDR = vitamin D receptor.

Figure 2

Hormonal regulation of vitamin D. The figure shows the hormonal regulation of the final step of vitamin D synthesis and the interplay at renal tubular cells (blue cells) of different signals. Green arrows indicate positive modulation; red arrows indicate inhibition. CYP24A1 = cytochrome P450 family 24 subfamily A member 1, also named 25(OH)-D 24-hydroxylase; CYP27B1 = cytochrome P450 family 27 subfamily B member 1, also named 25(OH)-D 1α-hydroxylase; FGF23 = fibroblast growth factor 23; FGFR1c = fibroblast growth factor receptor 1c; PTH = parathyroid hormone; PTHR1 = parathyroid hormone 1 receptor. Created with BioRender.com.

Figure 3

Vitamin D targets in the cardiovascular field. The figure shows main targets and effect of vitamin D related to cardiovascular diseases. Green arrowheads indicate increase, red arrowheads indicate inhibition. ANP = atrial natriuretic peptide; Ca = calcium; CMs = cardiomyocytes; ECs = endothelial cells; IL-1 = interleukin-1; IL-6 = interleukin-6; LDL = low-density lipoprotein; MMP-2 = matrix metalloprotease-2; MMP-8 = matrix metalloprotease-8; NF-kB = nuclear factor-kB; NO = nitric oxide; P = phosphate; RAAS = renin angiotensin aldosterone system; TNF-α = tumor necrosis factor-α; VSMCs = vascular smooth muscle cells. Created with BioRender.com.