**3. Vitamin D metabolism**

Vitamin D's active form, 1a,25-dihydroxyvitamin D (1,25[OH]2D3) plays a critical role in influencing a myriad of metabolic pathways [14].

Natural sunlight exposure contributes to more than 90% of vitamin D (D3-cholecalciferol) production in humans [15]. UV-B irradiation absorbed by skin

**215**

*Vitamin D and Cardiovascular Disease: The Final Chapter?*

fortified milk, orange juice, cereals, and cheese [11, 12].

which mediates transcriptional gene regulation [19].

activities in experimental settings [19].

**4. Biologic plausibility**

CVD [11, 18].

[24, 25].

muscle cell (VSMC) and cardiomyocyte proliferation [11, 20].

keratinocytes triggers photolysis of 7-dehydrocholesterol (pro-vitamin D3) in the plasma membrane, which is then swiftly modified into vitamin D3 by heat [4, 16]. Dietary supply of vitamin D (D2-ergocalciferol) contributes to the remainder of the total amount of vitamin D in the body. Foods containing vitamin D include oily fish (salmon, sardines, and mackerel), cod liver oil, egg yolk, mushrooms, and

D3 and D2 from the skin and diet, respectively, each undergo two sequential hydroxylation's: 25-hydroxylation in the liver and then 1,25-dihydroxylation in the kidney. In order to assess vitamin D status from oral intake and endogenous production, the primary metabolite of vitamin D, 25(OH)D, should be measured [11, 15, 17]. The hydroxylation of 25(OH)D to its biologically active form, 1,25(OH)2D3, is controlled

Most of the known biological effects of 1,25(OH)2D3 are mediated through the vitamin D3 receptor (VDR), part of the superfamily of nuclear hormone receptors,

Over 200 genes are regulated by 1,25(OH)2D3. These include genes directly or indirectly responsible for renin and insulin production, anti-inflammatory cytokine release, proinflammatory cytokine suppression, and regulation of vascular smooth

1,25(OH)2D3 is also involved in non-genomic mediated intracellular signaling, demonstrating immunomodulatory, antiproliferative, and pro-differentiative

Characterizing vitamin D deficiency as a primary risk factor for CVD is challenging due to the multitude of complex interacting pathways involving vitamin D. The vitamin D receptor is nearly ubiquitous in human cells including vascular smooth muscle cells (VSMC), endothelial cells, cardiac myocytes, juxtaglomerular, and most immune cells, all implicated in the pathogenesis and progression of

Immune cells such as activated CD4+ and CD8+ T cells, B cells, neutrophils, macrophages, and dendritic cells are capable of converting 25OHD3 into 1,25OHD3,

pathway, is present in activated macrophages [21–23]. Lastly, VSMC and endothelial cells also express 1,25 hydroxylase, suggesting that these cells have an autocrine mechanism allowing them to modulate the effects of vitamin D on the vasculature

Vitamin D has various direct and indirect effects on CV function. 1,25(OH)2D3 directly modulates VSMC and expression of vascular endothelial growth factor via the VDR and CYP27B1 expression in VSMC's and endothelial cells. 1,25(OH)2D3 has an inhibitory effect on hypertrophy and proliferation of VSMC in vitro and in cultured cardiac myocytes. It also plays an important role in inflammation and thrombosis [21, 24]. In a swine model of atherosclerosis, vitamin D deficiency accelerated plaque progression by enhancing inflammation in epicardial adipose tissue [26]. Inverse associations between vitamin D deficiency and thrombogenicity, vascular inflammation, and vascular calcification have been demonstrated [27–29]. Indirectly, the expression of renin in vivo is strongly regulated by vitamin D, and an inverse relationship between vitamin D levels and renin expression has been demonstrated experimentally [30–32]. 1,25(OH)2D3 binds to the renin promoter region and inhibits renin transcription [30]. VDR knockout mice were shown to have increased levels of renin and angiotensin II and, therefore, a higher prevalence

its active form. Moreover, 1,25 hydroxylase, the rate-limiting enzyme in this

*DOI: http://dx.doi.org/10.5772/intechopen.90106*

by PTH [11, 18].

*Vitamin D and Cardiovascular Disease: The Final Chapter? DOI: http://dx.doi.org/10.5772/intechopen.90106*

*Vitamin D Deficiency*

health and disease.

**2. Vitamin D deficiency**

insufficient or deficient [4, 11].

vitamin D insufficient [4].

**3. Vitamin D metabolism**

and acquired disorders (e.g. hyperthyroidism) [4].

cal role in influencing a myriad of metabolic pathways [14].

for this purpose had risen dramatically.

levels are known to be at their lowest due to lack of sunlight [5, 6]. A similar trend is noted in certain populations with poor cutaneous vitamin D production, such as African Americans, who are more prone to developing hypertension and CV disease [6]. Lastly, low vitamin D levels (<20 ng/mL) have been independently linked to increased morbidity and mortality [7, 8]. Although convincing, this evidence does

Prior to 2017, randomized controlled trials had mostly relied on surrogate or secondary endpoints for CV risk reduction. Study methodologies have been heterogeneous, and results have often been conflicting. In the absence of results from these trials, regular supplementation has not been recommended for CV risk modulation. Despite the lack of recommendations, use of vitamin D supplements

However, more recent trials have been conducted that have assessed CV risk reduction as a primary endpoint. These trials have given researchers and clinicians a better understanding of the effects of vitamin D supplementation and whether it

The following chapter will discuss the prevalence of vitamin D deficiency, describe vitamin D synthesis and metabolism, and provide an overview on the biologic plausibility and current state of the evidence linking vitamin D to CV

Vitamin D deficiency is found in 30–50% of the general population, and prevalence estimates suggest that more than 1 billion people worldwide are vitamin D

Vitamin D deficiency is indicated by serum levels of 25(OH)D < 20 ng/mL [4]. Serum levels >30 ng/mL are likely optimal for bone health, but some studies have shown benefits with lesser values. Parathyroid hormone (PTH) suppression appears to plateau at levels between 30 and 40 ng/mL [12]. There has been no agreement on optimum 25(OH)D levels required for purported health benefits beyond skeletal health. One study suggested that 25(OH)D levels below 11–14 ng/mL signify increased CVD risk [13]. Levels in the range of 21–29 ng/mL are considered by some as insufficient, a definition that would label the majority of the U.S. population

The Endocrine Society does not recommend screening for vitamin D deficiency in individuals who are not at risk for it [12]. Many of the risk factors for vitamin D deficiency have been identified. Some of these include inadequate cutaneous synthesis stemming from insufficient sun exposure or dark skin pigmentation and inadequate dietary intake. Other noted risk factors include aging, obesity, renal disease, liver disease, disorders that affect fat absorption (e.g. celiac disease, inflammatory bowel diseases, types of bariatric surgery), increased catabolism due to medications (e.g. steroids, anticonvulsants etc.), and other hereditable (e.g. rickets)

Vitamin D's active form, 1a,25-dihydroxyvitamin D (1,25[OH]2D3) plays a criti-

Natural sunlight exposure contributes to more than 90% of vitamin D (D3-cholecalciferol) production in humans [15]. UV-B irradiation absorbed by skin

not demonstrate causality, but supports a hypothesis for further study.

should be indicated to reduce the risk of developing CVD [9, 10].

**214**

keratinocytes triggers photolysis of 7-dehydrocholesterol (pro-vitamin D3) in the plasma membrane, which is then swiftly modified into vitamin D3 by heat [4, 16].

Dietary supply of vitamin D (D2-ergocalciferol) contributes to the remainder of the total amount of vitamin D in the body. Foods containing vitamin D include oily fish (salmon, sardines, and mackerel), cod liver oil, egg yolk, mushrooms, and fortified milk, orange juice, cereals, and cheese [11, 12].

D3 and D2 from the skin and diet, respectively, each undergo two sequential hydroxylation's: 25-hydroxylation in the liver and then 1,25-dihydroxylation in the kidney. In order to assess vitamin D status from oral intake and endogenous production, the primary metabolite of vitamin D, 25(OH)D, should be measured [11, 15, 17]. The hydroxylation of 25(OH)D to its biologically active form, 1,25(OH)2D3, is controlled by PTH [11, 18].

Most of the known biological effects of 1,25(OH)2D3 are mediated through the vitamin D3 receptor (VDR), part of the superfamily of nuclear hormone receptors, which mediates transcriptional gene regulation [19].

Over 200 genes are regulated by 1,25(OH)2D3. These include genes directly or indirectly responsible for renin and insulin production, anti-inflammatory cytokine release, proinflammatory cytokine suppression, and regulation of vascular smooth muscle cell (VSMC) and cardiomyocyte proliferation [11, 20].

1,25(OH)2D3 is also involved in non-genomic mediated intracellular signaling, demonstrating immunomodulatory, antiproliferative, and pro-differentiative activities in experimental settings [19].
