**4. Biologic plausibility**

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 CVD [11, 18].

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, its active form. Moreover, 1,25 hydroxylase, the rate-limiting enzyme in this 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 [24, 25].

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 of hypertension [32]. Thus, vitamin D is implicated in blood pressure regulation and myocardial thickening.

Another indirect effect of vitamin D on CVD is the regulation of matrix metalloproteinase 2 and 9 production. Increased metalloproteinases have been associated with cardiac fibrosis, hypertrophy and heart failure in mice [33, 34].

Vitamin D deficiency may also indirectly harm the CV system by inducing hyperparathyroidism, which may act upon parathyroid hormone (PTH) receptors within the blood vessel wall and the myocardium [35]. Multiple studies have been able to demonstrate an association between elevated PTH levels and hypertension, cardiac dysfunction and vascular disease [35, 36].

Lastly, hyperlipidemia has also been associated with vitamin D deficiency. This is likely a result of decreased transcriptional activity of the VDR, leading to the increase of hepatic cholesterol production [37].

### **5. The clinical evidence**

Vitamin D deficiency is prevalent in CVD patients [11]. Most studies showing an association between inadequate 25OHD3 and poor outcomes in CV health are observational, hindering the establishment of a causal relationship. Furthermore, significant differences across studies hamper the ability to make valid and consistent conclusions. These differences include varying definitions of vitamin D deficiency and lack of seasonal adjustment and properly defined CV outcomes. Further difficulties include the use of single baseline measurements of vitamin D (which may be an inaccurate assessment of overall vitamin D status), a poor understanding of the role of high PTH on CVD, and the use of other disease modulating drugs such as calcium and statins in active and placebo groups, which may affect study results.

However, newer studies implement clearly defined primary endpoints, differing frequencies of vitamin D supplementation, and a diverse cohort of participants. These studies allow for a clearer understanding of the effects of vitamin D supplementation on CVD health.

## **6. Observational data**

Several large-scale observational studies have been completed over the past decades. The NHANES III national cohort registry found a significant inverse relationship between 25(OH)D levels and all-cause mortality, but a non-significant association between 25(OH)D levels and CVD mortality [8].

In the Intermountain Heart Collaborative Study Group, significantly higher rates of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease were found in those with serum 25(OH)D levels below 30 ng/mL. Additionally, low serum 25(OH)D levels were also linked to coronary artery disease, myocardial infarction (MI), heart failure, stroke and incident death [38].

In the Health Professionals Follow-up Study, men deficient in 25(OH)D (≤15 ng/ mL) had a higher risk of MI than men with sufficient levels (≥30 ng/mL) [39].

In contrast, other prospective studies have had discordant results. In the MIDSPAN family study, with a median follow up of 14.4 years, plasma levels of 25OHD less than 15 ng/mL were associated with all-cause mortality, but not the risk of CV diseases [40].

Similiarly, in the MrOS Sleep Study, no relationship between circulating 25(OH) D levels and risk of CVD events was found [41].

**217**

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

vitamin D dosage, and ascertaining study outcomes.

positive effects on CVD were found [45–49].

D supplementation remain in question [10].

times, and participant diversity [9].

and the degree and severity of coronary artery disease [42].

Additionally, in a study involving 746 patients undergoing coronary angiography, no correlation was found between vitamin D levels (<20 ng/mL vs. >20 ng/mL)

Prior to 2017, most randomized interventional studies have assessed surrogate endpoints rather than hard CV outcomes. In the available studies, there has been considerable variation in defining baseline vitamin D status, assessing adequate

In a double-blind, placebo controlled, randomized trial where elderly participants in the United Kingdom received vitamin D3 supplements of 100,000 IU every

Additionally, in a systematic review of 18 randomized trials studying the efficacy of supplementation with vitamin D (with or without calcium) on various cardiometabolic outcomes, only four reported on incident CVD. There were no

Postmenopausal women in the Women's Health Initiative (WHI) receiving calcium carbonate (1000 mg/day) and vitamin D (400 IU/day) had no reduction in their risk of coronary events or stroke during the 7 year follow-up period. Treatment with calcium and vitamin D also had no effect on blood pressure reduction, hypertension development and coronary artery calcification. In the overall participant cohort, supplementation did not reduce the overall incidence of heart failure, yet some benefits were noted in participants considered to be at low risk for heart failure. Lastly, in a follow-up 4.9 years after the culmination of the study, no

More recent studies on vitamin D supplementation have made use of welldefined CV outcomes as primary endpoints. In 2017, the results of the Vitamin D Assessment study (VIDA), a randomized, double blinded, placebo-controlled study on the effects of high-dose, monthly vitamin D supplementation in the general population aged 50–84, were published. 5,110 patients were randomized to receive either an initial oral vitamin D dose of 200,000 IU followed by 100,000 IU monthly or placebo. Primary outcomes included incident CVD and death. Secondary outcomes included MI, angina, heart failure, hypertension, arrhythmias, chronic ischemic heart disease, arteriosclerosis, stroke, and venous thrombosis. Additionally, pre-specified subgroup analysis for the primary endpoint was done for patients with vitamin D deficiency (<20 ng/mL) and established CVD. Results of the study showed that high doses of monthly vitamin D supplementation provided no benefit to CV health over placebo. However, the study is limited by a low event rate and decreased power, especially for subgroup analysis in those deficient at baseline. Supplementation was monthly, leaving the question of whether daily dosing may be better. Finally, the funding of the clinical trial only allowed for a median follow-up time of 3.3 years and, therefore, the long-term effects of high dose, monthly vitamin

Another recent placebo-controlled trial, known as the VITAL study, assessed the effects of more frequent vitamin D supplementation (2,000 IU of vitamin D and 1 g of omega-3 per day) on CVD and cancer. The primary endpoint in the CV arm was major CV events, which included MI, stroke, and cardiac related death. 25,871 subjects participated in the study and the median follow-up time was 5.3 years. The trial found that daily vitamin D supplementation had no benefit on CV health. The strengths of the study included daily vitamin D supplementation, longer follow-up

4 months for 5 years, no benefits on CVD outcomes were shown [43].

significant reductions in CVD risk found in these trials [44].

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

**7. Randomized controlled trials**

Additionally, in a study involving 746 patients undergoing coronary angiography, no correlation was found between vitamin D levels (<20 ng/mL vs. >20 ng/mL) and the degree and severity of coronary artery disease [42].
