**Abstract**

Vitamin D deficiency is globally prevalent and has been associated with the pathogenesis and complications of cardiovascular disease (CVD) and its risk factors. Defining these relationships has been challenging, and the clinical applications of vitamin D screening and supplementation for CVD risk prevention and modification have only recently become clearer. Most of the available evidence includes large observational studies and smaller randomized trials that scarcely evaluate CV outcomes as primary endpoints. Additionally, these studies include methodological inconsistencies, making it difficult to ascertain the benefits of vitamin D supplementation. However, more recently, randomized trials have been conducted which utilize CVD outcomes as primary endpoints, while assessing the effects of high dose vitamin D supplementation on CV health. Despite observational evidence as well as a conventional consensus that vitamin D supplementation improves CV health, these studies suggest that vitamin D supplementation likely has no benefit in this regard, at least in the follow-up period and populations evaluated.

**Keywords:** vitamin D deficiency, cardiovascular disease, endothelial function, hypertension, heart failure, renal disease, prevention, vitamin D

### **1. Introduction**

Cardiovascular disease (CVD) is the most common cause of death in the developed world and is forecasted to be the leading cause of death and morbidity in developing countries by 2020 [1]. According to the American Heart Association, 9.0% (24.3 million in 2016) of adults (≥20 years of age) in the United States live with CVD (including coronary heart disease, heart failure, and stroke). This number increases to 48.0% when including hypertension [2]. CVD is a multifactorial disease that includes a complex interplay between genetics, environmental factors, and risk factors.

Despite effective measures for control and modification of traditional risk factors, a significant amount of risk remains. Therefore, the identification of easily modifiable novel risk factors has been heavily investigated over the past few decades.

In addition to the well-known relationship between vitamin D and bone health, there has been considerable interest of the possible linkage between vitamin D and CV health due to the expression of the vitamin D receptor (VDR) on cardiomyocytes and vascular cells [3, 4]. Vitamin D plays an extensive role in the regulation of numerous pathways implicated in CVD pathogenesis. Interestingly, various studies note that CVD events are higher in the winter months, a time when vitamin D

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

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 for this purpose had risen dramatically.

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

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 health and disease.
