**2. Vitamin D deficiency**

Vitamin D deficiency is prevalent in 30–50% of adults in developed countries [10, 15], and it is estimated that more than 1 billion individuals worldwide are vitamin insufficient or deficient [3, 10, 16, 17]. Vitamin D deficiency is prevalent in every segment of the US population but remains under recognized and under treated [15, 18].

Serum levels of 25(OH)D <20 ng/ml indicate deficiency, and levels >30 ng/ml are considered optimal for bone health (**Table 1**) [15, 19]. Vitamin D levels of 30–40 ng/ml are associated with maximal parathyroid hormone suppression [10, 16, 19, 20]. No consensus has been reached on the optimum level of 25(OH)D for purported benefits beyond skeletal health [3, 10, 16, 17, 21]. A recent study suggests a 25(OH)D threshold of 11–14 ng/ml below which signifies increased CVD risk [22].

Levels in the range of 21–29 ng/ml are considered insufficient. Using this definition, the majority of the US population would be labeled as vitamin D insufficient.

A decline in mean serum vitamin D levels in the US population was detected when comparing data from the National Health and Nutrition Examination Survey (NHANES). The NHANES survey from 1988 to 1994 (n = 18,883) showed a mean 25(OH)D level of 30 ng/ml as compared to a mean 25(OH)D level of 24 ng/ml in the 2001–2004 (n = 13,369) survey [23, 24]. This difference may have been explained by different assays used during the more current survey as compared to prior surveys, but there still remained a small but significant reduction after accounting for these differences [25]. The decline was likely related to behavioral factors most notably sun avoidance and obesity.


**Table 1.** 25(OH)D concentration and its effects [3, 7, 15].

The discovery of the vitamin D receptor (VDR) in multiple cell types, including cardiomyocytes and vascular cells [3, 4], has led to increasing interest in vitamin D's role in human health, including cardiovascular, beyond its well‐known role in bone health. Deficient vitamin D levels (<20 ng/ml) have been independently linked to increased morbidity and mortality [5–7].

Experimental evidence has linked vitamin D to regulation of multiple pathways involved in the pathogenesis of CVD. Several ecological and epidemiological studies have suggested a relationship between CVD and vitamin D status, as CVD events are higher in the winter, a period when vitamin D levels are lowest [8, 9]. Additionally, certain populations with poor cutaneous production of vitamin D and subsequently lower plasma levels, such as African Americans, tend to be at greater risk for hypertension and cardiovascular disease [3, 8, 10, 11]. These lines of evidence do not prove causality but support a hypothesis for further study.

Randomized controlled trials have mostly been based on surrogate or secondary endpoints for CV risk reduction [12]. Study methodology has been heterogeneous and results are often conflicting. To date, large well‐powered randomized trials of vitamin D featuring CV outcomes as a primary endpoint are still ongoing [13, 14]. In the absence of results from these trials, regular supplementation cannot be recommended for cardiovascular risk modulation. Despite the lack of recommendations, use of vitamin D supplements for this purpose has risen

The following chapter will provide an overview on the biologic plausibility and current evidence linking vitamin D to CV health and disease. But first, a brief review of the prevalence and definition of vitamin D deficiency and description of vitamin D synthesis and metabolism

Vitamin D deficiency is prevalent in 30–50% of adults in developed countries [10, 15], and it is estimated that more than 1 billion individuals worldwide are vitamin insufficient or deficient [3, 10, 16, 17]. Vitamin D deficiency is prevalent in every segment of the US population but

Serum levels of 25(OH)D <20 ng/ml indicate deficiency, and levels >30 ng/ml are considered optimal for bone health (**Table 1**) [15, 19]. Vitamin D levels of 30–40 ng/ml are associated with maximal parathyroid hormone suppression [10, 16, 19, 20]. No consensus has been reached on the optimum level of 25(OH)D for purported benefits beyond skeletal health [3, 10, 16, 17, 21]. A recent study suggests a 25(OH)D threshold of 11–14 ng/ml below which signifies increased

Levels in the range of 21–29 ng/ml are considered insufficient. Using this definition, the

A decline in mean serum vitamin D levels in the US population was detected when comparing data from the National Health and Nutrition Examination Survey (NHANES). The NHANES

majority of the US population would be labeled as vitamin D insufficient.

dramatically.

is necessary.

CVD risk [22].

**2. Vitamin D deficiency**

4 A Critical Evaluation of Vitamin D - Clinical Overview

remains under recognized and under treated [15, 18].

Risk factors for developing vitamin D deficiency include limited cutaneous synthesis due to inadequate sun exposure (sunscreen use, institutionalized or homebound patients) and low dietary intake [3]. Other risk factors include age >65, smoking, air pollution, dark skin pigmentation, obesity (resulting from storage in adipose tissue), kidney and/or liver disease, disorders affecting fat absorption (e.g., celiac disease, Crohn's disease, ulcerative colitis, some types of bariatric surgery), and end organ insensitivity to 1,25(OH)2D [3, 9, 17].
