IJCS | Volume 31, Nº4, July / August 2018

425 Jorge et al. Vitamin D and cardiovascular disease Int J Cardiovasc Sci. 2018;31(4)422-432 Review Article Despite the increased prevalence of vitamin D deficiency in the adult population and the growing evidence of its association with CVD, both American and Brazilian guidelines recommend that serum 25-hydroxyvitamin D levels should not be measured routinely in the general population and should only be measured in patients of populations considered at risk for deficiency of this vitamin. 10,17 Assoc i a t ion of vi t amin d def i c i ency and cardiovascular diseases Although numerous studies have confirmed an association between vitamin D and CVD, a cause-effect relationship between both remains unclear. In this review, we discuss the association of vitamin D deficiency with the main cardiovascular pathologies and, subsequently, we analyze some outcomes with vitamin replacement. Hypertension The association of vitamin D deficiency and hypertension has its basis on the renin-angiotensin- aldosterone system (RAAS). Renin is synthesized by renal juxtaglomerular cells and stimulates the production of angiotensin II (from angiotensin I) and aldosterone, which increase blood pressure (BP) directly by vasoconstriction and indirectly by fluid and salt retention. 18 Inappropriately increased RAAS activation has been reported in studies with VDR and 1 α -hydroxylase knockout mice. 19 Vitamin D acts by inhibiting renin gene expression, decreasing the synthesis of renin and, thus, preventing hyperstimulation by this system. 20 The ThirdNational Health andNutrition Examination Survey (NHANES III), 21 a large population study that analyzed a sample of 12,644 North-Americans, has shown that systolic BP and pulse pressure correlate inversely with levels of 25-hydroxyvitamin D. These results have been confirmed by subgroup analyses in which increases in BP associated with age were significantly lower in vitamin D sufficient individuals. 22 The prevalence of hypertension was also associated with vitamin D deficiency in other large studies such as the German National Interview and Examination Survey 23 and the British Birth Cohort. 24 A study carried out in Brazil with 91 hypertensive elderly patients has shown that the serum concentrations of 25-hydroxyvitamin D is inversely associated with BP and positively associated with the weekly frequency of fish consumption. 25 Few prospective studies have evaluated the association between vitamin D and changes in BP or emergence of hypertension. In 2015, van Ballegooijen et al. 26 followed up 5,066 individuals without hypertension at the Dutch city of Groningen; the individuals had their serum vitamin D level measured and were followed up for 6.4 years. At the end of follow-up, 1,036 (20.5%) developed hypertension and, as expected, low levels of vitamin D were associated with a greater risk of development of the disease. 26 Diabetes mellitus Type 1 diabetes occurs due to an autoimmune destruction of pancreatic beta cells leading to complete deficiency of insulin production. As for the development of type 2 diabetes, the major mechanisms involved are beta cell dysfunction, peripheral insulin resistance, and systemic inflammation. According to evidence, vitamin D deficiency is associated with all these processes. 27 Vitamin D may exert effects on beta cell function through a direct connection to VDR receptors and by local expression of the enzyme 1 α -hydroxylase. Vitamin D may also increase insulin sensitivity by stimulating VDR expression in peripheral tissues and activating peroxisome proliferator-activated receptor-gamma (PPAR) receptors, a factor that is involved in regulating the metabolism of fatty acids in skeletal muscles and adipose tissue. On the other hand, vitamin D may also act through indirect pathways in insulin secretion and sensitivity by regulating calcium concentration and flux in beta cell membranes and peripheral tissues. 27 Observational studies have shown that the incidence and prevalence of type 1 diabetes are higher in countries with higher latitude and that the disease is most often diagnosed in the winter months. 28 Some studies have related vitamin D deficiency in pregnant women with the incidence of type 1 diabetes in children after birth. 29 Other studies have evaluated the protective role of vitamin D supplementation in early childhood against the development of type 1 diabetes, showing a lower incidence of the disease in children who received vitamin supplementation. 30 With respect to insulin resistance and type 2 diabetes, the results have been conflicting. Some studies have associated low concentrations of 25-hydroxyvitamin D with insulin resistance and dysfunction of pancreatic