Dysfunctional immunometabolic effects of vitamin D deficiency, increased cardiometabolic risk. Potential epidemiological alert in America? | Endocrinología, Diabetes y Nutrición (English ed.)

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This emphasizes the importance of clarifying the role of vitamin D in the context of cardiovascular diseases and their most common risk factors.It has recently been reported that coronary artery disease, especially myocardial infarction and heart failure, affects 7.9 and 5.7 million adults in the United States respectively.<a class="elsevierStyleCrossRefs" href="#bib0535">8,9</a> Left ventricular abnormalities related to remodeling (progressive dilation of the predominant chamber, fibrosis, and systolic/diastolic dysfunction) and heart failure often complicate an acute myocardial infarction.<a class="elsevierStyleCrossRefs" href="#bib0545">10,11</a> Recent data suggest that the prevalence of ventricular dysfunction related to myocardial infarction and heart failure is associated with decreased vitamin D levels.<a class="elsevierStyleCrossRef" href="#bib0550">11</a> Thus, increasing attention is being paid to the role of vitamin D deficiency as a risk marker in the development of heart failure.As early as in 1981, a study had reported seasonal variations in CV mortality and the potential positive effects of protection from UVB (ultraviolet B) radiation on CV risk.<a class="elsevierStyleCrossRef" href="#bib0535">8</a> The association of vitamin D with CV risk factors and their associated diseases has been widely investigated in recent years. Multiple observational studies, prospective meta-analyses, and some interventional studies have addressed the potential link with vitamin D deficiency.<a class="elsevierStyleCrossRefs" href="#bib0540">9–12</a>Patients with advanced heart failure are known to have significantly lower serum 25 (OH) D levels, an independent risk factor associated with poor clinical outcomes and prolonged decompensation of heart failure.<a class="elsevierStyleCrossRefs" href="#bib0530">7,13–15</a> VDR agonists such as calcitriol and its analogs, including doxercalciferol, have been developed to treat secondary hyperparathyroidism in chronic kidney disease,<a class="elsevierStyleCrossRef" href="#bib0535">8</a> osteoporosis,<a class="elsevierStyleCrossRef" href="#bib0550">11</a> and psoriasis.<a class="elsevierStyleCrossRef" href="#bib0560">13</a>Researchers are currently developing another candidate as a selective and effective VDR agonist for treating vitamin D deficiency in heart failure and the phenotypes associated with dysfunction in the renin–angiotensin–aldosterone system (RAAS).<a class="elsevierStyleCrossRef" href="#bib0570">15</a>One of our central objectives is to lend scientific support to the urgent need to understand the prevalence of vitamin D deficiency in countries such as Mexico and elsewhere in Latin America, where the pandemic of non-communicable chronic diseases is the main factor responsible for overall morbidity and mortality.<a class="elsevierStyleCrossRef" href="#bib0575">16</a>Basic vitamin D metabolismVitamin D3 is a steroid prohormone mainly derived from the synthesis induced by UVB radiation on dehydrocholesterol in the skin (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Endogenous synthesis is the main source of vitamin D in the body and accounts for approximately 80% of the vitamin. After synthesis in the skin or absorption from diet, vitamin D is transported by a specific binding protein to the liver, where it is hydroxylated to 25-hydroxyvitamin D. This inactive form is the main metabolite circulating in blood, and is also used to determine vitamin D status.<a class="elsevierStyleCrossRefs" href="#bib0500">1–3</a>25-Hydroxyvitamin D is hydroxylated by the enzyme 1α-hydroxylase (1α-OHase) to its most active metabolite, 1α-25 (OH)2 D3, mainly in the kidneys. From this 1α-hydroxylation it is known that it can also be activated by extrarenal 1α-hydroxylation throughout the body<a class="elsevierStyleCrossRefs" href="#bib0560">13,14</a> (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). This has led to the assumption that vitamin D plays a wider role in overall health, including tissues beyond the musculoskeletal system such as the heart and blood vessels.<a class="elsevierStyleCrossRefs" href="#bib0570">15–17</a>Classification of vitamin D deficiencyVitamin D status is categorized based on serum 25 (OH) D levels, and the half-life of the vitamin is approximately 2–4 weeks. However, this half-life may be decreased even to less than a week in the event of hemodilution, infection, or other catabolic diseases, or after the administration of corticosteroids.A report by the United States Institute of Medicine (IOM) defines vitamin D deficiency as 25 (OH) D levels less then 12ng/mL (multiply by 2496 to convert ng/mL to nmol/L), while values of 20ng/mL or higher are considered adequate. On the other hand, the guidelines of the Endocrine Society of America<a class="elsevierStyleCrossRef" href="#bib0565">14</a> suggest that 25 (OH) D levels ≤20ng/mL are deficient and that values ≥30ng/mL are sufficient.<a class="elsevierStyleCrossRefs" href="#bib0565">14–16</a>Prevalence of vitamin D deficiencyVitamin D deficiency and insufficiency are highly prevalent, as is shown by the fact that more than half of the population worldwide has levels lower than 30ng/mL<a class="elsevierStyleCrossRefs" href="#bib0560">13,16</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). However, the prevalence of the deficiency in countries such as Mexico is not known, which should alert the medical community. There are various risk factors for vitamin D deficiency that should always be taken into account, including age, female sex, pigmentation in darker skin, decreased sun exposure, seasonal variation and distance from the Equator. Special mention should be made of air pollution.<a class="elsevierStyleCrossRefs" href="#bib0580">17,18</a> Studies on the impact of pollution on vitamin D should be conducted in cities with high pollution levels because of their unique population and geodemographic conditions.<a class="elsevierStyleCrossRefs" href="#bib0550">11,19–21</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Inflammation and vitamin D deficiencyApart from its traditional role as a modulator of calcium metabolism and bone homeostasis, vitamin D has been shown to have potent anti-inflammatory effects. Because of this, it has been considered as adjuvant therapy for many chronic diseases such as asthma, arthritis, prostate cancer and psoriasis, amongst others.<a class="elsevierStyleCrossRefs" href="#bib0515">4,22,23</a> A variety of both pro-inflammatory and anti-inflammatory effects of vitamin D had previously been reported.<a class="elsevierStyleCrossRefs" href="#bib0615">24,25</a> It has also been shown that vitamin D may directly induce the production of important antimicrobial peptides such as cathelicidins and defensin β4 in monocytes/macrophages and in human epithelial cells<a class="elsevierStyleCrossRefs" href="#bib0560">13,26</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia>1,25-(OH)2 D3 has been shown to have antiproliferative and proapoptotic activity in tumor cells due to the induction of the cyclin-dependent kinase inhibitors p27Kip1 and p21Waf/Cip1 and the inhibition of c-Myc and antiapoptotics such as Bcl-2.<a class="elsevierStyleCrossRef" href="#bib0610">23</a> Moreover, vitamin D was shown to suppress the action pathways of prostaglandins in tumor cell lines through the inhibition of cyclooxygenase-2 production and the stimulation of 15-hydroxyprostaglandin production by the cells.<a class="elsevierStyleCrossRef" href="#bib0610">23</a>Vitamin D has also been shown to interfere with the activation and signaling of nuclear factor (NF) kB by increasing the expression of IκBα in activated cells, and to interfere with the nuclear translocation of subunits of NF-κB.<a class="elsevierStyleCrossRef" href="#bib0515">4</a>It has also been reported that vitamin D may influence dendritic cell maturation and function.<a class="elsevierStyleCrossRef" href="#bib0630">27</a> Several studies have shown the ability of vitamin D to modulate the population and role of FOXP3-positive regulatory T cells and the production of IL-10<a class="elsevierStyleCrossRef" href="#bib0630">27</a> (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).<elsevierMultimedia ident="fig0025"></elsevierMultimedia>The interaction of peroxisome proliferator-activated receptors (PPARs) and the VDR has been widely studied, because they both form heterodimers with LXR. The potential modulation of PPARy activity has been implicated in many metabolic processes, especially in lipids and in mechanisms for insulin release from β cells in the islets of Langerhans. Additional results of this transcriptome have shown that vitamin D regulates proadipogenic PPARy in activated macrophages. PPARy agonists reverse the antiadipogenic and antimicrobial effects attributed to the vitamin D receptor, which suggests a link between the VDR and signaling in the regulation of processes of two-directional functions between vitamin D and PPARy.<a class="elsevierStyleCrossRef" href="#bib0635">28</a>Vitamin D and cardiovascular risk factorsHigh blood pressure and vitamin D deficiencyVitamin D deficiency has been associated with higher blood pressure levels, as is shown in most prospective studies and in meta-analyses of observational studies.<a class="elsevierStyleCrossRefs" href="#bib0540">9,29,30</a> Reported blood pressure variations may be explained by differences in vitamin D levels between the studies, which have often been relatively small. However, the additive role in antihypertensive drug treatment has clinical relevance.The potential mechanisms for this association of vitamin D and blood pressure include an inverse association of vitamin D with RAAS activity, the effect of improved endothelial function, and the prevention of secondary hyperparathyroidism, all of them mechanisms of interest.<a class="elsevierStyleCrossRefs" href="#bib0615">24–27</a>In this regard, it should be noted that high parathyroid hormone levels are a distinctive feature of vitamin D deficiency, and are known to be associated with myocardial infarction and higher blood pressure levels.<a class="elsevierStyleCrossRef" href="#bib0635">28</a> In addition, there is an increasing evidence to suggest that mutual interactions between PTH, vitamin D, and aldosterone are involved in damage to the cardiovascular system independently of the RAAS.<a class="elsevierStyleCrossRefs" href="#bib0650">31,32</a>A significant inverse association has been reported between circulating serum vitamin D levels and the incident risk of hypertension. The combined relative risk (RR) was 0.70; the confidence interval (95% confidence interval: 0.57–0.86) after comparing the highest value to the lowest tertile of the baseline 25 (OH) D levels, with no evidence of heterogeneity between the results. Therefore, when dosage response in the five studies that reported RRs for exposure to vitamin D was assessed, the authors found that the risk of high blood pressure decreased 12% with each 10ng/mL increase in 25 (OH) D levels.<a class="elsevierStyleCrossRef" href="#bib0640">29</a> Several randomized clinical trials assessing the effect of vitamin D on blood pressure levels published in 2012 reported different results.<a class="elsevierStyleCrossRefs" href="#bib0610">23–25</a> A controlled clinical study was conducted in Denmark on 130 hypertensive patients who during the winter months received supplements of 3000IU of vitamin D versus placebo.<a class="elsevierStyleCrossRef" href="#bib0610">23</a> Ambulatory blood pressure monitoring (ABPM) for 24h showed a non-significant decrease in blood pressure (−3mmHg, p=0.26–1mmHg, p=0.18). Interestingly, when only patients with vitamin D deficiency (25 [OH] D less than 32ng/mL) were analyzed, systolic and diastolic BP values significantly decreased in 24-h ABPM (−4mmHg, p=0.05–3mmHg, p=0.01) in the treatment group as compared to the placebo group.<a class="elsevierStyleCrossRef" href="#bib0610">23</a>In an unselected Black population, vitamin D supplementation decreased systolic BP by 0.2mmHg per each 1ng/mL increase in vitamin D during the 3 months of treatment (p=0.02).<a class="elsevierStyleCrossRef" href="#bib0615">24</a>Obesity and vitamin D deficiencyObesity is closely related to vitamin D deficiency.<a class="elsevierStyleCrossRef" href="#bib0620">25</a> It has been suggested that this may be due to vitamin D sequestration in adipose tissue, which results in lower circulating 25 (OH) D levels.<a class="elsevierStyleCrossRef" href="#bib0650">31</a> Other authors have hypothesized a causal relationship with vitamin D deficiency that may lead to the promotion of obesity.<a class="elsevierStyleCrossRef" href="#bib0630">27</a>A bidirectional Mendelian randomization study was conducted to address this question. The study showed a unidirectional causal relationship, which suggests that obesity leads to a reduction of vitamin D levels, rather than the opposite.<a class="elsevierStyleCrossRef" href="#bib0635">28</a> That research, including 21 cohort studies with a total sample of 42,024 patients, found 12 established single nucleotide polymorphisms (SNP) related to the BMI and four typical SNPs associated with vitamin D status. It cannot be ignored that there has been a great increase in the prevalence of overweight and obesity in countries such as Mexico and in Latin America in general. On the other hand, genetically determined 25 (OH) D levels are not significantly related to the body mass index. Thus, obesity is known to be a pro-inflammatory state that has been related to abnormally high C-reactive levels, with a significant role being played by pro-inflammatory mediation in vitamin D deficiency.<a class="elsevierStyleCrossRef" href="#bib0650">31</a>Glucose metabolism, vitamin D, and type 2 diabetes mellitusIn observational and prospective studies, low vitamin D levels have been related to changes in glucose metabolism and to a greater risk of the development of diabetes in the future.<a class="elsevierStyleCrossRefs" href="#bib0520">5,30–33</a> It should also be noted that vitamin D deficiency in diabetic patients may be partly due to a reduction of physical activity and to obesity, as well as to limited sun exposure. Thus, residual confusion in observational studies due to the close relationship of obesity with glucose intolerance and vitamin D deficiency cannot be ruled out with certainty.<a class="elsevierStyleCrossRefs" href="#bib0625">26,34</a> On the other hand, inverse causality may exist, as there are data suggesting that an inflammatory state may be decreased by 25 (OH) D.<a class="elsevierStyleCrossRefs" href="#bib0660">33,35–37</a>There are however several potential mechanisms that could explain the association of vitamin D deficiency with changes in glucose homeostasis and diabetes mellitus. Both the VDR and 1-α-hydroxylase are expressed in pancreatic beta cells, which suggests a potential role of vitamin D in beta cell function. In addition, the interaction of VDR and PPARy has been suggested as a mechanism related to adequate insulin release.<a class="elsevierStyleCrossRefs" href="#bib0505">2,38</a>However, randomized trials have not shown that vitamin D supplements clearly improve blood glucose or insulin resistance.<a class="elsevierStyleCrossRefs" href="#bib0680">37,38</a> It remains to be clarified whether drug treatment for diabetes may help optimize metabolic control. To address this issue, a randomized clinical study was conducted in subjects with prediabetes and hypovitaminosis D.<a class="elsevierStyleCrossRef" href="#bib0690">39</a> The study participants were randomized to treatment with high vitamin D doses compared to placebo (mean weekly dose, 88,865IU). After the administration of vitamin D for 1 year, no differences were seen in plasma glucose, insulin secretion and sensitivity, or in the development of diabetes between the treatment and placebo groups.<a class="elsevierStyleCrossRef" href="#bib0690">39</a>Vitamin D and serum lipidsSome observational studies suggest an association of vitamin D deficiency with low high density lipoprotein (HDL) levels, high triglyceride levels, and higher apolipoprotein E levels.<a class="elsevierStyleCrossRefs" href="#bib0695">40,41</a> A prospective evaluation of vitamin D and lipid levels showed a significant association between low 25 [OH] D levels and hypercholesterolemia.<a class="elsevierStyleCrossRef" href="#bib0705">42</a> It should be noted, however, that blood lipid and vitamin D levels may be confounded by the above mentioned relationship between vitamin D and obesity.<a class="elsevierStyleCrossRef" href="#bib0635">28</a> Recent clinical studies evaluating the effect of vitamin D supplementation on blood lipids provided no conclusive evidence.<a class="elsevierStyleCrossRefs" href="#bib0615">24,43–45</a>Chronic kidney disease and vitamin D deficiencyPatients with chronic kidney disease have significantly lower vitamin D levels as compared to the overall population. Thus, a high prevalence of vitamin D deficiency, with levels less than 20ng/mL, was seen in more than 70% of patients on dialysis.<a class="elsevierStyleCrossRef" href="#bib0725">46</a>In addition, several epidemiological studies showed that low 25 (OH) D levels are associated with albuminuria or progression to renal failure. Vitamin D deficiency has also been identified in patients with chronic kidney disease as an independent risk factor for increased mortality, which may mainly be attributed to cardiovascular death.<a class="elsevierStyleCrossRefs" href="#bib0730">47–51</a>In addition to low 25 (OH) D levels, 1,25 (OH)2 D has been associated with higher mortality rates in most observational studies in patients with chronic kidney disease.<a class="elsevierStyleCrossRefs" href="#bib0750">51,52</a> Thus, special attention has been paid to vitamin D in the field of nephrology, given the classical known effect of vitamin D supplementation on the reduction of parathyroid hormone (PTH) levels. This is of great clinical significance, because PTH itself is an independent cardiovascular risk factor,<a class="elsevierStyleCrossRef" href="#bib0760">53</a> and secondary hyperparathyroidism is very common in patients with chronic kidney failure. It should be noted that this therapeutic effect of PTH decrease is achieved with both the active form (1,25 [OH]2 D) and with natural supplementation with vitamin D, although greater effects are seen with 1,25 [OH]2 D.<a class="elsevierStyleCrossRef" href="#bib0765">54</a>To ascertain the role of active vitamin D in chronic kidney failure, a systematic review was conducted of seven studies with meta-analysis and seven retrospective observational studies in patients with chronic kidney failure supplemented with 1,25 (OH)2 D or with the different analogs of active vitamin D. The authors found a significant reduction in all-cause mortality (RR 0.73, 95% CI: 0.65–0.82), and a 37% decrease in cardiovascular mortality (RR 0.63; 95% CI 0.44–0.92) in patients treated with active vitamin D.<a class="elsevierStyleCrossRef" href="#bib0770">55</a>While these data suggest the beneficial effects of treatment with vitamin D in patients with chronic kidney failure, the greatest impact was seen in the cardiovascular area. By contrast, a meta-analysis of randomized trials in the overall study populations, a great part of whom had kidney failure, also showed decreases in fractures and all-cause mortality with vitamin D supplementation.<a class="elsevierStyleCrossRefs" href="#bib0775">56,57</a>Atherosclerosis and endothelial dysfunctionSince the VDR is also expressed in the vasculature, the hypothesis that vitamin D may also protect against vascular diseases, including atherosclerosis and endothelial dysfunction, is tempting.<a class="elsevierStyleCrossRef" href="#bib0650">31</a> According to experimental studies, some vasculoprotective actions attributable to vitamin D may be mediated by increased nitric oxide production, the inhibition of macrophages in foam cell formation, or the decreased expression of adhesion molecules in endothelial cells.<a class="elsevierStyleCrossRefs" href="#bib0785">58–71</a> This is in agreement with cross-sectional observational studies showing that low vitamin D levels are associated with endothelial dysfunction and with increased arterial stiffness.<a class="elsevierStyleCrossRefs" href="#bib0525">6,27</a>Vitamin D deficiency has been shown to have a harmful effect on the macrophage ABCA1 system, altering its function and preventing cholesterol efflux promoting foam cell formation. Cytokines also speed up cholesterol synthesis within macrophages (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>).<elsevierMultimedia ident="fig0030"></elsevierMultimedia>The data from controlled clinical trials addressing the effects of vitamin D on vascular diseases are limited and show inconsistent results. However, encouraging effects in endothelial function have been reported with vitamin D in randomized clinical trials, although not all of them showed that vitamin D improves endothelial function.<a class="elsevierStyleCrossRefs" href="#bib0855">72–74</a>Vitamin D and cardiovascular eventsAs previously noted, decreased vitamin D levels have been associated with a greater incidence of cardiovascular events.<a class="elsevierStyleCrossRefs" href="#bib0545">10,55,75–77</a> Even asymptomatic coronary artery disease is associated with lower vitamin D levels in high-risk patients such as patients with T2DM (adjusted OR 2.9 [95% CI 2.0–7.0]), as reported in a recent observational study.<a class="elsevierStyleCrossRef" href="#bib0885">78</a> Thus, vitamin D deficiency has been associated with an increased risk of myocardial infarction and a significant inverse relationship between 25 (OH) D and matrix metalloproteinase-9, a marker of myocardial infarction after myocardial remodeling.<a class="elsevierStyleCrossRefs" href="#bib0890">79,80</a>Vitamin D levels also appear to predict the risk of adverse events after acute infarction and cardiac surgery, thus suggesting a greater risk for subjects with very low vitamin D levels, as reported in recent publications.<a class="elsevierStyleCrossRefs" href="#bib0900">81,82</a>Data from prospective observational studies suggest that low vitamin D levels are a risk factor for stroke<a class="elsevierStyleCrossRefs" href="#bib0910">83–85</a>. In a meta-analysis of seven studies comprising 47,809 subjects and 926 strokes, the risk of cerebrovascular disease was significantly lower in subjects with higher 25 (OH) D levels as compared to those with inadequate vitamin D levels.<a class="elsevierStyleCrossRef" href="#bib0915">84</a>Other authors investigated 19 studies comprising 65,994 patients and 6123 strokes and found that the lower the 25 (OH) D levels, the greater the risk (12). It should be noted, however, that not all individual studies showed a significant association between low 25 (OH) D levels and a greater risk of cardiovascular disease.<a class="elsevierStyleCrossRef" href="#bib0925">86</a>When all the above-mentioned studies are reviewed, confounding factors such as decreased mobility in patients with chronic diseases should be carefully weighted. Other confounding factors such as age or obesity rate, as well as PTH, renin, calcium, and phosphorus, cannot be completely ruled out as long as they are included as potential confounding factors in most analyses.<a class="elsevierStyleCrossRefs" href="#bib0570">15,87</a>Vitamin D supplementation and cardiovascular diseaseSome small, controlled clinical trials reported mixed vitamin D results in cardiovascular events,<a class="elsevierStyleCrossRefs" href="#bib0665">34,88</a> while mention should be made of some meta-analyses of these controlled clinical trials that found no significant trends in CV event reduction in patients who received vitamin D supplements as compared to placebo.<a class="elsevierStyleCrossRefs" href="#bib0940">89,90</a>It should be noted that vitamin D supplementation was combined with calcium supplementation, and interpretation of the results of controlled clinical trials is therefore difficult, especially when we know that calcium intake may be associated with greater cardiovascular risk, as suggested by a previous meta-analysis.<a class="elsevierStyleCrossRefs" href="#bib0945">90–93</a>Discussion and early epidemiological alert on the effects of vitamin D deficiency and cardiovascular risk in AmericaBased on the evidence currently available in the literature, it may be concluded that vitamin D deficiency is an independent cardiovascular risk factor that is associated with a greater risk of cardiovascular events. It is not clear, however, if these associations are causal in nature. Vitamin D should not be used to treat chronic diseases. It may be of help, but that is all. However, it appears plausible to take vitamin D deficiency as a very relevant marker of poor health, especially in patients with chronic diseases, including cardiovascular diseases and subjects with greater cardiovascular risk, so that, in this way, vitamin D may have a direct impact on cardiovascular results.<a class="elsevierStyleCrossRef" href="#bib0965">94</a>Despite these conflicting results, it is quite clear that vitamin D supplements have significant benefits in healthy populations, and also in patients with various comorbidities, particularly as regards prevention. It should be noted that most clinical studies have shown that the most beneficial effects of vitamin D supplementation occur in patients with very low 25 (OH) D levels. Such patients appear to have a greater risk of suffering cardiovascular diseases.<a class="elsevierStyleCrossRefs" href="#bib0550">11,12,22,23,62,95</a>Large scale studies are ongoing, including a study of 1000 patients with heart failure in Germany, another study assessing vitamin D in more than 5000 subjects in New Zealand, and a final study (the VITAL trial) using vitamin D and omega-3 to assess cardiovascular mortality and cancer in more than 20,000 US adults with no cancer or cardiovascular diseases at study start.<a class="elsevierStyleCrossRefs" href="#bib0975">96–98</a>ConclusionsVitamin D deficiency has multiple causes, and affects not only the inhabitants of countries at latitudes above 35°–40°, where there are no ultraviolet B rays for a good part of the year, but also the inhabitants of tropical countries, people with darker skin, obese subjects, and the elderly. Other causes include pollution in big cities, as in Mexico and elsewhere, which decreases ultraviolet radiation on the skin, and clothes and sun protectors, which reduce the capacity of the skin to synthesize vitamin D.It may thus be concluded that vitamin D deficiency is a potential independent cardiovascular risk factor and is involved in immunomodulation events which are extremely significant for inflammation and in the processes that accelerate cell proliferation (cancer). It also participates actively in the stimulation of the release of substances with antibacterial properties, cathelicidins, and defensin B4.Crossed communication between vitamin D receptors and other LXR heterodimers such as PPARy appears to determine significant functions in lipid metabolism and insulin release, and also an indirect protective effect of β cells of the islets of Langerhans. The cumulative evidence suggests a potential role of vitamin D in heart failure.Mexico and other countries in Latin America urgently need adequate assessment of the prevalence of vitamin D deficiency and its association with the risk of chronic diseases and cardiovascular risk, but especially of the role of vitamin D in the prevention of such conditions. 25 (OH) D levels are already a potential risk marker of great value in cardiology, but specific randomized clinical trials, some of which are ongoing, are required to ascertain if vitamin D supplementation may significantly increase cardiovascular outcomes. However, vitamin D should not be considered as a mainstay treatment for chronic diseases.Conflict of interestThe authors state that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres839356" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec834986" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres839355" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec834985" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Background" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Basic vitamin D metabolism" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Classification of vitamin D deficiency" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Prevalence of vitamin D deficiency" ] ] ] 5 => array:2 [ "identificador" => "sec0025" "titulo" => "Inflammation and vitamin D deficiency" ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Vitamin D and cardiovascular risk factors" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "High blood pressure and vitamin D deficiency" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Obesity and vitamin D deficiency" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Glucose metabolism, vitamin D, and type 2 diabetes mellitus" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Vitamin D and serum lipids" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Chronic kidney disease and vitamin D deficiency" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Atherosclerosis and endothelial dysfunction" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Vitamin D and cardiovascular events" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Vitamin D supplementation and cardiovascular disease" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Discussion and early epidemiological alert on the effects of vitamin D deficiency and cardiovascular risk in America" ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0085" "titulo" => "Conflict of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-07-15" "fechaAceptado" => "2016-11-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec834986" "palabras" => array:5 [ 0 => "Vitamin D" 1 => "Cardiovascular risk" 2 => "Pandemic" 3 => "Atherothrombosis" 4 => "America" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec834985" "palabras" => array:5 [ 0 => "Vitamina D" 1 => "Riesgo cardiovascular" 2 => "Pandemia" 3 => "Aterotrombosis" 4 => "América" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Vitamin D deficiency is a serious public health problem worldwide that affects not only skeletal health, but also a wide range of acute and chronic diseases. However, there is still skepticism because of the lack of randomized, controlled trials to support association studies on the benefits of vitamin D for non-skeletal health. This review was based on articles published during the 1980–2015 obtained from the Cochrane Central Register of controlled trials, MEDLINE and PubMed, and focuses on recent challenges with regard to the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D levels from dietary sources, supplements, and sun exposure. The effect of vitamin D on epigenetic fetal programming and regulation of genes that may potentially explain why vitamin D could have such lifelong comprehensive health benefits is reviewed. Optimization of vitamin D levels in children and adults around the world has potential benefits to improve skeletal health and to reduce the risk of chronic diseases, including some types of cancer, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, and severe cardiovascular disorders such as atherothrombosis, neurocognitive disorders, and mortality." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La deficiencia de vitamina D es un problema grave de salud pública en todo el mundo y que afecta no solo la salud músculo-esquelética sino también una amplia gama de enfermedades agudas y crónicas, incluyendo las no trasmisibles de riesgo cardiovascular, algunas enfermedades autoinmunes, metabólicas y mecanismos fisiopatológicos en obesidad. Sin embargo, subsiste el escepticismo de la falta de ensayos controlados aleatorizados para apoyar los estudios de asociación sobre los beneficios de salud no esqueléticos de vitamina D. Esta revisión fue obtenida de las bases de datos de MEDLINE, PubMed de 1980–2015 con respecto a la definición de deficiencia de vitamina D y su participación en trastornos proinflamatorios, inmunometabólicos y factores de riesgo cardiovascular. Se revisan las acciones de la vitamina D sobre la programación epigenética fetal y regulación de los genes que potencialmente podrían explicar por qué la vitamina D podría tener tales beneficios para la salud a lo largo de la vida en el humano. Hay potencialmente una ventaja en optimizar los niveles de la vitamina D de niños y adultos mayores en todo el mundo para mejorar no solo la salud músculo-esquelética, sino también para reducir el riesgo de enfermedades crónicas, incluyendo algunos factores de riesgo cardiovascular, así como ciertos tipos de cáncer, enfermedades autoinmunes, enfermedades infecciosas, diabetes mellitus tipo 2, trastornos cardiovasculares, incluyendo aterotrombosis, alteraciones neurocognitivas y, como consecuencia sobre la morbimortalidad global." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Rosas-Peralta M, Holick MF, Borrayo-Sánchez G, Madrid-Miller A, Ramírez-Árias E, Arizmendi-Uribe E. Efectos inmunometabólicos disfuncionales de la deficiencia de vitamina D y aumento de riesgo cardiometabólico. ¿Potencial alerta epidemiológica en América? Endocrinol Diabetes Nutr. 2017;64:162–173." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1925 "Ancho" => 2500 "Tamanyo" => 318667 ] ] "descripcion" => array:1 [ "en" => "Action sites of vitamin D. Note extraosseous effects. ©Modified from Hossein-Nezhad and Holick.<a class="elsevierStyleCrossRef" href="#bib0990">99</a>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3923 "Ancho" => 3000 "Tamanyo" => 1367798 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of vitamin D synthesis and metabolism for skeletal and non-skeletal functions. 1-OHase: 25 (OH) D 1α-hydroxylase; 24-OHasa: 24 hydroxylase; 25(OH)D: 25-hydroxyvitamin D; 1,25(OH)2D: 1,25-dihydroxyvitamin D; CaBP: calcium binding protein; DBP: vitamin D binding protein; ECaC: epithelial calcium channel; FGF-23: fibroblast growth factor-23; PTH: parathyroid hormone; RANK: receptor activator of nuclear factor kB (NFkB); RANKL: receptor activator of NFkB ligand; RXR: retinoic acid receptor; TLR2/1: toll-like receptor 2/1; VDR: vitamin D receptor; vitamin D: vitamin D2 or D3. ©Copyright Holick MF, 2013, coauthor of this study.<a class="elsevierStyleCrossRef" href="#bib0990">99</a>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2142 "Ancho" => 3333 "Tamanyo" => 453894 ] ] "descripcion" => array:1 [ "en" => "Reported prevalence of vitamin D deficiency, defined as 25-hydroxyvitamin D levels less than 20ng/mL in the worldwide population of pregnant women and the general population. Note the lack of information for Latin America. To convert 25 (OH) D levels to nmol/L, multiply by 2496. ©Copyright Holick 2013, reproduced with permission.<a class="elsevierStyleCrossRef" href="#bib0990">99</a>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1370 "Ancho" => 1667 "Tamanyo" => 181631 ] ] "descripcion" => array:1 [ "en" => "Vitamin D stimulates the production of cathelicidins and defensin B." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1556 "Ancho" => 3000 "Tamanyo" => 344933 ] ] "descripcion" => array:1 [ "en" => "Effects of vitamin D on immune response." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1537 "Ancho" => 2500 "Tamanyo" => 358721 ] ] "descripcion" => array:1 [ "en" => "Effects of vitamin D in atherosclerosis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:99 [ 0 => array:3 [ "identificador" => "bib0500" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin D deficiency" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMra070553" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2007" "volumen" => "357" "paginaInicial" => "266" "paginaFinal" => "281" "link" => array:1 [ …1] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0505" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin D and human health: lessons from vitamin D receptor null mice" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/er.2008-0004" "Revista" => array:6 [ "tituloSerie" => "Endocr Rev" "fecha" => "2008" "volumen" => "29" "paginaInicial" => "726" "paginaFinal" => "776" "link" => array:1 [ …1] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0510" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin D – effects on skeletal and extraskeletal health and the need for supplementation" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3390/nu5010111" "Revista" => array:6 [ "tituloSerie" => "Nutrients" "fecha" => "2013" "volumen" => "5" "paginaInicial" => "111" "paginaFinal" => "148" "link" => array:1 [ …1] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0515" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical practice" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.autrev.2010.06.009" "Revista" => array:6 [ "tituloSerie" => "Autoimmun Rev" "fecha" => "2010" "volumen" => "9" "paginaInicial" => "709" "paginaFinal" => "715" "link" => array:1 [ …1] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0520" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Can vitamin D deficiency cause diabetes and cardiovascular diseases? 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Review article

Dysfunctional immunometabolic effects of vitamin D deficiency, increased cardiometabolic risk. Potential epidemiological alert in America?

Efectos inmunometabólicos disfuncionales de la deficiencia de vitamina D y aumento de riesgo cardiometabólico. ¿Potencial alerta epidemiológica en América?

Martin Rosas-Peraltaa,

Corresponding author

mrosas_peralta@hotmail.com

Corresponding author.

, Michael F. Holickb, Gabriela Borrayo-Sánchezc, Alejandra Madrid-Millerd, Erick Ramírez-Áriase, Efrain Arizmendi-Uribef

a División de Investigación en Salud, Hospital de Cardiología, UMAE CMN Siglo XXI, Mexico City, Mexico

b Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA, United States

c Dirección Médica, Hospital de Cardiología, UMAE CMN Siglo XXI, Mexico City, Mexico

d Dirección de Educación e Investigación, Hospital de Cardiología, UMAE CMN Siglo XXI, Mexico City, Mexico

e Urgencias del Hospital de Cardiología, UMAE CMN Siglo XXI, Mexico City, Mexico

f Dirección General, Hospital de Cardiología, UMAE CMN Siglo XXI, Mexico City, Mexico

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being important for maintaining calcium homeostasis&#44; ensuring its physiological absorption from the bowel&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">1</span></a> The discovery of the vitamin D nuclear receptor &#40;VDR&#41;&#44; ubiquitously expressed in almost all body cells&#44; including immune&#44; vascular and myocardial cells&#44; suggested an implication of effects mediated by vitamin D in several systems other than musculoskeletal tissues<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">2</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">This led to comprehensive research into vitamin D as a factor with an influence on the pathogenesis of various non-skeletal acute and chronic diseases such as infection&#44; cancer&#44; psychiatric disorders&#44; and autoimmune diseases&#44; as well as cardiovascular risk factors such as high blood pressure&#44; dyslipidemia&#44; diabetes mellitus&#44; obesity&#44; and atherosclerosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">4&#8211;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Cardiovascular &#40;CV&#41; risk factors&#44; and cardiovascular diseases&#44; including myocardial infarction&#44; coronary artery disease and stroke&#44; are recognized as the most common diseases and represent the leading causes of death worldwide&#44; particularly in Western countries&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">7</span></a> In Mexico&#44; there has been a clear increase in cardiovascular risk factors in the past two decades&#44; and the same pandemic has occurred elsewhere in Latin America&#46; This emphasizes the importance of clarifying the role of vitamin D in the context of cardiovascular diseases and their most common risk factors&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">It has recently been reported that coronary artery disease&#44; especially myocardial infarction and heart failure&#44; affects 7&#46;9 and 5&#46;7 million adults in the United States respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">8&#44;9</span></a> Left ventricular abnormalities related to remodeling &#40;progressive dilation of the predominant chamber&#44; fibrosis&#44; and systolic&#47;diastolic dysfunction&#41; and heart failure often complicate an acute myocardial infarction&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">10&#44;11</span></a> Recent data suggest that the prevalence of ventricular dysfunction related to myocardial infarction and heart failure is associated with decreased vitamin D levels&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">11</span></a> Thus&#44; increasing attention is being paid to the role of vitamin D deficiency as a risk marker in the development of heart failure&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">As early as in 1981&#44; a study had reported seasonal variations in CV mortality and the potential positive effects of protection from UVB &#40;ultraviolet B&#41; radiation on CV risk&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">8</span></a> The association of vitamin D with CV risk factors and their associated diseases has been widely investigated in recent years&#46; Multiple observational studies&#44; prospective meta-analyses&#44; and some interventional studies have addressed the potential link with vitamin D deficiency&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">9&#8211;12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Patients with advanced heart failure are known to have significantly lower serum 25 &#40;OH&#41; D levels&#44; an independent risk factor associated with poor clinical outcomes and prolonged decompensation of heart failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">7&#44;13&#8211;15</span></a> VDR agonists such as calcitriol and its analogs&#44; including doxercalciferol&#44; have been developed to treat secondary hyperparathyroidism in chronic kidney disease&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">8</span></a> osteoporosis&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">11</span></a> and psoriasis&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Researchers are currently developing another candidate as a selective and effective VDR agonist for treating vitamin D deficiency in heart failure and the phenotypes associated with dysfunction in the renin&#8211;angiotensin&#8211;aldosterone system &#40;RAAS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">One of our central objectives is to lend scientific support to the urgent need to understand the prevalence of vitamin D deficiency in countries such as Mexico and elsewhere in Latin America&#44; where the pandemic of non-communicable chronic diseases is the main factor responsible for overall morbidity and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">16</span></a></p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Basic vitamin D metabolism</span><p id="par0050" class="elsevierStylePara elsevierViewall">Vitamin D3 is a steroid prohormone mainly derived from the synthesis induced by UVB radiation on dehydrocholesterol in the skin &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Endogenous synthesis is the main source of vitamin D in the body and accounts for approximately 80&#37; of the vitamin&#46; After synthesis in the skin or absorption from diet&#44; vitamin D is transported by a specific binding protein to the liver&#44; where it is hydroxylated to 25-hydroxyvitamin D&#46; This inactive form is the main metabolite circulating in blood&#44; and is also used to determine vitamin D status&#46;<a class="elsevierStyleCrossRefs" href="#bib0500"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">25-Hydroxyvitamin D is hydroxylated by the enzyme 1&#945;-hydroxylase &#40;1&#945;-OHase&#41; to its most active metabolite&#44; 1&#945;-25 &#40;OH&#41;<span class="elsevierStyleInf">2</span> D3&#44; mainly in the kidneys&#46; From this 1&#945;-hydroxylation it is known that it can also be activated by extrarenal 1&#945;-hydroxylation throughout the body<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">13&#44;14</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; This has led to the assumption that vitamin D plays a wider role in overall health&#44; including tissues beyond the musculoskeletal system such as the heart and blood vessels&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">15&#8211;17</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Classification of vitamin D deficiency</span><p id="par0065" class="elsevierStylePara elsevierViewall">Vitamin D status is categorized based on serum 25 &#40;OH&#41; D levels&#44; and the half-life of the vitamin is approximately 2&#8211;4 weeks&#46; However&#44; this half-life may be decreased even to less than a week in the event of hemodilution&#44; infection&#44; or other catabolic diseases&#44; or after the administration of corticosteroids&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A report by the United States Institute of Medicine &#40;IOM&#41; defines vitamin D deficiency as 25 &#40;OH&#41; D levels less then 12<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;multiply by 2496 to convert ng&#47;mL to nmol&#47;L&#41;&#44; while values of 20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL or higher are considered adequate&#46; On the other hand&#44; the guidelines of the Endocrine Society of America<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">14</span></a> suggest that 25 &#40;OH&#41; D levels &#8804;20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL are deficient and that values &#8805;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL are sufficient&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">14&#8211;16</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Prevalence of vitamin D deficiency</span><p id="par0080" class="elsevierStylePara elsevierViewall">Vitamin D deficiency and insufficiency are highly prevalent&#44; as is shown by the fact that more than half of the population worldwide has levels lower than 30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">13&#44;16</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; However&#44; the prevalence of the deficiency in countries such as Mexico is not known&#44; which should alert the medical community&#46; There are various risk factors for vitamin D deficiency that should always be taken into account&#44; including age&#44; female sex&#44; pigmentation in darker skin&#44; decreased sun exposure&#44; seasonal variation and distance from the Equator&#46; Special mention should be made of air pollution&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">17&#44;18</span></a> Studies on the impact of pollution on vitamin D should be conducted in cities with high pollution levels because of their unique population and geodemographic conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">11&#44;19&#8211;21</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Inflammation and vitamin D deficiency</span><p id="par0085" class="elsevierStylePara elsevierViewall">Apart from its traditional role as a modulator of calcium metabolism and bone homeostasis&#44; vitamin D has been shown to have potent anti-inflammatory effects&#46; Because of this&#44; it has been considered as adjuvant therapy for many chronic diseases such as asthma&#44; arthritis&#44; prostate cancer and psoriasis&#44; amongst others&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">4&#44;22&#44;23</span></a> A variety of both pro-inflammatory and anti-inflammatory effects of vitamin D had previously been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">24&#44;25</span></a> It has also been shown that vitamin D may directly induce the production of important antimicrobial peptides such as cathelicidins and defensin &#946;<span class="elsevierStyleInf">4</span> in monocytes&#47;macrophages and in human epithelial cells<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">13&#44;26</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">1&#44;25-&#40;OH&#41;<span class="elsevierStyleInf">2</span> D3 has been shown to have antiproliferative and proapoptotic activity in tumor cells due to the induction of the cyclin-dependent kinase inhibitors p27Kip1 and p21Waf&#47;Cip1 and the inhibition of c-Myc and antiapoptotics such as Bcl-2&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">23</span></a> Moreover&#44; vitamin D was shown to suppress the action pathways of prostaglandins in tumor cell lines through the inhibition of cyclooxygenase-2 production and the stimulation of 15-hydroxyprostaglandin production by the cells&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Vitamin D has also been shown to interfere with the activation and signaling of nuclear factor &#40;NF&#41; kB by increasing the expression of <span class="elsevierStyleSmallCaps">I</span>&#954;B&#945; in activated cells&#44; and to interfere with the nuclear translocation of subunits of NF-&#954;B&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">4</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">It has also been reported that vitamin D may influence dendritic cell maturation and function&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">27</span></a> Several studies have shown the ability of vitamin D to modulate the population and role of FOXP3-positive regulatory T cells and the production of IL-10<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">27</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The interaction of peroxisome proliferator-activated receptors &#40;PPARs&#41; and the VDR has been widely studied&#44; because they both form heterodimers with LXR&#46; The potential modulation of PPARy activity has been implicated in many metabolic processes&#44; especially in lipids and in mechanisms for insulin release from &#946; cells in the islets of Langerhans&#46; Additional results of this transcriptome have shown that vitamin D regulates proadipogenic PPARy in activated macrophages&#46; PPARy agonists reverse the antiadipogenic and antimicrobial effects attributed to the vitamin D receptor&#44; which suggests a link between the VDR and signaling in the regulation of processes of two-directional functions between vitamin D and PPARy&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Vitamin D and cardiovascular risk factors</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">High blood pressure and vitamin D deficiency</span><p id="par0110" class="elsevierStylePara elsevierViewall">Vitamin D deficiency has been associated with higher blood pressure levels&#44; as is shown in most prospective studies and in meta-analyses of observational studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">9&#44;29&#44;30</span></a> Reported blood pressure variations may be explained by differences in vitamin D levels between the studies&#44; which have often been relatively small&#46; However&#44; the additive role in antihypertensive drug treatment has clinical relevance&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The potential mechanisms for this association of vitamin D and blood pressure include an inverse association of vitamin D with RAAS activity&#44; the effect of improved endothelial function&#44; and the prevention of secondary hyperparathyroidism&#44; all of them mechanisms of interest&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">24&#8211;27</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In this regard&#44; it should be noted that high parathyroid hormone levels are a distinctive feature of vitamin D deficiency&#44; and are known to be associated with myocardial infarction and higher blood pressure levels&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a> In addition&#44; there is an increasing evidence to suggest that mutual interactions between PTH&#44; vitamin D&#44; and aldosterone are involved in damage to the cardiovascular system independently of the RAAS&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">31&#44;32</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">A significant inverse association has been reported between circulating serum vitamin D levels and the incident risk of hypertension&#46; The combined relative risk &#40;RR&#41; was 0&#46;70&#59; the confidence interval &#40;95&#37; confidence interval&#58; 0&#46;57&#8211;0&#46;86&#41; after comparing the highest value to the lowest tertile of the baseline 25 &#40;OH&#41; D levels&#44; with no evidence of heterogeneity between the results&#46; Therefore&#44; when dosage response in the five studies that reported RRs for exposure to vitamin D was assessed&#44; the authors found that the risk of high blood pressure decreased 12&#37; with each 10<span class="elsevierStyleHsp" style=""></span>ng&#47;mL increase in 25 &#40;OH&#41; D levels&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">29</span></a> Several randomized clinical trials assessing the effect of vitamin D on blood pressure levels published in 2012 reported different results&#46;<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">23&#8211;25</span></a> A controlled clinical study was conducted in Denmark on 130 hypertensive patients who during the winter months received supplements of 3000<span class="elsevierStyleHsp" style=""></span>IU of vitamin D versus placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">23</span></a> Ambulatory blood pressure monitoring &#40;ABPM&#41; for 24<span class="elsevierStyleHsp" style=""></span>h showed a non-significant decrease in blood pressure &#40;&#8722;3<span class="elsevierStyleHsp" style=""></span>mmHg&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;26&#8211;1<span class="elsevierStyleHsp" style=""></span>mmHg&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;18&#41;&#46; Interestingly&#44; when only patients with vitamin D deficiency &#40;25 &#91;OH&#93; D less than 32<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; were analyzed&#44; systolic and diastolic BP values significantly decreased in 24-h ABPM &#40;&#8722;4<span class="elsevierStyleHsp" style=""></span>mmHg&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#8211;3<span class="elsevierStyleHsp" style=""></span>mmHg&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; in the treatment group as compared to the placebo group&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">23</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">In an unselected Black population&#44; vitamin D supplementation decreased systolic BP by 0&#46;2<span class="elsevierStyleHsp" style=""></span>mmHg per each 1<span class="elsevierStyleHsp" style=""></span>ng&#47;mL increase in vitamin D during the 3 months of treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Obesity and vitamin D deficiency</span><p id="par0135" class="elsevierStylePara elsevierViewall">Obesity is closely related to vitamin D deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">25</span></a> It has been suggested that this may be due to vitamin D sequestration in adipose tissue&#44; which results in lower circulating 25 &#40;OH&#41; D levels&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">31</span></a> Other authors have hypothesized a causal relationship with vitamin D deficiency that may lead to the promotion of obesity&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">27</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">A bidirectional Mendelian randomization study was conducted to address this question&#46; The study showed a unidirectional causal relationship&#44; which suggests that obesity leads to a reduction of vitamin D levels&#44; rather than the opposite&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a> That research&#44; including 21 cohort studies with a total sample of 42&#44;024 patients&#44; found 12 established single nucleotide polymorphisms &#40;SNP&#41; related to the BMI and four typical SNPs associated with vitamin D status&#46; It cannot be ignored that there has been a great increase in the prevalence of overweight and obesity in countries such as Mexico and in Latin America in general&#46; On the other hand&#44; genetically determined 25 &#40;OH&#41; D levels are not significantly related to the body mass index&#46; Thus&#44; obesity is known to be a pro-inflammatory state that has been related to abnormally high C-reactive levels&#44; with a significant role being played by pro-inflammatory mediation in vitamin D deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Glucose metabolism&#44; vitamin D&#44; and type 2 diabetes mellitus</span><p id="par0145" class="elsevierStylePara elsevierViewall">In observational and prospective studies&#44; low vitamin D levels have been related to changes in glucose metabolism and to a greater risk of the development of diabetes in the future&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">5&#44;30&#8211;33</span></a> It should also be noted that vitamin D deficiency in diabetic patients may be partly due to a reduction of physical activity and to obesity&#44; as well as to limited sun exposure&#46; Thus&#44; residual confusion in observational studies due to the close relationship of obesity with glucose intolerance and vitamin D deficiency cannot be ruled out with certainty&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">26&#44;34</span></a> On the other hand&#44; inverse causality may exist&#44; as there are data suggesting that an inflammatory state may be decreased by 25 &#40;OH&#41; D&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">33&#44;35&#8211;37</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">There are however several potential mechanisms that could explain the association of vitamin D deficiency with changes in glucose homeostasis and diabetes mellitus&#46; Both the VDR and 1-&#945;-hydroxylase are expressed in pancreatic beta cells&#44; which suggests a potential role of vitamin D in beta cell function&#46; In addition&#44; the interaction of VDR and PPARy has been suggested as a mechanism related to adequate insulin release&#46;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">2&#44;38</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">However&#44; randomized trials have not shown that vitamin D supplements clearly improve blood glucose or insulin resistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">37&#44;38</span></a> It remains to be clarified whether drug treatment for diabetes may help optimize metabolic control&#46; To address this issue&#44; a randomized clinical study was conducted in subjects with prediabetes and hypovitaminosis D&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">39</span></a> The study participants were randomized to treatment with high vitamin D doses compared to placebo &#40;mean weekly dose&#44; 88&#44;865<span class="elsevierStyleHsp" style=""></span>IU&#41;&#46; After the administration of vitamin D for 1 year&#44; no differences were seen in plasma glucose&#44; insulin secretion and sensitivity&#44; or in the development of diabetes between the treatment and placebo groups&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Vitamin D and serum lipids</span><p id="par0160" class="elsevierStylePara elsevierViewall">Some observational studies suggest an association of vitamin D deficiency with low high density lipoprotein &#40;HDL&#41; levels&#44; high triglyceride levels&#44; and higher apolipoprotein E levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0695"><span class="elsevierStyleSup">40&#44;41</span></a> A prospective evaluation of vitamin D and lipid levels showed a significant association between low 25 &#91;OH&#93; D levels and hypercholesterolemia&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">42</span></a> It should be noted&#44; however&#44; that blood lipid and vitamin D levels may be confounded by the above mentioned relationship between vitamin D and obesity&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">28</span></a> Recent clinical studies evaluating the effect of vitamin D supplementation on blood lipids provided no conclusive evidence&#46;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">24&#44;43&#8211;45</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Chronic kidney disease and vitamin D deficiency</span><p id="par0170" class="elsevierStylePara elsevierViewall">Patients with chronic kidney disease have significantly lower vitamin D levels as compared to the overall population&#46; Thus&#44; a high prevalence of vitamin D deficiency&#44; with levels less than 20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; was seen in more than 70&#37; of patients on dialysis&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">46</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In addition&#44; several epidemiological studies showed that low 25 &#40;OH&#41; D levels are associated with albuminuria or progression to renal failure&#46; Vitamin D deficiency has also been identified in patients with chronic kidney disease as an independent risk factor for increased mortality&#44; which may mainly be attributed to cardiovascular death&#46;<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">47&#8211;51</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In addition to low 25 &#40;OH&#41; D levels&#44; 1&#44;25 &#40;OH&#41;<span class="elsevierStyleInf">2</span> D has been associated with higher mortality rates in most observational studies in patients with chronic kidney disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">51&#44;52</span></a> Thus&#44; special attention has been paid to vitamin D in the field of nephrology&#44; given the classical known effect of vitamin D supplementation on the reduction of parathyroid hormone &#40;PTH&#41; levels&#46; This is of great clinical significance&#44; because PTH itself is an independent cardiovascular risk factor&#44;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">53</span></a> and secondary hyperparathyroidism is very common in patients with chronic kidney failure&#46; It should be noted that this therapeutic effect of PTH decrease is achieved with both the active form &#40;1&#44;25 &#91;OH&#93;<span class="elsevierStyleInf">2</span> D&#41; and with natural supplementation with vitamin D&#44; although greater effects are seen with 1&#44;25 &#91;OH&#93;<span class="elsevierStyleInf">2</span> D&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">54</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">To ascertain the role of active vitamin D in chronic kidney failure&#44; a systematic review was conducted of seven studies with meta-analysis and seven retrospective observational studies in patients with chronic kidney failure supplemented with 1&#44;25 &#40;OH&#41;<span class="elsevierStyleInf">2</span> D or with the different analogs of active vitamin D&#46; The authors found a significant reduction in all-cause mortality &#40;RR 0&#46;73&#44; 95&#37; CI&#58; 0&#46;65&#8211;0&#46;82&#41;&#44; and a 37&#37; decrease in cardiovascular mortality &#40;RR 0&#46;63&#59; 95&#37; CI 0&#46;44&#8211;0&#46;92&#41; in patients treated with active vitamin D&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">55</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">While these data suggest the beneficial effects of treatment with vitamin D in patients with chronic kidney failure&#44; the greatest impact was seen in the cardiovascular area&#46; By contrast&#44; a meta-analysis of randomized trials in the overall study populations&#44; a great part of whom had kidney failure&#44; also showed decreases in fractures and all-cause mortality with vitamin D supplementation&#46;<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">56&#44;57</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Atherosclerosis and endothelial dysfunction</span><p id="par0195" class="elsevierStylePara elsevierViewall">Since the VDR is also expressed in the vasculature&#44; the hypothesis that vitamin D may also protect against vascular diseases&#44; including atherosclerosis and endothelial dysfunction&#44; is tempting&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">31</span></a> According to experimental studies&#44; some vasculoprotective actions attributable to vitamin D may be mediated by increased nitric oxide production&#44; the inhibition of macrophages in foam cell formation&#44; or the decreased expression of adhesion molecules in endothelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0785"><span class="elsevierStyleSup">58&#8211;71</span></a> This is in agreement with cross-sectional observational studies showing that low vitamin D levels are associated with endothelial dysfunction and with increased arterial stiffness&#46;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">6&#44;27</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Vitamin D deficiency has been shown to have a harmful effect on the macrophage ABCA1 system&#44; altering its function and preventing cholesterol efflux promoting foam cell formation&#46; Cytokines also speed up cholesterol synthesis within macrophages &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0205" class="elsevierStylePara elsevierViewall">The data from controlled clinical trials addressing the effects of vitamin D on vascular diseases are limited and show inconsistent results&#46; However&#44; encouraging effects in endothelial function have been reported with vitamin D in randomized clinical trials&#44; although not all of them showed that vitamin D improves endothelial function&#46;<a class="elsevierStyleCrossRefs" href="#bib0855"><span class="elsevierStyleSup">72&#8211;74</span></a></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Vitamin D and cardiovascular events</span><p id="par0210" class="elsevierStylePara elsevierViewall">As previously noted&#44; decreased vitamin D levels have been associated with a greater incidence of cardiovascular events&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">10&#44;55&#44;75&#8211;77</span></a> Even asymptomatic coronary artery disease is associated with lower vitamin D levels in high-risk patients such as patients with T2DM &#40;adjusted OR 2&#46;9 &#91;95&#37; CI 2&#46;0&#8211;7&#46;0&#93;&#41;&#44; as reported in a recent observational study&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">78</span></a> Thus&#44; vitamin D deficiency has been associated with an increased risk of myocardial infarction and a significant inverse relationship between 25 &#40;OH&#41; D and matrix metalloproteinase-9&#44; a marker of myocardial infarction after myocardial remodeling&#46;<a class="elsevierStyleCrossRefs" href="#bib0890"><span class="elsevierStyleSup">79&#44;80</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Vitamin D levels also appear to predict the risk of adverse events after acute infarction and cardiac surgery&#44; thus suggesting a greater risk for subjects with very low vitamin D levels&#44; as reported in recent publications&#46;<a class="elsevierStyleCrossRefs" href="#bib0900"><span class="elsevierStyleSup">81&#44;82</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Data from prospective observational studies suggest that low vitamin D levels are a risk factor for stroke<a class="elsevierStyleCrossRefs" href="#bib0910"><span class="elsevierStyleSup">83&#8211;85</span></a>&#46; In a meta-analysis of seven studies comprising 47&#44;809 subjects and 926 strokes&#44; the risk of cerebrovascular disease was significantly lower in subjects with higher 25 &#40;OH&#41; D levels as compared to those with inadequate vitamin D levels&#46;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">84</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Other authors investigated 19 studies comprising 65&#44;994 patients and 6123 strokes and found that the lower the 25 &#40;OH&#41; D levels&#44; the greater the risk &#40;12&#41;&#46; It should be noted&#44; however&#44; that not all individual studies showed a significant association between low 25 &#40;OH&#41; D levels and a greater risk of cardiovascular disease&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">86</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">When all the above-mentioned studies are reviewed&#44; confounding factors such as decreased mobility in patients with chronic diseases should be carefully weighted&#46; Other confounding factors such as age or obesity rate&#44; as well as PTH&#44; renin&#44; calcium&#44; and phosphorus&#44; cannot be completely ruled out as long as they are included as potential confounding factors in most analyses&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">15&#44;87</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Vitamin D supplementation and cardiovascular disease</span><p id="par0235" class="elsevierStylePara elsevierViewall">Some small&#44; controlled clinical trials reported mixed vitamin D results in cardiovascular events&#44;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">34&#44;88</span></a> while mention should be made of some meta-analyses of these controlled clinical trials that found no significant trends in CV event reduction in patients who received vitamin D supplements as compared to placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0940"><span class="elsevierStyleSup">89&#44;90</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">It should be noted that vitamin D supplementation was combined with calcium supplementation&#44; and interpretation of the results of controlled clinical trials is therefore difficult&#44; especially when we know that calcium intake may be associated with greater cardiovascular risk&#44; as suggested by a previous meta-analysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0945"><span class="elsevierStyleSup">90&#8211;93</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion and early epidemiological alert on the effects of vitamin D deficiency and cardiovascular risk in America</span><p id="par0245" class="elsevierStylePara elsevierViewall">Based on the evidence currently available in the literature&#44; it may be concluded that vitamin D deficiency is an independent cardiovascular risk factor that is associated with a greater risk of cardiovascular events&#46; It is not clear&#44; however&#44; if these associations are causal in nature&#46; Vitamin D should not be used to treat chronic diseases&#46; It may be of help&#44; but that is all&#46; However&#44; it appears plausible to take vitamin D deficiency as a very relevant marker of poor health&#44; especially in patients with chronic diseases&#44; including cardiovascular diseases and subjects with greater cardiovascular risk&#44; so that&#44; in this way&#44; vitamin D may have a direct impact on cardiovascular results&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">94</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">Despite these conflicting results&#44; it is quite clear that vitamin D supplements have significant benefits in healthy populations&#44; and also in patients with various comorbidities&#44; particularly as regards prevention&#46; It should be noted that most clinical studies have shown that the most beneficial effects of vitamin D supplementation occur in patients with very low 25 &#40;OH&#41; D levels&#46; Such patients appear to have a greater risk of suffering cardiovascular diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">11&#44;12&#44;22&#44;23&#44;62&#44;95</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Large scale studies are ongoing&#44; including a study of 1000 patients with heart failure in Germany&#44; another study assessing vitamin D in more than 5000 subjects in New Zealand&#44; and a final study &#40;the VITAL trial&#41; using vitamin D and omega-3 to assess cardiovascular mortality and cancer in more than 20&#44;000 US adults with no cancer or cardiovascular diseases at study start&#46;<a class="elsevierStyleCrossRefs" href="#bib0975"><span class="elsevierStyleSup">96&#8211;98</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conclusions</span><p id="par0260" class="elsevierStylePara elsevierViewall">Vitamin D deficiency has multiple causes&#44; and affects not only the inhabitants of countries at latitudes above 35&#176;&#8211;40&#176;&#44; where there are no ultraviolet B rays for a good part of the year&#44; but also the inhabitants of tropical countries&#44; people with darker skin&#44; obese subjects&#44; and the elderly&#46; Other causes include pollution in big cities&#44; as in Mexico and elsewhere&#44; which decreases ultraviolet radiation on the skin&#44; and clothes and sun protectors&#44; which reduce the capacity of the skin to synthesize vitamin D&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">It may thus be concluded that vitamin D deficiency is a potential independent cardiovascular risk factor and is involved in immunomodulation events which are extremely significant for inflammation and in the processes that accelerate cell proliferation &#40;cancer&#41;&#46; It also participates actively in the stimulation of the release of substances with antibacterial properties&#44; cathelicidins&#44; and defensin B4&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Crossed communication between vitamin D receptors and other LXR heterodimers such as PPARy appears to determine significant functions in lipid metabolism and insulin release&#44; and also an indirect protective effect of &#946; cells of the islets of Langerhans&#46; The cumulative evidence suggests a potential role of vitamin D in heart failure&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Mexico and other countries in Latin America urgently need adequate assessment of the prevalence of vitamin D deficiency and its association with the risk of chronic diseases and cardiovascular risk&#44; but especially of the role of vitamin D in the prevention of such conditions&#46; 25 &#40;OH&#41; D levels are already a potential risk marker of great value in cardiology&#44; but specific randomized clinical trials&#44; some of which are ongoing&#44; are required to ascertain if vitamin D supplementation may significantly increase cardiovascular outcomes&#46; However&#44; vitamin D should not be considered as a mainstay treatment for chronic diseases&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0280" class="elsevierStylePara elsevierViewall">The authors state that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Background"
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              "identificador" => "sec0010"
              "titulo" => "Basic vitamin D metabolism"
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            1 => array:2 [
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              "titulo" => "Classification of vitamin D deficiency"
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            2 => array:2 [
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          "titulo" => "Inflammation and vitamin D deficiency"
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          "titulo" => "Vitamin D and cardiovascular risk factors"
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              "titulo" => "Glucose metabolism&#44; vitamin D&#44; and type 2 diabetes mellitus"
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              "titulo" => "Vitamin D and serum lipids"
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              "titulo" => "Chronic kidney disease and vitamin D deficiency"
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              "titulo" => "Atherosclerosis and endothelial dysfunction"
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          "titulo" => "Vitamin D supplementation and cardiovascular disease"
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          "titulo" => "Discussion and early epidemiological alert on the effects of vitamin D deficiency and cardiovascular risk in America"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Vitamin D deficiency is a serious public health problem worldwide that affects not only skeletal health&#44; but also a wide range of acute and chronic diseases&#46; However&#44; there is still skepticism because of the lack of randomized&#44; controlled trials to support association studies on the benefits of vitamin D for non-skeletal health&#46; This review was based on articles published during the 1980&#8211;2015 obtained from the Cochrane Central Register of controlled trials&#44; MEDLINE and PubMed&#44; and focuses on recent challenges with regard to the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D levels from dietary sources&#44; supplements&#44; and sun exposure&#46; The effect of vitamin D on epigenetic fetal programming and regulation of genes that may potentially explain why vitamin D could have such lifelong comprehensive health benefits is reviewed&#46; Optimization of vitamin D levels in children and adults around the world has potential benefits to improve skeletal health and to reduce the risk of chronic diseases&#44; including some types of cancer&#44; autoimmune diseases&#44; infectious diseases&#44; type 2 diabetes mellitus&#44; and severe cardiovascular disorders such as atherothrombosis&#44; neurocognitive disorders&#44; and mortality&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La deficiencia de vitamina D es un problema grave de salud p&#250;blica en todo el mundo y que afecta no solo la salud m&#250;sculo-esquel&#233;tica sino tambi&#233;n una amplia gama de enfermedades agudas y cr&#243;nicas&#44; incluyendo las no trasmisibles de riesgo cardiovascular&#44; algunas enfermedades autoinmunes&#44; metab&#243;licas y mecanismos fisiopatol&#243;gicos en obesidad&#46; Sin embargo&#44; subsiste el escepticismo de la falta de ensayos controlados aleatorizados para apoyar los estudios de asociaci&#243;n sobre los beneficios de salud no esquel&#233;ticos de vitamina D&#46; Esta revisi&#243;n fue obtenida de las bases de datos de MEDLINE&#44; PubMed de 1980&#8211;2015 con respecto a la definici&#243;n de deficiencia de vitamina D y su participaci&#243;n en trastornos proinflamatorios&#44; inmunometab&#243;licos y factores de riesgo cardiovascular&#46; Se revisan las acciones de la vitamina D sobre la programaci&#243;n epigen&#233;tica fetal y regulaci&#243;n de los genes que potencialmente podr&#237;an explicar por qu&#233; la vitamina D podr&#237;a tener tales beneficios para la salud a lo largo de la vida en el humano&#46; Hay potencialmente una ventaja en optimizar los niveles de la vitamina D de ni&#241;os y adultos mayores en todo el mundo para mejorar no solo la salud m&#250;sculo-esquel&#233;tica&#44; sino tambi&#233;n para reducir el riesgo de enfermedades cr&#243;nicas&#44; incluyendo algunos factores de riesgo cardiovascular&#44; as&#237; como ciertos tipos de c&#225;ncer&#44; enfermedades autoinmunes&#44; enfermedades infecciosas&#44; diabetes mellitus tipo 2&#44; trastornos cardiovasculares&#44; incluyendo aterotrombosis&#44; alteraciones neurocognitivas y&#44; como consecuencia sobre la morbimortalidad global&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Rosas-Peralta M&#44; Holick MF&#44; Borrayo-S&#225;nchez G&#44; Madrid-Miller A&#44; Ram&#237;rez-&#193;rias E&#44; Arizmendi-Uribe E&#46; Efectos inmunometab&#243;licos disfuncionales de la deficiencia de vitamina D y aumento de riesgo cardiometab&#243;lico&#46; &#191;Potencial alerta epidemiol&#243;gica en Am&#233;rica&#63; Endocrinol Diabetes Nutr&#46; 2017&#59;64&#58;162&#8211;173&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Action sites of vitamin D&#46; Note extraosseous effects&#46; &#169;Modified from Hossein-Nezhad and Holick&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">99</span></a></p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of vitamin D synthesis and metabolism for skeletal and non-skeletal functions&#46; 1-OHase&#58; 25 &#40;OH&#41; D 1&#945;-hydroxylase&#59; 24-OHasa&#58; 24 hydroxylase&#59; 25&#40;OH&#41;D&#58; 25-hydroxyvitamin D&#59; 1&#44;25&#40;OH&#41;2D&#58; 1&#44;25-dihydroxyvitamin D&#59; CaBP&#58; calcium binding protein&#59; DBP&#58; vitamin D binding protein&#59; ECaC&#58; epithelial calcium channel&#59; FGF-23&#58; fibroblast growth factor-23&#59; PTH&#58; parathyroid hormone&#59; RANK&#58; receptor activator of nuclear factor kB &#40;NFkB&#41;&#59; RANKL&#58; receptor activator of NFkB ligand&#59; RXR&#58; retinoic acid receptor&#59; TLR2&#47;1&#58; toll-like receptor 2&#47;1&#59; VDR&#58; vitamin D receptor&#59; vitamin D&#58; vitamin D2 or D3&#46; &#169;Copyright Holick MF&#44; 2013&#44; coauthor of this study&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">99</span></a></p>"
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              "identificador" => "bib0505"
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            ]
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              "identificador" => "bib0515"
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                  "contribucion" => array:1 [
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                  ]
                  "host" => array:1 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
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Article information

ISSN: 25300180
Original language: English

DOI:10.1016/j.endien.2017.04.006

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Year/Month	Html	Pdf	Total

2024 October	25	5	30
2024 September	42	13	55
2024 August	40	18	58
2024 July	45	2	47
2024 June	30	6	36
2024 May	25	11	36
2024 April	45	7	52
2024 March	70	6	76
2024 February	99	18	117
2024 January	72	9	81
2023 December	89	15	104
2023 November	141	7	148
2023 October	161	14	175
2023 September	80	4	84
2023 August	66	7	73
2023 July	114	5	119
2023 June	101	12	113
2023 May	179	16	195
2023 April	195	72	267
2023 March	185	14	199
2023 February	188	12	200
2023 January	149	10	159
2022 December	110	22	132
2022 November	156	21	177
2022 October	178	28	206
2022 September	157	34	191
2022 August	102	26	128
2022 July	121	20	141
2022 June	133	22	155
2022 May	146	26	172
2022 April	182	32	214
2022 March	187	48	235
2022 February	163	26	189
2022 January	246	28	274
2021 December	144	31	175
2021 November	189	35	224
2021 October	196	46	242
2021 September	133	38	171
2021 August	160	41	201
2021 July	140	30	170
2021 June	330	25	355
2021 May	262	24	286
2021 April	548	59	607
2021 March	463	50	513
2021 February	373	19	392
2021 January	204	32	236
2020 December	182	28	210
2020 November	261	52	313
2020 October	150	30	180
2020 September	234	38	272
2020 August	203	28	231
2020 July	197	55	252
2020 June	192	34	226
2020 May	248	64	312
2020 April	239	41	280
2020 March	182	27	209
2020 February	154	33	187
2020 January	140	31	171
2019 December	156	15	171
2019 November	174	25	199
2019 October	162	24	186
2019 September	133	19	152
2019 August	89	9	98
2019 July	125	26	151
2019 June	131	36	167
2019 May	114	38	152
2019 April	122	47	169
2019 March	30	2	32
2019 February	76	13	89
2019 January	39	11	50
2018 December	42	7	49
2018 November	84	7	91
2018 October	93	3	96
2018 September	205	16	221
2018 August	84	1	85
2018 July	50	6	56
2018 June	63	10	73
2018 May	63	15	78
2018 April	48	12	60
2018 March	23	0	23
2018 February	28	2	30
2018 January	11	0	11
2017 December	6	1	7
2017 November	12	1	13
2017 October	19	2	21
2017 September	26	7	33
2017 August	1	0	1

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