A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Effect of vitamin D supplementation on inflammation: protocol for a systematic review The effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease Effect of a single, oral, high-dose vitamin D supplementation on endothelial function in patients with peripheral arterial disease: a randomised controlled pilot study. Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Impact of vitamin D supplementation on markers of inflammation in adults with cystic fibrosis hospitalized for a pulmonary exacerbation Effects of vitamin D supplementation on markers of vascular function after myocardial infarction--a randomised controlled trial. Effect of short-term vitamin D supplementation on markers of vascular health in South Asian women living in the UK--a randomised controlled trial. Effect of vitamin D supplementation on inflammation and nuclear factor kappa-B activity in overweight/obese adults: a randomized placebo-controlled trial Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. A randomised controlled trial evaluating the impact of targeted vitamin D supplementation on endothelial function in type 2 diabetes mellitus: The DIMENSION trial Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol Supplementation with orange and blackcurrant juice, but not vitamin E, improves inflammatory markers in patients with peripheral arterial disease. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Effects of sodium and potassium supplementation on endothelial function: a fully controlled dietary intervention study. Why randomized controlled trials of calcium and vitamin D sometimes fail
Introduction Vitamin D has potential benefits for extraskeletal health . These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction . We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function ( EF ) , possibly through the abrogation of systemic inflammation . Methods and analysis We will conduct a systematic review of all r and omised controlled trials on  vitamin D supplementation and EF lasting 12 weeks or more . The search will cover the period 2000–2015 and include studies that describe direct measures of EF  , markers of endothelial cell ( EC ) activation  and if concurrently reported , indicators of systemic inflammation  . Study selection will follow the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis . If sufficient data are available , a meta- analysis will be conducted . The effect sizes will be generated using Hedges ’ g score , for both fixed and r and om effect models . I2 statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources . Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger 's test . Meta-regression analysis ( if feasible ) will be conducted with restricted maximum likelihood ( REML ) estimation method , controlling for potential confounders ( demographics , study methods , location , etc ) . A backward elimination process will be applied in the regression modelling procedure . Subgroup analysis , conditional on number of studies retrieved and their sample size , will be stratified on participant disease category , total dose administered , degree of 25(OH)D change and type of supplement used . Ethics and dissemination Formal ethical approval is not required as primary data will not be collected . The results will be disseminated through a peer- review ed publication , conference presentation and the popular press . Trial registration number International Prospect i ve Register for Systematic Review s ( PROSPERO ) number CRD42014013523 Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104 Adequate vitamin D levels may promote cardiovascular health by improving endothelial function and down-regulating inflammation . The objective of this pilot trial was to investigate the effects of vitamin D repletion on endothelial function and inflammation in patients with coronary artery disease ( CAD ) . Using a double-blind placebo wait-list control design , 90 subjects with CAD and vitamin D deficiency ( < 20 ng/ml ) were r and omized 1:1 to 50,000 IU of oral ergocalciferol or placebo weekly for 12 weeks . Endothelial function ( reactive hyperemia peripheral arterial tonometry , RH-PAT ) , circulating adhesion molecules , and pro-inflammatory cytokines were measured at baseline and 12 weeks . The median increase in serum 25-vitamin D from baseline was 26 ± 17 ng/ml in the active group and 4 ± 8 ng/ml in the placebo group ( between-group difference = 22 ng/ml , p < 0.001 ) . The median within-subject change in RH-PAT score was 0.13 ± 0.73 with active treatment and −0.04 ± 0.63 with placebo ( between-group difference = 0.17 , p = 0.44 ) . Within-group and between-group differences in intercellular adhesion molecule levels were greater with placebo ( between-group difference = 6 ng/ml , p = 0.048 ) . Vascular cell adhesion molecule levels decreased in both groups by a similar magnitude ( median difference between groups = 8.5 ng/ml , p = 0.79 ) . There was no difference between groups in magnitude of reduction in interleukin (IL)-12 ( −8.6 ng/ml , p = 0.72 ) and interferon-gamma ( 0.52 ng/ml , p = 0.88 ) . No significant differences in blood pressure , e-selectin , high-sensitivity c-reactive protein , IL-6 or the chemokine CXCL-10 were found with treatment . In conclusion , repleting vitamin D levels in subjects with CAD failed to demonstrate any benefits on surrogate markers of cardiovascular health . These results question the role of vitamin D supplementation in modifying cardiovascular disease OBJECTIVE Apart from its role in bone metabolism , vitamin D may also influence cardiovascular disease . The objective of this study was : ( 1 ) to determine the effect of a single , oral , high-dose vitamin D supplementation on endothelial function and arterial stiffness in patients with peripheral arterial disease ( PAD ) and ( 2 ) to investigate the impact of this supplementation on coagulation and inflammation parameters . METHODS In this double-blind , placebo-controlled , interventional pilot study , we screened 76 Caucasian patients with PAD for vitamin D deficiency . Sixty-two were r and omised to receive a single , oral supplementation of 100,000 IU vitamin D3 or placebo . At baseline and after 1 month , we measured serum vitamin D and parathormone levels , and surrogate parameters for cardiovascular disease . RESULTS Sixty-five of 76 patients ( 86 % ) had low 25-hydroxyvitamin D levels ( < 30 ng ml(-1 ) ) ; of those , 62 agreed to participate in the study . At baseline , only parathormone was related to vitamin D. In supplemented patients , vitamin D levels increased from 16.3 ± 6.7 to 24.3 ± 6.2 ng ml(-1 ) ( P < 0.001 ) , with wide variations between single patients ; in the placebo group vitamin levels did not change . Seasonal factors accounted for a decrease of vitamin D levels by 8 ng ml(-1 ) between summer and winter . After 1 month , none of the measured parameters was influenced by vitamin substitution . CONCLUSION In this pilot study , most patients with PAD were vitamin D deficient . Vitamin D supplementation  increased serum 25-hydroxyvitamin D without influencing endothelial function , arterial stiffness , coagulation and inflammation parameters , although the study was underpowered for definite conclusions BACKGROUND Suboptimal vitamin D status is associated with endothelial dysfunction and an increased risk of cardiovascular diseases but it is unclear whether vitamin D supplementation is beneficial . The aim was to investigate the effect of vitamin D supplementation on endothelial function in patients with type 2 diabetes mellitus ( DM ) . METHODS In a double-blind , placebo-controlled trial , we r and omized 100 type 2 DM patients to vitamin D supplement  ( 5000 IU/day , n = 50 ) or placebo ( controls , n = 50 ) for 12 weeks . Assessment of vascular function with brachial artery flow-mediated dilatation ( FMD ) , circulating levels of endothelial progenitor cells ( EPCs ) and brachial-ankle pulse wave velocity , and metabolic parameter , high-sensitivity C-reactive protein ( hsCRP ) and oxidative stress markers were performed before and after the supplementation . RESULTS After 12 weeks , vitamin D treated patients had significant increases in serum 25-hydroxyvitamin D [ 25(OH)D ] concentration ( treatment effect 34.7 ng/mL , 95 % CI 26.4 - 42.9 , P < 0.001 ) and serum ionized calcium ( treatment effect 0.037 mmol/L , 95 % CI 0.007 - 0.067 , P = 0.018 ) ; decreased serum parathyroid hormone concentration ( treatment effect -0.55 pmol/L , 95 % CI -1.08 to -0.02 , P = 0.042 ) compared to patients who received placebo . Nevertheless , vitamin D supplementation did not improve vascular function as determined by FMD , circulating EPC count or baPWV ( all P > 0.05 ) . Furthermore , hsCRP , oxidative stress markers , low- and high-density lipoprotein and glycated hemoglobin were also similar between two groups ( all P > 0.05 ) . CONCLUSION In patients with type 2 DM , 12 weeks oral supplementation of vitamin D did not significantly affect vascular function or serum biomarkers of inflammation and oxidative stress . CLINICAL TRIAL NUMBER HKCTR-867 , www.hk clinical trials.com Patients with cystic fibrosis ( CF ) suffer from chronic lung infection and inflammation leading to respiratory failure . Vitamin D deficiency is common in patients with CF , and correction of vitamin D deficiency may improve innate immunity and reduce inflammation in patients with CF . We conducted a double-blinded , placebo-controlled , r and omized clinical trial of high-dose vitamin D to assess the impact of vitamin D therapy on antimicrobial peptide concentrations and markers of inflammation . We r and omized 30 adults with CF hospitalized with a pulmonary exacerbation to 250 000 IU of cholecalciferol or placebo  , and evaluated changes in plasma concentrations of inflammatory markers and the antimicrobial peptide LL-37 at baseline and 12 weeks post intervention . In the vitamin D group , there was a 50.4 % reduction in tumor necrosis factor-α ( TNF-α ) at 12 weeks ( P<0.01 ) , and there was a trend for a 64.5 % reduction in interleukin-6 ( IL-6 ) ( P=0.09 ) . There were no significant changes in IL-1β , IL-8 , IL-10 , IL-18BP and NGAL ( neutrophil gelatinase-associated lipocalin ) . We conclude that a large bolus dose of vitamin D is associated with reductions in two inflammatory cytokines , IL-6 and TNF-α . This study supports the concept that vitamin D may help regulate inflammation in CF , and that further research is needed to eluci date the potential mechanisms involved and the impact on clinical outcomes BACKGROUND Low vitamin D levels are common , and are associated with a higher incidence of future vascular events . We tested whether vitamin D supplementation could improve endothelial function and other markers of vascular function in patients with a history of myocardial infa rct ion . METHODS Parallel group , placebo-controlled , double-blind r and omised trial . Patients with a history of myocardial infa rct ion were r and omised to receive 100,000 units of oral vitamin D3 or placebo at baseline , 2 months and 4 months . Outcomes were measured at baseline , 2 and 6 months . Reactive hyperaemia index on fingertip plethysmography was the primary outcome . Secondary outcome measures included blood pressure , cholesterol , C-reactive protein , von Willebr and factor , tumour necrosis factor alpha , E-selectin , B-type natriuretic peptide , thrombomodulin and 25-hydroxyvitamin D levels . RESULTS 75 patients were r and omised , mean age 66 years . 74/75 ( 99 % ) completed 6 month follow-up . 25 hydroxyvitamin D levels increased in the intervention group relative to placebo ( + 13 vs + 1 nmol/L , p=0.04 ) . There was no between-group difference in change in reactive hyperaemia index between baseline and 6 months ( -0.18 vs -0.07 , p=0.40 ) . Of the secondary outcomes , only C-reactive protein showed a significant decline in the intervention arm relative to placebo at 6 months ( -1.3 vs 2.0mg/L , p=0.03 ) . Systolic blood pressure ( + 1.4 vs + 2.3 mmHg , p=0.79 ) , diastolic blood pressure ( + 2.0 vs + 0.8 mmHg , p=0.54 ) and total cholesterol ( + 0.26 vs + 0.24 mmol/L , p=0.88 ) showed no between-group difference at 6 months . CONCLUSIONS Supplementation with vitamin D did not improve markers of vascular function in patients with a history of myocardial infa rct ion OBJECTIVE Low vitamin D levels and risk factors for vascular disease are both common in South Asian women . This trial evaluated whether vitamin D supplementation could improve markers of vascular health in South Asian women with low 25-hydroxyvitamin D levels . METHODS Parallel-group , double-blind , r and omised placebo-controlled trial . Healthy South Asian women with baseline serum 25-hydroxyvitamin D levels of < 75 nmol/L were r and omised to receive a single dose of 100,000 units oral vitamin D3 or matching placebo . Outcomes were measured at baseline , 4 and 8 weeks . The primary outcome was change in endothelial function measured using brachial artery flow-mediated dilatation . Secondary outcomes included blood pressure , arterial stiffness , microvascular function measured using laser Doppler iontophoresis , insulin resistance , serum lipids , circulating markers of inflammation , thrombosis and adipokines . RESULTS 50 women were r and omised , 25 to each group . Mean age was 41 years ; mean baseline 25-hydroxyvitamin D level was 27 nmol/L.  25-Hydroxyvitamin D levels rose in the vitamin D group relative to the placebo group by 4 weeks ( 16 nmol/L , 95 % CI 11 to 21 , p < 0.001 ) . There was no improvement in flow-mediated dilatation in the vitamin D group relative to placebo at 4 weeks ( 0.1 % , 95 % CI -0.9 to 1.1 , p = 0.84 ) or 8 weeks ( 0.0 % , 95 % CI -1.4 to 1.4 , p = 0.98 ) . There was no improvement in cholesterol , insulin resistance or markers of inflammation . Both platelet activation inhibitor-1 and tissue plasminogen activator levels fell significantly in the vitamin D group relative to placebo at 8 weeks . CONCLUSION A single large dose of vitamin D3 did not improve blood pressure or endothelial function in South Asian women with low baseline 25-hydroxyvitamin D levels . TRIAL REGISTRATION IS RCT N75081811 In-vitro studies suggest that vitamin D reduces inflammation by inhibiting nuclear factor kappa-B ( NFκB ) activity . Yet , no trials have examined the effects of vitamin D supplementation on NFκB activity in-vivo in humans . We conducted a double-blind r and omized trial ( RCT ) examining effects of vitamin D supplementation on inflammatory markers and NFκB activity in peripheral blood mononuclear cells ( P BMC s ) . Sixty-five overweight/obese , vitamin D-deficient ( 25-hydroxyvitamin D [ 25(OH)D ] ≤ 50 nmol/L ) adults were r and omized to a single 100,000 IU bolus followed by 4,000 IU daily cholecalciferol or matching placebo for 16 weeks . We measured BMI , % body fat , serum 25(OH)D , high-sensitivity C-reactive protein ( hsCRP ) , tumour necrosis factor ( TNF ) , monocyte chemoattractant protein-1 ( MCP-1 ) , interferon-gamma ( IFN-γ ) , several interleukins , and NFκB activity in P BMC s. Fifty-four participants completed the study . Serum 25(OH)D concentrations  increased with vitamin D supplementation compared to placebo ( p < 0.001 ) . Vitamin D and placebo groups did not differ in any inflammatory markers or NFκB activity ( all p > 0.05 ) . Results remained non-significant after adjustment for age , sex , and % body fat , and after further adjustment for sun exposure , physical activity , and dietary vitamin D intake . Although in-vitro studies report anti-inflammatory effects  of vitamin D , our RCT data show no effect of vitamin D supplementation on inflammatory markers or NFκB activity in-vivo in humans CONTEXT Vitamin D receptors are present in many tissues . Hypovitaminosis D is considered to be a risk factor for atherosclerosis . OBJECTIVE This study explores the effects of vitamin D replacement on insulin sensitivity , endothelial function , inflammation , oxidative stress , and leptin in vitamin D-deficient subjects . DESIGN , SETTING , AND PATIENTS Twenty-three asymptomatic vitamin D-deficient subjects with 25-hydroxyvitamin D [ 25(OH)D ] levels below 25 nmol/liter were compared with a control group that had a mean 25(OH)D level of 75 nmol/liter . The vitamin D-deficient group received 300,000 IU i m monthly for 3 months . The following parameters were evaluated before and after treatment : vitamin D metabolites , leptin , endothelial function by brachial artery flow mediated dilatation ( FMD ) , insulin sensitivity index based on oral glucose tolerance test , and lipid peroxidation as measures of thiobarbituric acid reactive substances ( TBARS ) . RESULTS FMD measurements were significantly lower in 25(OH)D-deficient subjects than controls ( P = 0.001 ) and improved after replacement therapy ( P = 0.002 ) . Posttreatment values of TBARS were significantly lower than pretreatment levels ( P < 0.001 ) . A positive correlation between FMD and 25(OH)D ( r = 0.45 ; P = 0.001 ) and a negative correlation between FMD and TBARS ( r = -0.28 ; P < 0.05 ) were observed . There was a significant increase in leptin levels after therapy , and the leptin levels were positively correlated with 25(OH)D levels ( r = 0.45 ; P < 0.05 ) . CONCLUSIONS This study shows that 25(OH)D deficiency is associated with endothelial dysfunction and increased lipid peroxidation . Replacement of vitamin D has favorable effects on endothelial function . Vitamin D deficiency can be seen as an independent risk factor of atherosclerosis . Hypovitaminosis D-associated endothelial dysfunction may predispose to higher rates of cardiovascular disease in the winter We sought to determine if vitamin D supplementation , to target 25(OH)D concentrations of 30–40 ng/mL , improves endothelial function in Singapore ’s multi-ethnic type 2 diabetes mellitus population . We r and omised 64 type 2 diabetes mellitus patients with hypovitaminosis D to cholecalciferol 4000 International Unit/matching placebo [ baseline 25(OH)D < 20 ng/mL ] or cholecalciferol 2000 International Unit/matching placebo [ baseline 25(OH)D : 20–30 ng/mL ] daily for 16 weeks with a down titration at 8 weeks if 25(OH)D > 30 ng/mL. Endothelial function was assessed by peripheral tonometry ( reactive hyperaemia index – endothelial peripheral arterial tonometry ) and vascular biomarkers : E-selectin , von-Willebr and factor and high-sensitivity C-reactive protein . We compared the change from baseline parameters in the two groups using Student ’s t-test or Kruskal – Wallis test . A log-normal multivariate regression analysis was used to adjust for relevant baseline variables . The median reactive hyperaemia index in the vitamin D group increased from 0.65 ( interquartile range : 0.42 ) to 0.73 ( interquartile range : 0.36 ) , whereas it decreased from 0.73 ( interquartile range : 0.65 ) to 0.65 ( interquartile range : 0.38 ) ( p = 0.02 ) in the placebo group . After adjustment for baseline variables , the change was not statistically significant for reactive hyperaemia index ( p = 0.07 ) and for other vascular biomarkers ( p > 0.05 ) . Targeted vitamin D supplementation for 16 weeks result ed in a small but non-significant improvement in endothelial function in a type 2 diabetes mellitus cohort Background —Hyperlipidemia is associated with endothelial dysfunction , an early event in atherosclerosis and predictor of risk for future coronary artery disease . Epidemiological studies suggest that increased dietary intake of antioxidants reduces the risk of coronary artery disease . The purpose of this study was to determine whether antioxidant vitamin therapy improves endothelial function and affects surrogate biomarkers for oxidative stress and inflammation in hyperlipidemic children . Methods and Results —In a r and omized , double-blind , placebo-controlled trial , the effects of antioxidant vitamins C ( 500 mg/d ) and E ( 400 IU/d ) for 6 weeks and the National Cholesterol Education Program Step II ( NCEP-II ) diet for 6 months on endothelium-dependent flow-mediated dilation ( FMD ) of the brachial artery were examined in 15 children with familial hypercholesterolemia ( FH ) or the phenotype of familial combined hyperlipidemia ( FCH ) .  Antioxidant vitamin therapy  improved FMD of the brachial artery compared with baseline ( P < 0.001 ) without an effect on biomarkers for oxidative stress ( autoantibodies to epitopes of oxidized LDL , F2-isoprostanes , 8-hydroxy-2′-deoxyguanosine ) , inflammation ( C-reactive protein ) , or levels of asymmetric dimethylarginine , an endogenous inhibitor of nitric oxide . Conclusions —Antioxidant therapy with vitamins C and E restores endothelial function in hyperlipidemic children . Early detection and treatment of endothelial dysfunction in high-risk children may retard the progression of atherosclerosis Background The role of vitamin D in management of depression is unclear . Results from observational and emerging r and omized controlled trials ( RCTs ) investigating the efficacy of vitamin D in depression lack consistency - with some suggesting a positive association while others show a negative or inconclusive association . Methods / Design The primary aim of this study is to conduct a systematic review of RCTs to assess the effect of oral vitamin D supplementation versus placebo on depression symptoms measured by scales and the proportion of patients with symptomatic improvement according to the authors ’ original definition . Secondary aims include assessing the change in quality of life , adverse events and treatment discontinuation . We will conduct the systematic review and meta- analysis according to the recommendations of the Cochrane H and book for Systematic Review s of Interventions . We will search the Cochrane Central Register of Controlled Trials ( CENTRAL ) , MEDLINE ( 1966 to present ) , EMBASE ( 1980 to present ) , CINAHL ( 1982 to present ) , PsychINFO ( 1967 to present ) and Clinical Trials.gov . Unpublished work will be identified by search ing two major conferences : the International Vitamin Conference , the Anxiety Disorders and Depression Conference , while grey literature will be acquired by contacting authors of included studies . We will use the r and om-effects meta- analysis to synthesize the data by pooling the results of included studies . Discussion The results of this systematic review will be helpful in clarifying the efficacy of vitamin D supplementation and providing evidence to establish guidelines for implementation of vitamin D for depression in general practice and other relevant setting s. Study registration Unique identifier : CRD42013003849 Inflammation and endothelial activation are associated with an increased risk of CVD and epidemiological evidence suggests an association between levels of markers of inflammation or endothelial activation and the intake of fruit . Also , vitamin E , a fat-soluble antioxidant , has anti-inflammatory properties . We performed a r and omised 2 x 2 factorial , crossover trial to determine the effect of orange and blackcurrant juice ( 500 ml/d ) and vitamin E ( 15 mg RRR-alpha-tocopherol/d ) supplementation on markers of inflammation and endothelial activation in forty-eight patients with peripheral arterial disease . Patients were r and omly allocated to two dietary supplements from the four possible combinations of juice and vitamin E : juice+vitamin E ; juice+placebo ; reference beverage ( sugar drink)+vitamin E ; and reference beverage+placebo . The supplementations were given for 28 d , separated by a 4-week wash-out period . Analysis of main effects showed that juice decreased C-reactive protein ( CRP ) by 11 % and fibrinogen by 3 % while the reference drink increased CRP by 13 % and fibrinogen by 2 % ( P<0.008 and P<0.002 , respectively ) . No significant differences were measured for IL-6 and the endothelial activation markers von Willebr and factor , tissue-plasminogen activator and plasmin activator inhibitor-1 .  Vitamin E supplementation had no significant effects on the various markers . We observed no significant interaction between juice and vitamin E. In this study , orange and blackcurrant juice reduced markers of inflammation , but not markers of endothelial activation , in patients with peripheral arterial disease , relative to sugar drinks AIMS To test whether a single large dose of vitamin D2 can improve endothelial function in patients with Type 2 diabetes mellitus and low serum 25-hydroxyvitamin D levels . METHODS Double-blind , parallel group , placebo-controlled r and omized trial . A single dose of 100,000 IU vitamin D2 or placebo was administered to patients with Type 2 diabetes over the winter , when levels of circulating 25-hydroxyvitamin D were likely to be lowest . Patients were enrolled if their baseline 25-hydroxyvitamin D level was < 50 nmol/l .  Endothelial function and blood pressure were measured and fasting blood sample s were taken at baseline and 8 weeks after administration of vitamin D. RESULTS Forty-nine per cent of subjects screened had 25-hydroxyvitamin D levels < 50 nmol/l . Thirty-four subjects completed the study , with a mean age of 64 years and a baseline 25-hydroxyvitamin D level of 38.3 nmol/l .  Vitamin D supplementation  increased 25-hydroxyvitamin D levels by 15.3 nmol/l relative to placebo and significantly improved flow mediated vasodilatation ( FMD ) of the brachial artery by 2.3 % . The improvement in FMD remained significant after adjusting for changes in blood pressure .  Vitamin D supplementation significantly decreased systolic blood pressure by 14 mmHg compared with placebo ; this did not correlate with change in FMD . CONCLUSIONS Vitamin D insufficiency is common in patients with Type 2 diabetes during winter in Scotl and . A single large dose of oral vitamin D2 improves endothelial function in patients with Type 2 diabetes and vitamin D insufficiency High Na and low K intakes have adverse effects on  blood pressure  , which increases the risk for CVD . The role of endothelial dysfunction and inflammation in this pathophysiological process is not yet clear . In a r and omised placebo-controlled cross-over study in untreated (pre)hypertensives , we examined the effects of Na and K supplementation on endothelial function and inflammation . During the study period , subjects were provided with a diet that contained 2·4 g/d of Na and 2·3 g/d of K for a 10 460 kJ ( 2500 kcal ) intake . After 1-week run-in , subjects received capsules with supplemental Na ( 3·0 g/d ) , supplemental K ( 2·8 g/d ) or placebo , for 4 weeks each , in r and om order . After each intervention , circulating biomarkers of endothelial function and inflammation were measured . Brachial artery flow-mediated dilation ( FMD ) and skin microvascular vasomotion were assessed in sub-groups of twenty-two to twenty-four subjects . Of thirty-seven r and omised subjects , thirty-six completed the study .  Following Na supplementation  , serum endothelin-1 was increased by 0·24 pg/ml ( 95 % CI 0·03 , 0·45 ) , but no change was seen in other endothelial or inflammatory biomarkers . FMD and microvascular vasomotion were unaffected by Na supplementation . K supplementation  reduced IL-8 levels by 0·28 pg/ml ( 95 % CI 0·03 , 0·53 ) , without affecting other circulating biomarkers . FMD was 1·16 % ( 95 % CI 0·37 , 1·96 ) higher after K supplementation than after  placebo . Microvascular vasomotion was unaffected . In conclusion , a 4-week increase in Na intake increased endothelin-1 , but had no effect on other endothelial or inflammatory markers . Increased K intake had a beneficial effect on FMD and possibly IL-8 , without affecting other circulating endothelial or inflammatory biomarkers The importance of nutrients for promotion of health and prevention of disease has long been recognized . Nonetheless , scientists are still trying to delineate the optimal intakes of various nutrients and their potential benefits for different population s. To that end , evidence -based medicine ( EBM ) has been applied to the study of nutrition . EBM methods basically call for the use of r and omized controlled trials ( RCTs ) to establish causal connection between the intervention and any particular endpoint . This paper focuses on problems that arise in the use of RCTS to establish a causal link between nutrients and various clinical endpoints . While many RCTS of calcium and vitamin D have been positive , many others have been null . In this paper , we discuss the reasons why effective nutrient agents may be found to be ineffective in particular studies , giving examples of such null results , and focusing on the nearly universal failure to consider biological criteria in design ing RCTs . Our purpose is ( 1 ) to inform future study design so as to ensure that relevant biological facts are considered and ( 2 ) to aid in the interpretation of the abundant , but often inconsistent literature on this topic
Evidence from the studies included in this systematic review did not demonstrate that vitamin D supplementation in adults , results in an improvement in circulating inflammatory and endothelial function biomarkers/parameters .
This systematic review does not therefore support the use of vitamin D supplementation as a therapeutic or preventative measure for CVD in this respect
This systematic review aims to evaluate r and omised controlled trials ( RCTs ) investigating the effect of vitamin D supplementation on  endothelial function and inflammation in adults .