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We conducted a systematic review and meta-analysis of randomized clinical trials examining the effect of inorganic nitrate or nitrite supplementation on cognitive function (CF) and cerebral blood flow (CBF). Two databases (PubMed, Embase) were searched for articles from inception until May 2017. Inclusion criteria were: randomized clinical trials; participants >18 years old; trials comparing a nitrate/nitrite intervention with a control. Thirteen and nine trials were included in the meta-analysis to assess CF and CBF, respectively. Random-effects models were used and the effect size described as standardized mean differences (SMDs). A total of 297 participants (median of 23 per trial) were included for CF; 163 participants (median of 16 per trial) were included for CBF. Nitrate/nitrite supplementation did not influence CF (SMD +0.06, 95% CI: -0.06, 0.18, P = 0.32) or CBF under resting (SMD +0.14, 95% CI: -0.13, 0.41, P = 0.31), or stimulated conditions (SMD + 0.23, 95% CI: -0.11, 0.56, P = 0.19). The meta-regression showed an inverse association between duration of the intervention and CBF (P = 0.02) but no influence of age, BMI or dose (P < 0.05). Nitrate and nitrite supplementation did not modify CBF or CF. Further trials employing larger samples sizes and interventions with longer duration are warranted.

OBJECTIVES Dietary nitrate supplementation has been shown to lower blood pressure (BP) particularly in short-term clinical trials. Whether these effects are sustained in the long-term remains to be established. The objective was to conduct a meta-analysis of randomized controlled trials that examined whether dietary nitrate supplementation for more than 1 week has beneficial effects on SBP and DBP. METHODS Electronic databases were searched from inception until May 2016. Specific inclusion criteria were duration at least 1 week, report of effects on SBP or DBP or both and comparison of inorganic nitrate or beetroot juice supplementation with placebo control groups. Random-effects models were used to calculate the pooled BP effect sizes. RESULTS Thirteen trials met eligibility criteria. The trials included a total of 325 participants with seven to 65 participants per study. The duration of each intervention ranged from 1 to 6 weeks. Ten trials assessed BP in resting clinic conditions, whereas 24-h ambulatory and daily home monitorings were used in six and three trials, respectively. Overall, dietary nitrate was associated with a significant decline in SBP [-4.1 mmHg (95% confidence interval: -6.1, -2.2); P

Randomised controlled trials (RCTs) have observed contrasting results on the effects of vitamin C on circulating biomarkers of glycaemic and insulin regulation. We conducted a systematic review and meta-analysis of RCTs testing the effect of vitamin C administration on glucose, HbA1c and insulin concentrations. Four databases (PubMed, Embase, Scopus and Cochrane Library) were used to retrieve RCTs published from inception until April 2016 and testing the effects of vitamin C in adult participants. The screening of 2008 articles yielded 22 eligible studies (937 participants). Overall, vitamin C did not modify glucose, HbA1c and insulin concentrations. However, subgroup analyses showed that vitamin C significantly reduced glucose concentrations (−0.44 mmol/l, 95% CI: −0.81, −0.07, P=0.01) in patients with type 2 diabetes and in interventions with a duration greater than 30 days (−0.53%, 95% CI: −0.79, −0.10, P=0.02). Vitamin C administration had greater effects on fasting (−13.63 pmol/l, 95% CI: −22.73, −4.54, P

BACKGROUND: The endothelium plays a key role in the maintenance of vascular health and represents a potential physiological target for dietary and other lifestyle interventions designed to reduce the risk of cardiovascular diseases (CVD) including stroke or coronary heart disease. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the effects of the Mediterranean dietary pattern (MedDiet) on endothelial function. METHODS: Medline, Embase, and Scopus databases were searched from inception until January 2019 for studies that met the following criteria: 1) RCTs including adult participants, 2) interventions promoting the MedDiet, 3) inclusion of a control group, and 4) measurements of endothelial function. A random-effects meta-analysis was conducted. Metaregression and subgroup analyses were performed to identify whether effects were modified by health status (i.e., healthy participants versus participants with existing comorbidities), type of intervention (i.e., MedDiet alone or with a cointervention), study duration, study design (i.e., parallel or crossover), BMI, and age of participants. RESULTS: Fourteen articles reporting data for 1930 participants were included in the meta-analysis. Study duration ranged from 4 wk to 2.3 y. We observed a beneficial effect of the MedDiet on endothelial function [standardized mean difference (SMD): 0.35; 95% CI: 0.17, 0.53; P 0.05). CONCLUSIONS: MedDiet interventions improve endothelial function in adults, suggesting that the protective effects of the MedDiet are evident at early stages of the atherosclerotic process with important implications for the early prevention of CVD. This study has the PROSPERO registration number: CRD42018106188.

Background and aims\ud \ud Epidemiological evidence suggests an association between consumption of tomato products or lycopene and lower risk for cardiovascular diseases (CVD). Our aim was to evaluate the state of the evidence from intervention trials on the effect of consuming tomato products and lycopene on markers of cardiovascular (CV) function. We undertook a systematic review and meta-analysis on the effect of supplementing tomato and lycopene on CV risk factors.\ud \ud Methods\ud \ud Three databases including Medline, Web of science, and Scopus were searched from inception to August 2016. Inclusion criteria were: intervention randomised controlled trials reporting effects of tomato products and lycopene supplementation on CV risk factors among adult subjects >18 years of age. The outcomes of interest included blood lipids (total-, HDL-, LDL-cholesterol, triglycerides, oxidised-LDL), endothelial function (flow-mediated dilation (FMD), pulse wave velocity (PWV)) and blood pressure (BP) inflammatory factors (CRP, IL-6) and adhesion molecules (ICAM-1). Random-effects models were used to determine the pooled effect sizes.\ud \ud Results\ud \ud Out of 1189 publications identified, 21 fulfilled inclusion criteria and were meta-analysed. Overall, interventions supplementing tomato were associated with significant reductions in LDL-cholesterol (−0.22 mmol/L; p = 0.006), IL-6 (standardised mean difference −0.25; p = 0.03), and improvements in FMD (2.53%; p = 0.01); while lycopene supplementation reduced Systolic-BP (−5.66 mmHg; p = 0.002). No other outcome was significantly affected by these interventions.\ud \ud Conclusions\ud \ud The available evidence on the effects of tomato products and lycopene supplementation on CV risk factors supports the view that increasing the intake of these has positive effects on blood lipids, blood pressure and endothelial function. These results support the development of promising individualised nutritional strategies involving tomatoes to tackle CVD.

Summary Background & aims Randomised controlled trials (RCTs) in humans revealed contradictory results regarding the effect of vitamin C supplementation on blood lipids. We aimed to conduct a systematic review and meta-analysis of RCTs investigating the effect of vitamin C supplementation on total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides and to determine whether the effects are modified by the participants' or intervention characteristics. Methods Four databases (PubMed, Embase, Scopus and Cochrane Library) were searched from inception until August 2014 for RCTs supplementing adult participants with vitamin C for ≥ 2 weeks and reporting changes in blood lipids. Results Overall, vitamin C supplementation did not change blood lipids concentration significantly. However, supplementation reduced total cholesterol in younger participants (≤52 years age) (−0.26 mmol/L, 95% CI: −0.45, −0.07) and LDL-C in healthy participants (−0.32 mmol/L, 95% CI: −0.57, −0.07). In diabetics, vitamin C supplementation reduced triglycerides significantly (−0.15 mmol/L, 95% CI: −0.30, −0.002) and increased HDL-C significantly (0.06 mmol/L, 95% CI: 0.02, 0.11). Meta-regression analyses showed the changes in total cholesterol (β: −0.24, CI: −0.36, −0.11) and in triglycerides (β: −0.17, CI: −0.30, −0.05) following vitamin C supplementation were greater in those with higher concentrations of these lipids at baseline. Greater increase in HDL-C was observed in participants with lower baseline plasma concentrations of vitamin C (β: −0.002, CI: −0.003, −0.0001). Conclusions Overall, vitamin C supplementation had no significant effect on lipid profile. However, subgroup and sensitivity analyses showed significant reductions in blood lipids following supplementation in sub-populations with dyslipidaemia or low vitamin C status at baseline. PROSPERO Database registration: CRD42014013487, http://www.crd.york.ac.uk/prospero/ .

Background and aims: Worldwide, cardiovascular diseases (CVDs) remains as the main cause of mortality. Observational studies supports an association between intake of tomato products or lycopene with a reduced CVDs risk. Our aim was to undertake a systematic review and meta-analysis of the evidence on the topic.\ud \ud Methods: Medline, Web of Science, and Scopus were searched from inception until July 2017. We included longitudinal and cross-sectional studies reporting associations between lycopene and tomato consumption and cardiovascular morbidity and mortality among adult subjects. Random-effects models were used to determine the pooled effect sizes.\ud \ud Results: Twenty-eight publications met our inclusion criteria and 25 studies provided quantitative data for meta-analysis. Results showed that individuals in the highest consumption category of, or with the highest serum concentration of, lycopene had significantly lower risk of stroke (hazard ratio (HR) 0.74, 0.62–0.89, p = 0.02; I2 = 32) and CVDs (HR 0.86, 0.77–0.95, p = 0.003; I2 = 0). In addition, individuals categorised in the highest serum concentration of lycopene also had significantly lower risk of mortality (HR 0.63, 0.49–0.81, p

Risk variants of fat mass and obesity-associated (FTO) gene have been associated with increased obesity. However, the evidence for associations between FTO genotype and macronutrient intake has not been reviewed systematically. Our aim was to evaluate the potential associations between FTO genotype and intakes of total energy, fat, carbohydrate and protein. We undertook a systematic literature search in OVID MEDLINE, Scopus, EMBASE and Cochrane of associations between macronutrient intake and FTO genotype in adults. Beta coefficients and confidence intervals (CIs) were used for per allele comparisons. Random-effect models assessed the pooled effect sizes. We identified 56 eligible studies reporting on 213,173 adults. For each copy of the FTO risk allele, individuals reported 6.46kcal day-1 (95% CI: 10.76, 2.16) lower total energy intake (P=0.003). Total fat (P=0.028) and protein (P=0.006), but not carbohydrate intakes, were higher in those carrying the FTO risk allele. After adjustment for body weight, total energy intakes remained significantly lower in individuals with the FTO risk genotype (P=0.028). The FTO risk allele is associated with a lower reported total energy intake and with altered patterns of macronutrient intake. Although significant, these differences are small and further research is needed to determine whether the associations are independent of dietary misreporting. © 2015 International Association for the Study of Obesity. Chemicals/CAS: alcohol, 64-17-5; protein, 67254-75-5

Randomised controlled trials (RCT) testing the effects of antioxidant supplements on endothelial function (EF) have reported conflicting results. We aimed to investigate the effects of supplementation with antioxidant vitamins C and E on EF and to explore factors that may provide explanations for the inconsistent results. We searched four databases (MEDLINE, Embase, Cochrane Library and Scopus) from inception until May 2014 for RCT involving adult participants aged ≥ 18 years who were supplemented with vitamins C and E alone or in combination for more than 2 weeks and reporting changes in EF measured using flow mediated dilation or forearm blood flow. Data were pooled as standardised mean difference (SMD) and analysed using a random-effects model. Significant improvements in EF were observed in trials supplementing with vitamin C alone (500–2000 mg/d) (SMD: 0·25, 95 % CI 0·02, 0·49,P= 0·043) and vitamin E alone (300–1800 IU/d; 1 IU vitamin E = 0·67 mg natural vitamin E) (SMD: 0·48, 95 % CI 0·23, 0·72,P= 0·0001), whereas co-administration of both vitamins was ineffective (vitamin C: 500–2000 mg/d; vitamin E: 400–1200 IU/d) (SMD: 0·12, 95 % CI − 0·18, 0·42,P= 0·428). The effect of vitamin C supplementation on EF increased significantly with age (β 0·023, 95 % CI 0·001, 0·05,P= 0·042). There was a significant negative correlation between baseline plasma vitamin E concentration and the effect of vitamin E supplementation on EF (β − 0·03, 95 % CI − 0·06, − 0·001,P= 0·029). Supplementation with either vitamin C or vitamin E alone improves EF. However, subgroup analysis emphasises the importance of careful characterisation and selection of a population group which may benefit from such supplementation.

Regular exercise is associated with enhanced nitric oxide (NO) bioavailability. Flow-mediated dilation (FMD) is used widely to assess endothelial function (EF) and NO release.The aims of this systematic review and meta-analysis were to (i) investigate the effect of exercise modalities (aerobic, resistance or combined) on FMD; and (ii) determine which exercise and participant characteristics are most effective in improving FMD.We searched the MEDLINE, Embase, Cochrane Library, and Scopus databases for studies that met the following criteria: (i) randomized controlled trials of exercise with comparative non-exercise, usual care or sedentary groups; (ii) duration of exercise intervention ≥4 weeks; (iii) age ≥18 years; and (iv) EF measured by FMD before and after the intervention. Weighted mean differences (WMDs) with 95% confidence interval were entered into a random effect model to estimate the pooled effect of the exercise interventions.All exercise modalities enhanced EF significantly: aerobic (WMD 2.79, 95% CI 2.12-3.45, p = 0.0001), resistance (WMD 2.52, 95% CI 1.11-3.93, p = 0.0001) and combined (WMD 2.07, 95% CI 0.70-3.44, p = 0.003). A dose-response relationship was observed between aerobic exercise intensity and improvement in EF. A 2 metabolic equivalents (MET) increase in absolute exercise intensity or a 10% increase in relative exercise intensity resulted in a 1% unit improvement in FMD. There was a positive relationship between frequency of resistance exercise sessions and improvement in EF (β 1.14, CI 0.16-2.12, p = 0.027).All exercise modalities improve EF significantly and there was a significant, positive relationship between aerobic exercise intensity and EF. Greater frequency, rather than intensity, of resistance exercise training enhanced EF.

Risk variants of the fat-mass and obesity-associated (FTO) gene have been associated with increased obesity. However, the evidence for associations between FTO genotype and macronutrients intake has not been reviewed systematically. Our aim was to evaluate potential associations between FTO genotype and intakes of total energy, fat, carbohydrate and protein. We undertook a systematic literature search in Medline, Scopus, EMBASE and Cochrane of associations between macronutrients intake and FTO genotype in adults. Beta coefficients and confidence intervals were used for per-allele comparisons. Random-effects models assessed the pooled effect sizes. We identified 56 eligible studies reporting on 213 173 adults. For each copy of the FTO risk allele, individuals reported 6.46 kcal/day (95% CI: 10.76, 2.16) lower total energy intake (P=0.003). Total fat (P=0.028) and protein (P=0.006), but not carbohydrate intakes, were higher in those carrying the FTO risk allele. After adjustment for body weight, total energy intakes remained significantly lower in individuals with the FTO risk genotype (P=0.028). The FTO risk allele is associated with a lower reported total energy intake and with altered patterns of macronutrients intake. Although significant, these differences are small and further research is needed to determine whether the associations are independent of dietary misreporting.

Background: In addition to regulating calcium homoeostasis and bone health, vitamin D influences vascular and metabolic processes including endothelial function (EF) and insulin signalling. This systematic review and meta-analysis of randomised clinical trials (RCTs) were conducted to investigate the effect of vitamin D supplementation on EF and to examine whether the effect size was modified by health status, study duration, dose, route of vitamin D administration, vitamin D status (baseline and post-intervention), body mass index (BMI), age and type of vitamin D. Methods: We searched the Medline, Embase, Cochrane Library and Scopus databases from inception until March 2015 for studies meeting the following criteria: (1) RCT with adult participants, (2) vitamin D administration alone, (3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography, applanation tonometry and laser Doppler. Results: Sixteen articles reporting data for 1177 participants were included. Study duration ranged from 4 to 52 weeks. The effect of vitamin D on EF was not significant (SMD: 0.08, 95 % CI −0.06, 0.22, p = 0.28). Subgroup analysis showed a significant improvement of EF in diabetic subjects (SMD: 0.31, 95 % CI 0.05, 0.57, p = 0.02). A non-significant trend was found for diastolic blood pressure (β = 0.02; p = 0.07) and BMI (β = 0.05; p = 0.06). Conclusions: Vitamin D supplementation did not improve EF. The significant effect of vitamin D in diabetics and a tendency for an association with BMI may indicate a role of excess adiposity and insulin resistance in modulating the effects of vitamin D on vascular function. This remains to be tested in future studies.

Endothelial dysfunction is caused by excessive free radical production and nitric oxide (NO) inadequacy. Endothelial dysfunction is the primary cause of vascular disorders and is related to the progression of clinical complications. Human trials examining the effects of antioxidant vitamins on endothelial function (EF) showed inconclusive results. We undertook as systematic review and meta-analysis of the evidence from randomised controlled trials (RCTs) for effects of supplementation with vitamins C and E on EF. We searched the Medline, Embase, Scopus and the Cochrane Library databases for studies that met the following criteria: 1) RCTs with adult participants, 2) vitamin C or E administered alone or in combination, 3) studies that quantified EF using forearm blood flow or flow mediated dilation. EF responses across studies were pooled as standardised mean differences and analysed using a random-effects model using STATA 12 (StataCorp. 2011. College Station, TX, USA). Meta-analysis showed a significant improvement in EF in trials supplementing with vitamins C (SMD: 0·25, 95% CI: 0·02, 0·49, P= 0·043) and E (SMD: 0·48, 95% CI: 0·23, 0·72, P= 0·0001) alone whereas the co-administration of both vitamins was ineffective (SMD: 0·12, 95% CI: −0·18, 0·42, P= 0·428). The effect of vitamin C on EF increased with participant age (β: 0·023, CI: 0·001, 0·05, P= 0·042). There was as significant negative correlation between baseline plasma vitamin E concentration and the EF response to vitamin E (β: −0·03, CI: -0·06, −0·001, P= 0·029). Separate supplementation with vitamins C and E improves EF. Furthermore, subgroup analysis emphasises the importance of careful selection of the population group which may benefit from such supplementation.

Ourobjective was to conduct a systematic review and meta-analysis investigating the effect of antioxidant vitamins on arterial stiffness.The second objective was to determine whether the effects on arterial stiffness vary according to dose of antioxidant vitamins, durationof intervention, and health or nutritional status of the included participants.We searched 3 databases (Medline, Embase and Scopus) for articles with the following criteria: 1) randomized controlled trialscomparing antioxidant vitamins (vitamins C, E, A, beta-carotene) with either placebo or no active control; 2) adult participants⩾18 years; 3) antioxidant vitamins administered alone or in combination; 4) changes in arterial stiffness or arterial compliance.Data were pooled as standardized mean difference (SMD) and analysed using a fixed effects model.Pooled analysis (20 studies, 1,909 participants) showed that antioxidant vitamins supplementation reduced arterial stiffness sign-ificantly (SMD: −0·17, 95% CI: −0·26, −0·08, P=0·0001). This effect was significant in both experimental and primary preventionstudies but not in studies including participants with diseases (SMD: −0·19, 95% CI: −0·40, −0·02, P=0·081). Vitamins supplemen-tation improved arterial stiffness irrespective of age group and duration of intervention. Antioxidant vitamins were more effective inparticipants with low baseline plasma concentrations of vitamin C and E.In conclusion, supplementation with antioxidant vitamins has a small, protective effect on arterial stiffness. The effect may be aug-mented in those with lower baseline plasma vitamin E and C concentrations.

The Dietary Approach to Stop Hypertension (DASH) is recommended to lower blood pressure (BP), but its effects on cardiometabolic biomarkers are unclear. A systematic review and meta-analysis of randomised controlled trials (RCT) was conducted to determine the effects of the DASH diet on cardiovascular risk factors. Medline, Embase and Scopus databases were searched from inception to December 2013. Inclusion criteria were as follows: (1) DASH diet; (2) RCT; (3) risk factors including systolic and diastolic BP and glucose, HDL, LDL, TAG and total cholesterol concentrations; (4) control group. Random-effects models were used to determine the pooled effect sizes. Meta-regression analyses were carried out to examine the association between effect sizes, baseline values of the risk factors, BMI, age, quality of trials, salt intake and study duration. A total of twenty articles reporting data for 1917 participants were included in the meta-analysis. The duration of interventions ranged from 2 to 24 weeks. The DASH diet was found to result in significant decreases in systolic BP ( − 5·2 mmHg, 95 % CI − 7·0, − 3·4; PPPP= 0·03). Changes in both systolic and diastolic BP were greater in participants with higher baseline BP or BMI. These changes predicted a reduction of approximately 13 % in the 10-year Framingham risk score for CVD. The DASH diet improved cardiovascular risk factors and appeared to have greater beneficial effects in subjects with an increased cardiometabolic risk. The DASH diet is an effective nutritional strategy to prevent CVD.

BACKGROUND Several studies tested the effects of supplementation with antioxidant vitamins on arterial stiffness, but the results were contradictory. OBJECTIVES The aim of our study was to conduct a systematic review and meta-analysis investigating the effect of antioxidant vitamins on arterial stiffness and to determine whether the effects on arterial stiffness vary according to dose, duration of intervention, and health or nutritional status of the included participants. METHODS We searched 3 databases (Medline, Embase, and Scopus) for articles that potentially met the following eligibility criteria: 1) randomized controlled trials comparing antioxidant vitamins (vitamins C, E, and A and β-carotene) to either placebo or no active control in 2) adult participants aged ≥18 y; 3) antioxidant vitamins administered alone or in combination, irrespective of dose, duration, and route of administration; and 4) changes in arterial stiffness or arterial compliance. Data were pooled as standardized mean differences (SMDs) and analyzed using fixed- and random-effects models. RESULTS Data synthesis showed that antioxidant vitamins reduced arterial stiffness significantly (SMD: -0.17; 95% CI: -0.26, -0.08; P < 0.001). This effect was significant in experimental (SMD: -1.02; 95% CI: -1.54, -0.49; P < 0.001) and primary prevention (SMD: -0.14; 95% CI: -0.24, -0.04; P < 0.01) studies, whereas a trend for reduced arterial stiffness was observed in studies including participants with diseases (SMD: -0.19; 95% CI: -0.40, 0.02; P = 0.08). Vitamin supplementation improved arterial stiffness irrespective of age group and duration of intervention. Antioxidant vitamins were more effective in participants with low baseline plasma concentrations of vitamins C (SMD: -0.35; 95% CI: -0.62, -0.07; P < 0.016) and E (SMD: -0.79; 95% CI: -1.23, -0.33; P < 0.01). CONCLUSIONS Supplementation with antioxidant vitamins has a small, protective effect on arterial stiffness. The effect may be augmented in those with lower baseline plasma vitamin E and C concentrations. This trial was registered at PROSPERO as CRD42014007260.

Observational studies indicate that higher vitamin C intake is associated with reduced risk for cardiovascular diseases. However, randomised controlled trials (RCT) examining the effect of vitamin C on endothelial function (EF) have reported inconsistent results. The aims of this systematic review and meta-analysis were to determine the effect of vitamin C supplementation on EF and to investigate whether the effect was influenced by health status, study duration, dose and route of vitamin C administration.We searched the Medline, Embase, Cochrane Library, and Scopus databases from inception to May 2013 for studies that met the following criteria: 1) RCT with adult participants, 2) vitamin C administered alone, 3) studies that quantified EF using commonly applied methods including ultrasound, plethysmography and pulse wave analysis.Pooling the data from 44 clinical trials showed a significant positive effect of vitamin C on EF (SMD: 0.50, 95% CI: 0.34, 0.66, P0.001). Stratification of the analysis by health outcome revealed improved EF in atherosclerotic (SMD: 0.84, 95% CI: 0.41, 1.26, P0.001), diabetic (SMD: 0.52, 95% CI: 0.21, 0.82, P0.001) and heart failure patients (SMD: 0.48, 95% CI: 0.08, 0.88, P0.02) after vitamin C supplementation. The effect size appeared to be unaffected by study design, duration, baseline plasma vitamin C concentration or route of administration of vitamin C. The meta-regression showed a significant positive association between vitamin C dose and improvement in EF (β: 0.00011, 95% CI: 0.00001, 0.00021, P = 0.03).Vitamin C supplementation improved EF. The effect of vitamin C supplementation appeared to be dependent on health status, with stronger effects in those at higher cardiovascular disease risk. PROSPERO Database registration: CRD42013004567, http://www.crd.york.ac.uk/prospero/