Double-blind controlled dietary cross-over intervention with differentially fertilised intact lettuce leaves shows acute reduction in blood pressure in young adults, associated with faster uptake of nitrate than of phenolics.

PURPOSE: To compare acute effects on blood pressure (BP) of ingestion of visually similar lettuce with controlled high and low content of either nitrate or phenolic compounds. METHODS: In a randomised cross-over design, 19 healthy participants (22-31 years) received 50 g of lettuce containing either 530 mg (8.4 mmol) nitrate + 11 mg (0.03 mmol) phenolic compounds (HNLP); or 3 mg nitrate (0.05 mmol) + 77 mg (0.2 mmol) phenolic compounds (LNHP), obtained by differential fertilisation. Ambulatory BP was recorded along with plasma, salivary and urinary nitrate and nitrite and plasma concentrations of cyclic guanosine monophosphate (cGMP), phenolic metabolites, Trolox equivalent antioxidant capacity (TEAC) and ferric reducing antioxidant power (FRAP). RESULTS: Compared with LNHP, 3 h post ingestion of HNLP, plasma nitrate increased 0.31 ± (95%CI) 0.12 mM (+ 240%), and salivary nitrate 5.5 ± 1.4 mM (+ 910%); accumulated urinary nitrate excretion increased 188 ± 72 mg (+ 296%) (all P < 0.001). Systolic BP was reduced 4.9 ± 4.2 mmHg (P = 0.031) between 3 and 6 h after ingestion of HNLP compared with LNHP; systolic BP differences were negatively correlated (P = 0.004) with differences in saliva nitrate concentrations. LNHP increased plasma phenolics at 6 h, predominantly 3'-methoxycinnamic acid-4'-glucuronide (ferulic acid-4'-glucuronide), 116%, 204 ± 138 nM more than HNLP (P = 0.001); increased cGMP 14% (P = 0.019); and reduced FRAP 3.1% (P = 0.009). CONCLUSION: The acute BP difference within 6 h of consumption matched the plasma/saliva nitrate peak, not the slower changes of plasma phenolics. This is the first double-blind controlled dietary intervention demonstrating differential effects on human physiology by consumption of an intact plant food, where compositional differences were obtained by controlling growing conditions, indicating potential opportunities for health claims relating to precision/vertical farming. CLINICAL TRIAL REGISTRATION: The trial was retrospectively registered on ClinicalTrials.gov, with identifier NCT02701959, on March 8, 2016.

Mediterranean Diet Increases Endothelial Function in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

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 <0.001; I2 = 73.68%]. MedDiet interventions improved flow-mediated dilation (FMD)-the reference method for noninvasive, clinical measurement of endothelial function-by 1.66% (absolute change; 95% CI: 1.15, 2.17; P <0.001; I2 = 0%). Effects of the MedDiet on endothelial function were not modified by health status, type of intervention, study duration, study design, BMI, or age of participants (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.

Lycopene and tomato and risk of cardiovascular diseases: A systematic review and meta-analysis of epidemiological evidence.

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. 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. 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<0.001; I2 = 46). Lycopene was not significantly associated with myocardial infarction, while scarce evidence on the association of lycopene with atherosclerosis, congestive heart failure, or atrial fibrillation was evident. Evidence from three studies suggested that higher intakes of tomato were associated with non-significantly lower stroke, CVDs and CHD. CONCLUSIONS: This comprehensive meta-analysis suggests that high-intakes or high-serum concentration of lycopene are associated with significant reductions in the risk of stroke (26%), mortality (37%) and CVDs (14%).

Effects of vitamin D supplementation on endothelial function: a systematic review and meta-analysis of randomised clinical trials.

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 (ß = 0.02; p = 0.07) and BMI (ß = 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.

Inorganic Nitrate Supplementation in Young and Old Obese Adults Does Not Affect Acute Glucose and Insulin Responses but Lowers Oxidative Stress.

BACKGROUND: Aging and obesity are associated with raised oxidative stress and a reduction of nitric oxide (NO) bioavailability, with subsequent decline in insulin sensitivity and endothelial function. Inorganic nitrate is converted into NO via a 2-step reduction process and may be an effective nutritional intervention to modify vascular and metabolic functions. OBJECTIVES: This study tested whether inorganic nitrate supplementation improved glucose disposal and attenuated the acute effects of hyperglycemia on oxidative stress, inflammation, and vascular function in young and old obese participants. METHODS: Ten young (aged 18-44 y) and 10 old (aged 55-70 y) obese participants consumed 75 g glucose followed by either potassium nitrate (7 mg/kg body weight) or potassium chloride (placebo) in a randomized, double-blind crossover design. Resting blood pressure (BP), endothelial function, and blood biomarkers were measured for 3 h postintervention. Biomarkers included plasma nitrate/nitrite (NOx), glucose, insulin, cyclic GMP, interleukin 6, 3-nitrotyrosine, E- and P-selectins, intercellular adhesion molecule 3 (ICAM-3), and thrombomodulin, as well as superoxide in freshly isolated peripheral blood mononuclear cells (PBMCs). RESULTS: Inorganic nitrate supplementation did not affect plasma glucose (P = 0.18) or insulin (P = 0.26) responses. The increase in plasma NOx concentrations 3 h after the administration of inorganic nitrate was significantly higher in young than in old participants (234% increase compared with 149% increase, respectively, P < 0.001). Plasma 3-nitrotyrosine concentrations declined significantly after inorganic nitrate supplementation compared with placebo (3 h postdose, 46% decrease compared with 27% increase, respectively, P = 0.04), and a similar nonsignificant trend was observed for superoxide concentrations (3 h postdose, 16% decrease compared with 23% increase, respectively, P = 0.06). Plasma cyclic GMP, ICAM-3, and thrombomodulin concentrations differed between young and old participants (P < 0.01). Inorganic nitrate supplementation did not improve BP or endothelial function. CONCLUSIONS: Oral supplementation with inorganic nitrate did not improve glucose and insulin responses but reduced oxidative stress in old individuals during acute hyperglycemia. This trial was registered at www.controlled-trials.com as ISRCTN42776917.

Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis.

BACKGROUND: Diets rich in inorganic nitrate are associated with lower blood pressure, an effect that may be mediated by an improvement of endothelial function (EF). Therefore, a systematic review and meta-analysis of randomised controlled trials (RCTs) were conducted to examine the effects of inorganic nitrate and beetroot supplementation on measures of EF. METHODS: MEDLINE, EMBASE and Scopus databases were searched from inception until November 2014. Specific inclusion criteria were as follows: (1) RCTs; (2) trials comparing inorganic nitrate or beetroot supplementation with placebo control groups; and (3) trials reporting effects of these interventions on outcomes of vascular function. Random-effect models were used to assess the pooled effect sizes showed as standardised mean differences (SMD). RESULTS: Nine crossover trials and three parallel trials met our inclusion criteria. The trials were conducted between 2008 and 2014 and included a total of 246 participants with 10-64 participants per study. The duration of each intervention ranged from 1.5 h to 28 days. Inorganic nitrate and beetroot consumption was associated with an improvement in vascular function (SMD 0.36; 95 % CI 0.16, 0.56; P < 0.001). The effect on EF was significantly associated with the dose of inorganic nitrate (ß = 0.04, SE = 0.01, P < 0.001), age (ß = -0.01, SE = 0.004, P = 0.02), baseline BMI (ß = -0.04, SE = 0.02, P = 0.05) and systolic BP (ß = -0.01, SE = 0.005, P = 0.02). CONCLUSIONS: Inorganic nitrate and beetroot supplementation was associated with beneficial effects on EF. These effects appear to be reduced in older subjects and in subjects with greater cardiometabolic risk.

Effect of vitamin C and vitamin E supplementation on endothelial function: a systematic review and meta-analysis of randomised controlled trials.

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 (ß 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 (ß-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.

Antioxidant vitamin supplementation reduces arterial stiffness in adults: a systematic review and meta-analysis of randomized controlled trials.

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 ß-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.

Population attributable fractions of modifiable risk factors for dementia: a systematic review and meta-analysis.

BACKGROUND: More than 57 million people have dementia worldwide. Evidence indicates a change in dementia prevalence and incidence in high-income countries, which is likely to be due to improved life-course population health. Identifying key modifiable risk factors for dementia is essential for informing risk reduction and prevention strategies. We therefore aimed to estimate the population attributable fraction (PAF) for dementia associated with modifiable risk factors. METHODS: In this systematic review and meta-analysis, we searched Embase, MEDLINE, and PsycINFO, via Ovid, from database inception up to June 29, 2023, for population-derived or community-based studies and reviews reporting a PAF value for one or more modifiable risk factor for later-life dementia (prevalent or incident dementia in people aged ≥60 years), with no restrictions on dementia subtype, the sex or baseline age of participants, or the period of study. Articles were independently screened for inclusion by four authors, with disagreements resolved through consensus. Data including unweighted and weighted PAF values (weighted to account for communality or overlap in risk) were independently extracted into a predefined template by two authors and checked by two other authors. When five or more unique studies investigated a given risk factor or combination of the same factors, random-effects meta-analyses were used to calculate a pooled PAF percentage estimate for the factor or combination of factors. The review protocol was registered on PROSPERO, CRD42022323429. FINDINGS: 4024 articles were identified, and 74 were included in our narrative synthesis. Overall, PAFs were reported for 61 modifiable risk factors, with sufficient data available for meta-analysis of 12 factors (n=48 studies). In meta-analyses, the highest pooled unweighted PAF values were estimated for low education (17·2% [95% CI 14·4-20·0], p<0·0001), hypertension (15·8% [14·7-17·1], p<0·0001), hearing loss (15·6% [10·3-20·9], p<0·0001), physical inactivity (15·2% [12·8-17·7], p<0·0001), and obesity (9·4% [7·3-11·7], p<0·0001). According to weighted PAF values, low education (9·3% [6·9-11·7], p<0·0001), physical inactivity (7·3% [3·9-11·2], p=0·0021), hearing loss (7·2% [5·2-9·7], p<0·0001), hypertension (7·1% [5·4-8·8], p<0·0001), and obesity (5·3% [3·2-7·4], p=0·0001) had the highest pooled estimates. When low education, midlife hypertension, midlife obesity, smoking, physical inactivity, depression, and diabetes were combined (Barnes and Yaffe seven-factor model; n=9 studies), the pooled unweighted and weighted PAF values were 55·0% (46·5-63·5; p<0·0001) and 32·0% (26·6-37·5; p<0·0001), respectively. The pooled PAF values for most individual risk factors were higher in low-income and middle-income countries (LMICs) versus high-income countries. INTERPRETATION: Governments need to invest in a life-course approach to dementia prevention, including policies that enable quality education, health-promoting environments, and improved health. This investment is particularly important in LMICs, where the potential for prevention is high, but resources, infrastructure, budgets, and research focused on ageing and dementia are limited. FUNDING: UK Research and Innovation (Medical Research Council).

Effects of dietary-based weight loss interventions on biomarkers of endothelial function: a systematic review and meta-analysis.

Endothelial dysfunction is closely linked to the development of atherosclerosis. This systematic review and meta-analysis reviewed the evidence on the effect of weight loss, achieved by dietary-based interventions, on biomarkers of endothelial function (EF). Two databases (Medline, Embase) were searched from inception until November 2022 for studies that met the following criteria: 1) adult subjects (≥ 18 years) without exclusion for health status, 2) dietary interventions for weight loss, and 3) measurements of changes in EF biomarkers. Random-effect meta-analysis and meta-regression were performed. Thirty-seven articles including 1449 participants were included in the systematic review. Study duration ranged from 3-52 weeks. Overall, weight loss significantly improved biomarkers of EF [standardised mean difference (SMD):0.65; 95%CI:0.49,0.81; P < 0.001;I2 = 91.9%]. Subgroup analyses showed weight loss significantly improved levels of E-selectin (P < 0.001), intercellular adhesion molecule-1 (ICAM-1) (P < 0.001), vascular cell adhesion molecule-1 (VCAM-1) (P < 0.001), nitrite/nitrate (NOx) (P < 0.001) and vascular endothelial growth factor (VEGF) (P < 0.001). Conversely, there was no significant improvement for von Willebrand Factor (vWF). Meta-regression analysis revealed that changes in EF biomarkers were not affected by age, BMI, quality of the studies or the amount of weight lost. A significant heterogeneity was observed for the effects of weight loss on changes in EF biomarkers. Dietary-induced weight loss may be associated with biomarkers changes indicating an improvement of EF, and it may represent a potential strategy to reduce atherosclerotic risk.

Variable influence of the degree of smoking dependence on adult attention deficit/hyperactivity disorder in Iraqi medical students.

OBJECTIVE: To demonstrate the differences in the patterns of adult attention deficit/hyperactivity disorder (ADHD) symptoms among non, light, and heavy smokers. METHODS: A cross-sectional study involving 400 medical students (representing first to sixth year students) was conducted in the Department of Pharmacology, University of Al-Mustansiriya, Baghdad, Iraq from March to June 2011. The medical students completed a questionnaire containing the adult ADHD self-report scale (ASRS-screener) and the Fagerstrom Test for Nicotine Dependence (FTND). An ADHD score ≥14 was considered positive. An FTND score ≥6 signifies heavy smokers, and an FTND score ≤5 signifies light smokers. RESULTS: Three hundred and sixty-one medical students completed the questionnaire, 16.6% reported ADHD symptoms (19.8% male, 12.1% females). Forty-five percent of ADHD adults were smokers; more than half of them were categorized as heavy smokers (51.8%). In comparison with non-smokers, heavy smokers displayed significant deterioration in their inattentive and total ASRS score (p=0.0001). Light smokers show significantly higher hyperactive symptoms in comparison with non-smokers (p=0.041). A high FTND score was associated with severer deterioration in inattentive (r=0.391, p=0.001) but not hyperactive symptoms (r=0.153, p=0.117). CONCLUSION: The ADHD symptoms are highly prevalent among Iraqi medical students, and smoking among ADHD students is higher and heavier than non-ADHD controls. Heavy smoking tends to deteriorate rather than ameliorate (self-medicate) ADHD symptoms.

Degree of dependence influences the effects of smoking on psychomotor performance and working memory capacity.

OBJECTIVE: Exploration of the variable effect of the degree of smoking dependence on psychomotor performance and working memory capacity. METHODS: This is a randomized, controlled, prospective study conducted in the Department of Pharmacology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq from 15 January 2011 to 25 February 2011. After third stage male medical students completed the Fagerstrom Test for Nicotine Dependence questionnaire, we randomly selected a sample of 32 students and divided them into 3 groups: 10 participants with zero score (non-smokers), 11 participants with a score of 5 or less (light smokers), and 11 participants with a score of 6 or more (heavy smokers). Choice reaction time and flicker fusion were measured by the Leeds psychomotor performance test battery, and working memory capacity was measured by the N-back working memory test. RESULTS: We found significant improvement in ascending flicker fusion test in heavy smokers in comparison with non-smokers (p=0.005, confidence interval [CI] 0.99-6), and light smokers (p=0.053, CI 0.39-4.5). Heavy smokers significantly deteriorated in the 3-back task in comparison with non-smokers (p=0.006, CI 4-25.8), and light smokers (p=0.009, CI 3-24.4). No significant changes were seen between groups in the descending critical flicker fusion, the components of choice reaction time, and in 1-, 2- back working memory tests. CONCLUSION: Heavy smoking (high nicotine) enhances arousal, but impairs working memory capacity.

Mediterranean diet and the hallmarks of ageing.

Ageing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process, and collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively-effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research.

Effects of inorganic nitrate and vitamin C co-supplementation on blood pressure and vascular function in younger and older healthy adults: A randomised double-blind crossover trial.

BACKGROUND: Vitamin C and inorganic nitrate have been linked to enhanced nitric oxide (NO) production and reduced oxidative stress. Vitamin C may also enhance the conversion of nitrite into NO. AIMS: We investigated the potential acute effects of vitamin C and inorganic nitrate co-supplementation on blood pressure (BP) and peripheral vascular function. The secondary aim was to investigate whether age modified the effects of vitamin C and inorganic nitrate on these vascular outcomes. METHODS: Ten younger (age 18-40 y) and ten older (age 55-70 y) healthy participants were enrolled in a randomised double-blind crossover clinical trial. Participants ingested a solution of potassium nitrate (7 mg/kg body weight) and/or vitamin C (20 mg/kg body weight) or their placebos. Acute changes in resting BP and vascular function (post-occlusion reactive hyperemia [PORH], peripheral pulse wave velocity [PWV]) were monitored over a 3-h period. RESULTS: Vitamin C supplementation reduced PWV significantly (vitamin C: -0.70 ± 0.31 m/s; vitamin C placebo: +0.43 ± 0.30 m/s; P = 0.007). There were significant interactions between age and vitamin C for systolic, diastolic, and mean arterial BP (P = 0.02, P = 0.03, P = 0.02, respectively), with systolic, diastolic and mean BP decreasing in older participants and diastolic BP increasing in younger participants following vitamin C administration. Nitrate supplementation did not influence BP (systolic: P = 0.81; diastolic: P = 0.24; mean BP: P = 0.87) or vascular function (PORH: P = 0.05; PWV: P = 0.44) significantly in both younger and older participants. However, combined supplementation with nitrate and vitamin C reduced mean arterial BP (-2.6 mmHg, P = 0.03) and decreased PWV in older participants (PWV: -2.0 m/s, P = 0.02). CONCLUSIONS: The co-administration of a single dose of inorganic nitrate and vitamin C lowered diastolic BP and improved PVW in older participants. Vitamin C supplementation improved PWV in both age groups but decreased systolic and mean BP in older participants only. CLINICAL TRIAL REGISTRATION: Current Controlled Trials (ISRCTN98942199).

Limited evidence for a beneficial effect of vitamin C supplementation on biomarkers of cardiovascular diseases: an umbrella review of systematic reviews and meta-analyses.

Vitamin C is an essential nutrient with important antioxidant properties. Higher vitamin C intake appears to be associated with positive effects on cardiovascular risk factors in cohort studies, whereas large randomized controlled clinical trials did not confirm the benefits of supplemental vitamin C on cardiovascular disease (CVD) outcomes. In this overview of systematic reviews and meta-analyses, an "umbrella review," we investigated the effects of vitamin C supplementation on biomarkers of cardiovascular risk, that is, arterial stiffness, blood pressure, endothelial function, glycemic control, and lipid profile. In addition, we assessed the strength of the evidence and the methodological qualities of available studies. Two independent investigators searched 4 databases (Medline, Embase, Scopus, and The Cochrane Library databases) from inception until February 2018. After full text examination, 10 systematic reviews and meta-analyses were included in the umbrella review which included 6409 participants. Three systematic reviews investigated the effects of vitamin C on endothelial function with contrasting results (2 reviews reported a significant effect, and all 3 showed a high heterogeneity [I2> 50%]); 1 systematic review reported significant improvement for each of the following risk factors: blood pressure, and blood concentrations of glucose, low-density lipoprotein cholesterol, and triglycerides. There were no overall effects of vitamin C on arterial stiffness and blood concentration of insulin, total cholesterol, and high-density lipoprotein cholesterol, but subgroup analyses revealed some evidence for significant improvements in subpopulations with higher body mass index, higher plasma concentrations of glucose or cholesterol, and low plasma concentration of vitamin C. Results from this umbrella review emphasize the weakness of the current evidence base about effects of vitamin C supplementation on markers of CVD risk. There is limited evidence that some population subgroups (older people, the obese, those with lower vitamin C status at baseline, and those at higher CVD risk) may be more responsive to vitamin C supplementation and offer opportunities for tailored nutritional interventions to improve cardiometabolic health. Future studies should implement a selective recruitment strategy that is informed by evidence-based literature synthesis.

Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research.

CVD are characterised by a multi-factorial pathogenesis. Key pathogenetic steps in the development of CVD are the occurrence of endothelial dysfunction and formation of atherosclerotic lesions. Reduced nitric oxide (NO) bioavailability is a primary event in the initiation of the atherosclerotic cascade. NO is a free radical with multiple physiological functions including the regulation of vascular resistance, coagulation, immunity and oxidative metabolism. The synthesis of NO proceeds via two distinct pathways identified as enzymatic and non-enzymatic. The former involves the conversion of arginine into NO by the NO synthases, whilst the latter comprises a two-step reducing process converting inorganic nitrate into nitrite and subsequently NO.Inorganic is present in water and food, particularly beetroot and green leafy vegetables. Several investigations have therefore used the non-enzymatic NO pathway as a target for nutritional supplementation ( salts) or dietary interventions (high- foods) to increase NO bioavailability and impact on cardiovascular outcomes. Some studies have reported positive effects of dietary on systolic blood pressure and endothelial function in patients with hypertension and chronic heart failure. Nevertheless, results have been inconsistent and the size of the effect appears to be declining in older individuals. Additionally, there is a paucity of studies for disorders such as diabetes, CHD and chronic kidney failure. Thus, whilst dietary supplementation could represent an effective and viable strategy for the primary and secondary prevention of age-related cardiovascular and metabolic diseases, more large-scale, robust studies are awaited to confirm or refute this notion.

Medium-term effects of dietary nitrate supplementation on systolic and diastolic blood pressure in adults: a systematic review and meta-analysis.

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 < 0.001] and DBP [-2.0 mmHg (95% confidence interval: -3.0, -0.9); P < 0.001]. However, the effect was only significant when measured in resting clinical settings as no significant changes in BP were observed using 24-h ambulatory and daily home BP monitorings. CONCLUSION: Positive effects of medium-term dietary nitrate supplementation on BP were only observed in clinical settings, which were not corroborated by more accurate methods such as 24-h ambulatory and daily home monitorings.

Systematic review and meta-analysis of randomised controlled trials testing the effects of vitamin C supplementation on blood lipids.

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 (ß: -0.24, CI: -0.36, -0.11) and in triglycerides (ß: -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 (ß: -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/.

Dietary nitrate does not affect physical activity or outcomes in healthy older adults in a randomized, cross-over trial.

Although dietary nitrate (NO3-) ingestion appears to enhance exercise capacity and performance in young individuals, inconclusive findings have been reported in older people. Therefore, we conducted a double-blind, crossover randomized clinical trial using beetroot juice in older healthy participants, who were classified as normal weight and overweight. We tested whether consumption of beetroot juice (a rich source of NO3-) for 1 week would increase nitric oxide bioavailability via the nonenzymatic pathway and enhance (1) exercise capacity during an incremental exercise test, (2) physical capability, and (3) free-living physical activity. Twenty nonsmoking, healthy participants between 60 and 75 years of age and with a body mass index of 20.0 to 29.9 kg/m2 were included. Presupplementation and postsupplementation resting, submaximal, maximal, and recovery gas exchanges were measured. Physical capability was measured by hand-grip strength, time-up-and-go, repeated chair rising test, and 10-m walking speed. Free-living physical activity was assessed by triaxal accelerometry. Changes in urinary and plasmaNO3-concentrations were measured by gas chromatography-mass spectrometry. Nineteen participants (male-to-female ratio, 9:10) completed the study.Beetroot juice increased significantly both plasma and urinary NO3-concentrations (P<.001) when compared with placebo. Beetroot juice did not influence resting or submaximal and maximal oxygen consumption during the incremental exercise test. In addition, measures of physical capability and physical activity levels measured in free-living conditions were not modified by beetroot juice ingestion. The positive effects of beetroot juice ingestion on exercise performance seen in young individuals were not replicated in healthy, older adults. Whether aging represents a modifier of the effects of dietary NO3-on muscular performance is not known, and mechanistic studies and larger trials are needed to test this hypothesis.

Exercise modalities and endothelial function: a systematic review and dose-response meta-analysis of randomized controlled trials.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (ß 1.14, CI 0.16-2.12, p = 0.027). CONCLUSIONS: 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.