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Background: marine omega3FA has been shown to be beneficial for cardiovascular health. In Saudi diabetics with minimum intake of marine diet the cardiovascular effect of marine omega3FA never been investigated. Objectives: to test the effect of nutritional supplements of 4 g marine omega3FA (EPA, DHA) in reducing the CV risk biomarkers (omega index, lipids profile and inflammatory markers), in diabetic Saudis with moderate hypertriglyceridemia. Design: cross sectional study conducted as preliminary study before the intervention, to test the relation between the low intake of fish and CV risk biomarkers in 96 participants including healthy and diabetic. At baseline, fasting blood test measured for omega index, lipids profile (triglycerides, cholesterol, LDL-c, HDL-c) and inflammatory markers (CRP and 1L-6). The intervention was randomized, controlled trial compared the effect of 4 g marine omega (EPA, DHA) over 5 months in 89 diabetics with moderate hypertriglyceridemia randomly assigned to the treatment or the control group. The intervention tested the same biomarkers measured in the preliminary study with adding new inflammatory markers TNF-a and adhesion molecules tests (s-ICAM, s- VCAM). All the biomarker tests conducted at baseline and at the end of the treatment. Results: the intake offish in Saudis living in the internal region showed to meet only 25% of the current recommendation with a mean of 2.45 ± 2.57portion I month. Fish intake showed positive relation (r=0.309, p=0.003) with the lower omega index (4%) and the lower triglycerides (r = -0.231, p=0.024). Omega contents (EPA, DHA) in erythrocytes correlated positively with HDL-c (r=0.303, p=0.006). The 4g daily dose of EPA and DHA lowered triglycerides in the treatment group by 33% compared to control (Mean ± SD: 1.01± 1.12 compared with 0.36±0.68 mmollL, P=0.002). The treatment had significant increment in omega contents (EPA, DHA) in erythrocytes over the time of the treatment (Mean ± SD: 4.82±1.06 to 11.83±2.45 %, P<O.OOI) and significantly different than the control p<O.OO 1). The treatment significantly reduced the level of cholesterol (20%) P=0.003, and LDL-c (10.9%) P=0.008 over the 5 months period. No effect was observed on HDL-c or inflammatory markers CRP, TNF-a and s-ICAM. Tendency of reduction observed in the s-VCAM (8%) and 1L-6 (13%) over the time of the treatment, but not significant. Conclusion: the low intake offish showed an adverse effect on cardiovascular risk biomarkers and increased the risk of diabetic Saudis for CVD. The 4 g of marine omega3FA in diabetics with moderate hypertriglyceridemia reduced the CV risk biomarkers through reducing the level of triglycerides, cholesterol and LDL-c and improving the omega contents in erythrocytes. Thus diabetics with minimum intake of fish and have moderate hypertriglyceridemia may benefit from 4 g of marine omega3FA in reducing their risk of CVD.

Human and animal studies indicate that cell-signalling, anti-inflammatory and anti-oxidant properties of flavonoids and carotenoids in fruits and vegetables (F&V) may protect against, or slow, age-related decline in cognitive functioning. The Flavonoid University of Reading Study (FLA VURS), designed to explore the dose-response relationship between dietary F&V flavonoids and cardiovascular disease, enabled the investigation of such an association with cognitive function. FLA VURS was an 18-week parallel 3-arm randomised controlled dietary intervention trial with four time points, measured at 6-weekly intervals from baseline. Low F&V consumers were randomly assigned to a high flavonoid (HP), low flavonoid (LF), or control group. HF or LF F&V intake was increased by two daily 80g portions every 6 weeks, while controls maintained their habitual diet. Cognitive function and mood were measured at each visit. While no overall group differences in cognition or mood were found, age group sub-analyses (26- 50 and 51-70 years of age) showed differences from 0-18 weeks for younger adults in spatial working memory (SWM), with LF improving significantly more than the other two groups. Subsequent regression analysis was performed irrespective of dietary group, with F & V components as predictors. For the group as a whole, improvements in SWM were associated with increased flavonoid levels. For the group as a whole, better baseline SWM performance was associated with higher BDNF levels, and better baseline recognition and executive function performance were associated with higher flavonoid levels. For younger adults, better executive function at baseline was associated with higher carotenoid levels, whereas for older adults, it was associated with higher flavonoid levels. The overall lack of flavonoid treatment effects was surprising, although epidemiological predictions were supported. Further research is required to determine the relationship between F&V intake and cognitive function, the mechanisms by which age-dependent differences in F&V responsiveness may occur, and also to understand differences between F&V components on cognition when consumed as part of a normal healthy diet. The theoretical, practical and methodological implications of these findings are discussed.

The literature reports that phytochemicals from fruits and vegetables, and fruit and vegetable- based products have been associated with decreased risk of cardiovascular disease (CVD). The current research has investigated the effects of fruits and vegetables and blackcurrant juice intake on endothelial function, vascular reactivity and biomarkers of consumption using two human interventions, one acute and one chronic. In addition, gene/nutrient interactions have been investigated with three genotypes linked to markers of CVD in the chronic study. / The acute study was a randomised, cross over, double blind, placebo controlled test meal study with 20 healthy volunteers (11 females 9 males). Subjects consumed a 20% blackcurrant juice drink or a control drink. Vascular reactivity was assessed at baseline and 120 mins after juice consumption by Laser Doppler Imaging (LDI). Acute consumption of 20% blackcurrant juice significantly increased plasma vitamin C (P=0.006), and urinary anthocyanins (P<O.OOI) although the drink caused no significant effects on acute measures of vascular reactivity, or biomarkers of endothelial function. The chronic study was a large, parallel, randomised, controlled intervention trial with increased fruit and vegetable intake in a stepwise manner in two intervention groups, consuming either high flavonoid (HF) or low flavonoid (LF) fruits and vegetables. The control group (CT) continued on their habitual diet.: while the HF and LF groups sequentially increased their daily fruit and vegetable intake by 2 portions every 6 weeks to a maximum of 6 extra portions, with flavonoid-rich or flavonoid-poor fruits and vegetables respectively. Study groups were balanced for gender, age, body mass index (BMI), smoking status and consumption of tea and red wine. Fasting blood and 24 hour urine samples were collected, pulse wave velocity (PWV) and pulse wave analysis (PWA), vascular reactivity by LDI, reflection (RI) and stiffness (SI) indexes, plasma nitric oxide (NO), soluble adhesion molecules (I CAM, VCAM and E-selectin) were measured at baseline and at weeks 6, 12 and 18. Eight to twelve randomised 24 hour dietary recalls were analysed using Dietplan6 for determination of daily nutrient intake. There was a significant increase in the consumption of flavonoid-rich fruits and vegetables with a significantly dose-dependent increase in dietary and urinary total flavonoid levels (P=O.OOO I) compared with CT and LF groups. There was also a significant increase in dietary and plasma vitamin C concentrations (P=O.OOOI) in the HF and LF groups compared with the CT group at all intervention visits and total plasma and dietary carotenoids (P=O.OOOI) in addition to individual plasma carotenoids: a-carotene (P=0.0001); p-carotene (p=0.0001); p- cryptoxanthin (P=0.016) and Iycopene (P=0.0043). There was a significant correlation at all visits between dietary intakes and biomarker concentrations- for urinary total flavonoids (r = 0.385, P = 0.0001), flavanones (r = 0.412, P = 0.0001) and vitamin C (r = 0.341, P = 0.0001). Urinary total flavonoids (r ~-= 0.327, P = 0.000), plasma vitamin C (r = 0.300, P = 0.000), plasma carotenoids (r =.0.400, P = 0.000) and plasma folate (r = 0.422" P = 0.000) concentrations moderately correlated with the number of fruit and vegetable portions consumed, but urinary potassium showed no significant correlation. Endothelium-dependent vasodilation was higher in individuals with the wildtype COMT - GG (P =0.003) and MTHFR - CC (P = 0.007) genotypes. Plasma nitric oxide (NO) concentrations were significantly increased (P = 0.03) in the eNOS GG genotype with 2 and 4 additional portions of flavonoid-rich fruits and vegetables compared with baseline and 6 portions whereas the variant T carriers had significantly increased serum NO concentrations only after 6 additional flavonoid-rich fruits and vegetables. There was a significant decrease in VCAM (P = 0.02) in individuals with variant COMT - GA+AA genotype from baseline with consumption of 2, 4 and 6 portions of high flavonoid fruits and vegetables, while carriers of COMT GA+AA genotype had higher VCAM levels compared with GG with 4 and 6 low flavonoid fruit and vegetable portions. In conclusion, the current study provided evidence that plasma carotenoids, vitamin C and folate but not urinary potassium can be used as a moderate biomarker of fruit and vegetable intake whereas urinary total flavonoids reflected dietary intake of flavonoids rather than consumption of fruit and vegetables in general. Carriers of wildtype genotypes were found to be more active with increased fruit and vegetable intake and affect markers of endothelial function and vasodilatation better compared with risk alleles; however these findings require further investigation.

Several epidemiological studies hove reported on inverse association between flavonoid intake and cardiovascular disease risk and mortality. Furthermore, acute ingestion of flavonoid-rich foods and beverages has been shown to improve parameters of endothelial function, a major cardiovascular disease risk factor and an early stage of atherogenesis. Here we report that flavonoids may improve endothelial function by 1) direct scavenging of the biologically relevant oxidant peroxynitrite, 2) preventing peroxynitrite-induced fibroblast injury via direct reaction with peroxynitrite and/or activation of pro-survival signalling, and 3) down-regulating inflammatory cytokine induced adhesion molecule expression (ICAM-l and VCAM-1).

The link between HDL and cardiovascular disease (CVD) is substantially more complex than ) originally thought. Until recently, the concentration of HDL was deemed sufficient in predicting future cardiovascular events. However, HDL function can become compromised in various disease states, resulting in reduced cardio-protection and the production of dysfunctional HDL with reduced anti-atherogenic properties. Antioxidants have been implicated in ameliorating the damaging oxidative processes associated with dysfunctional HDL and atherosclerosis. Therefore, this thesis focuses on the evolving role of HDL function and had three main aims: i) to assess the complex relationship between HDL-cholesterol concentration and HDL function, ii) to assess the modulation of HDL function by the ) predominant form of vitamin E, α-tocopherol, encompassing in vitro and ex vivo investigations and iii) to assess the modulation of HDL function by lycopene by dietary interventions. Various HDL-associated enzymes, including SAA, PON-I, CETP and LCAT, indicative of HDL function, were measured in serum and in HDL2&3 by a combination of ELISA., spectrophotometric and fluorometric assays. The main findings demonstrated that HDL-cholesterol concentration was modestly predictive of serum aspects of HDL function, however, this was enhanced upon analysis of the HDL subfractions, distinctly regarding PON-I and CETP activity, which were particularly efficient in predicting HDL function. This may be of particular use to the pharmaceutical industry for the manufacture of drugs which specifically target these enzymes. Furthermore, it has also provided evidence for the cautious use of antioxidant vitamins in improving HDL function, as indicated by: i) a detrimental decrease in HDL function by α-tocopherol supplementation in a normal weight population and ii) a beneficial increase in HDL function attributed to lycopene in an overweight population. Therapeutic normalisation of attenuated anti-atherogenic HDL function in terms of both quantity and quality of HDL particles is the target of innovative pharmacological approaches to raising HDL.

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Cardiovascular disease (CVD) is the leading cause of death in Europe responsible for more than 4.3 million deaths annually. The World Health Organisation funded the Monica project (1980s-1990s) which monitored ten million subjects aged 22-65yrs, and demonstrated that coronary heart disease (CHD) mortality declined over 10 years, was due in two thirds of cases to reduced incidence of CHD (reduced risk behaviours e.g. poor diet and smoking) and one third by improved treatments. Epidemiological evidence suggests diets rich in antioxidants decrease incidence of CVD. Regular consumption of nuts, rich in vitamin E and polyphenols reduces atherosclerosis, an important risk for heart disease. Intervention studies to date using alpha tocopherol (an active component of vitamin E) have not consistently proved beneficial.

Oligomeric procyanidins (OPC) are naturally occurring dietary substances, which studies suggest can protect against cardiovascular disease. To explore this further a double-blind randomised controlled crossover trial, EPICURE (Evaluation of high procyanidin intervention with dark chocolate on underlying age-related elements of cardiovascular risk) examined the effects of high procyanidin dark chocolate (HPDC) versus low procyanidin dark chocolate (LPDC) on various cardiovascular parameters in subjects with early hypertension. This was complemented by in vitro studies of OPC on cultured bovine aortic endothelial cells (BAEC) to determine the effect on cellular cholesterol levels. HPDC reduced 24 h blood pressure (-2/0.6 mmHg) and heart rate (-3.3 bpm), but only the latter reached statistical significance (p < 0.001). Augmentation pressure, augmentation index, plasma lipid levels, apolipoproteins, HDL subclasses, and hsCRP were not different amongst the groups. Retrospective analysis suggests that the study was underpowered and there were only 21 subjects with completed data due to technical issues. Future clinical studies should be designed with sufficient statistical power to detect changes in vascular function. In addition, compliance should be checked, technical errors detected earlier and FMD rather than PWA should be used to measure endothelial vascular function. OPC in vitro increased expression of the oxysterol cholesterol 25-hydroxylase (peaking at 1 h; p < 0.001) which suppressed the mRNA levels of HMGCR as previously reported (at 6 h; p < 0.01). In addition the mRNA for ABCG1 was increased (at 24 h p < 0.01), which has not been described to date in the literature. This implicates that OPC favour overall reduced cellular cholesterol via increased efflux and reduced synthesis. But when BAEC were loaded with LDLC, OPC reduced both cell media and solubilised cell extract cholesterol levels, the former being greater, suggesting no enhancement in cholesterol efflux. Also there was poor reproducibility of the ABCG1 mRNA expression which was likely to be due to variable transcription of the reference gene. Despite this the in vitro results support a potential role for OPC in reducing cellular cholesterol levels and future studies should employ radioactive methods to measure cholesterol efflux.