Improved arterial inflammation with high dose omega-3 fatty acids in patients with elevated lipoprotein(a): Selective effect of eicosapentaenoic acid?

Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease. However, there are no approved and effective treatments for lowering Lp(a) and the associated cardiovascular risks. Omega-3 fatty acids (ω-3FAs), primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have both triglyceride-lowering and anti-inflammatory properties. This pilot study investigated the effect of high dose ω-3FAs (3.6 g/day) on arterial inflammation in 12 patients with elevated Lp(a) (> 0.5 g/L) and stable coronary artery disease (CAD) receiving cholesterol-lowering treatment. Arterial inflammation was determined using 18F-fluorodexoyglucose positron emission tomography/computed tomography before and after 12-weeks intervention. ω-3FAs significantly lowered plasma concentrations of triglycerides (-17%, p < 0.01), Lp(a) (-5%, p < 0.01) as well as aortic maximum standardized uptake value (SUVmax) (-4%, p < 0.05). The reduction in SUVmax was significantly inversely associated with average on-treatment EPA (r = -0.750, p < 0.01), but not DHA and triglyceride, concentrations. In conclusion, high dose ω-3FAs decrease arterial inflammation in patients with elevated Lp(a) and stable CAD, which may involve a direct arterial effect of EPA.

Long-term dietary nitrate supplementation slows the progression of established atherosclerosis in ApoE-/- mice fed a high fat diet.

BACKGROUND AND AIMS: Atherosclerosis is associated with a reduction in the bioavailability and/or bioactivity of endogenous nitric oxide (NO). Dietary nitrate has been proposed as an alternate source when endogenous NO production is reduced. Our previous study demonstrated a protective effect of dietary nitrate on the development of atherosclerosis in the apoE-/- mouse model. However most patients do not present clinically until well after the disease is established. The aims of this study were to determine whether chronic dietary nitrate supplementation can prevent or reverse the progression of atherosclerosis after disease is already established, as well as to explore the underlying mechanism of these cardiovascular protective effects. METHODS: 60 apoE-/- mice were given a high fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis. The mice were then randomized to (i) control group (HFD + 1 mmol/kg/day NaCl), (ii) moderate-dose group (HFD +1 mmol/kg/day NaNO3), or (iii) high-dose group (HFD + 10 mmol/kg/day NaNO3) (20/group) for a further 12 weeks. A group of apoE-/- mice (n = 20) consumed a normal laboratory chow diet for 24 weeks and were included as a reference group. RESULTS: Long-term supplementation with high dose nitrate resulted in ~ 50% reduction in plaque lesion area. Collagen expression and smooth muscle accumulation were increased, and lipid deposition and macrophage accumulation were reduced within atherosclerotic plaques of mice supplemented with high dose nitrate. These changes were associated with an increase in nitrite reductase as well as activation of the endogenous eNOS-NO pathway. CONCLUSION: Long-term high dose nitrate significantly attenuated the progression of established atherosclerosis in the apoE-/- mice fed a HFD. This appears to be mediated in part through a XOR-dependent reduction of nitrate to NO, as well as enhanced eNOS activation via increased Akt and eNOS phosphorylation.

Beneficial effects of inorganic nitrate in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic representation of the metabolic disorders. Inorganic nitrate/nitrite can be converted to nitric oxide, regulate glucose metabolism, lower lipid levels, and reduce inflammation, thus raising the hypothesis that inorganic nitrate/nitrite could be beneficial for improving NAFLD. This study assessed the therapeutic effects of chronic dietary nitrate on NAFLD in a mouse model. 60 ApoE-/- mice were fed a high-fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis with associated NAFLD. The mice were then randomly assigned to different groups (20/group) for a further 12 weeks: (i) HFD + NaCl (1 mmol/kg/day), (ii) HFD + NaNO3 (1 mmol/kg/day), and (iii) HFD + NaNO3 (10 mmol/kg/day). A fourth group of ApoE-/- mice consumed a normal chow diet for the duration of the study. At the end of the treatment, caecum contents, serum, and liver were collected. Consumption of the HFD resulted in significantly greater lipid accumulation in the liver compared to mice on the normal chow diet. Mice whose HFD was supplemented with dietary nitrate for the second half of the study, showed an attenuation in hepatic lipid accumulation. This was also associated with an increase in hepatic AMPK activity compared to mice on the HFD. In addition, a significant difference in bile acid profile was detected between mice on the HFD and those receiving the high dose nitrate supplemented HFD. In conclusion, dietary nitrate attenuates the progression of liver steatosis in ApoE-/- mice fed a HFD.

Quantifying dietary vitamin K and its link to cardiovascular health: a narrative review.

Cardiovascular disease is the leading cause of death and disability worldwide. Recent work suggests a link between vitamin K insufficiency and deficiency with vascular calcification, a marker of advanced atherosclerosis. Vitamin K refers to a group of fat-soluble vitamins important for blood coagulation, reducing inflammation, regulating blood calcium metabolism, as well as bone metabolism, all of which may play a role in promoting cardiovascular health. Presently, there is a lack of a comprehensive vitamin K database on individual foods, which are required to accurately calculate vitamin K1 and K2 intake for examination in epidemiological studies. This has likely contributed to ambiguity regarding the recommended daily intake of vitamin K, including whether vitamin K1 and K2 may have separate, partly overlapping functions. This review will discuss the presence of: (i) vitamin K1 and K2 in the diet; (ii) the methods of quantitating vitamin K compounds in foods; and (iii) provide an overview of the evidence for the cardiovascular health benefits of vitamin K in observational and clinical trials.

The gut microbiome and cardiovascular disease: current knowledge and clinical potential.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The human body is populated by a diverse community of microbes, dominated by bacteria, but also including viruses and fungi. The largest and most complex of these communities is located in the gastrointestinal system and, with its associated genome, is known as the gut microbiome. Gut microbiome perturbations and related dysbiosis have been implicated in the progression and pathogenesis of CVD, including atherosclerosis, hypertension, and heart failure. Although there have been advances in the characterization and analysis of the gut microbiota and associated bacterial metabolites, the exact mechanisms through which they exert their action are not well understood. This review will focus on the role of the gut microbiome and associated functional components in the development and progression of atherosclerosis. Potential treatments to alter the gut microbiome to prevent or treat atherosclerosis and CVD are also discussed.

Effect of adding milk to black tea on vascular function in healthy men and women: a randomised controlled crossover trial.

BACKGROUND: Tea consumption may improve endothelial function and blood pressure via increased bioavailability and bioactivity of nitric oxide. However, questions remain as to the impact of the common practice of adding milk. OBJECTIVE: To investigate the effect of regular consumption of black tea, with and without milk, on vascular function and blood pressure in healthy volunteers. DESIGN: A randomised, controlled, crossover study was performed in 17 healthy volunteers; 7 men and 10 women, mean age 22.4 ± 3.0 years. Participants received each of the following treatments in random order for 4 weeks, with no washout period in between, (i) hot water, (ii) black tea and (iii) black tea with milk. Vascular function was assessed using flow-mediated dilatation (FMD) of the brachial artery at the end of each treatment period. In addition, participants monitored their home blood pressure for the last 7 days of each treatment period. A blood and urine sample was also collected at the end of each treatment period. RESULTS: Black tea increased FMD compared to the hot water control group (1.00 ± 0.18%, P < 0.0001). Black tea with milk decreased FMD compared to both the hot water control (-0.64 ± 0.19%, P = 0.001) and black tea (-1.64 ± 0.19%, P < 0.0001). Compared with hot water, black tea did not alter blood pressure, while black tea with milk increased systolic (1.1 ± 0.5 mmHg, P = 0.03) and diastolic blood pressure (2.0 ± 0.5 mmHg, P < 0.0001). Black tea (-1.8 ± 0.5 bpm, P < 0.001) and black tea with milk (-1.8 ± 0.6 bpm, P < 0.001) lowered heart rate compared to hot water. No significant difference for plasma nitrate or nitrite was observed between treatment groups. CONCLUSIONS: The addition of milk to black tea alters the acute/short-term impact of regular tea consumption on vascular function and blood pressure in young healthy men and women. The exact mechanism for this affect remains unknown and longer-term trials to establish this effect in a range of populations are warranted.

Nutraceuticals in the management of patients with statin-associated muscle symptoms, with a note on real-world experience.

There is considerable evidence for the role of low-density lipoprotein cholesterol (LDL-C) in the development of atherosclerotic cardiovascular disease. Although statin therapy remains the most frequency prescribed medication to reduce LDL-C and lower risk of cardiovascular disease, a considerable number of patients develop muscle-related side affects. This review summarizes recent literature supporting the role of nutraceuticals as LDL-C-lowering therapy in statin-intolerant patients, with evidence from our own clinical practices.

Screening plant derived dietary phenolic compounds for bioactivity related to cardiovascular disease.

The potential health benefits of phenolic acids found in food and beverages has been suggested from a number of large population studies. However, the mechanism of how these compounds may exert biological effects is less well established. It is also now recognised that many complex polyphenols in the diet are metabolised to simple phenolic acids which can be taken up in the circulation. In this paper a number of selected phenolic compounds have been tested for their bioactivity in two cell culture models. The expression and activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells and the uptake of glucose in muscle cells. Our data indicate that while none of the compounds tested had a significant effect on eNOS expression or activation in endothelial cells, several of the compounds increased glucose uptake in muscle cells. These compounds also enhanced the translocation of the glucose transporter GLUT4 to the plasma membrane, which may explain the observed increase in cellular glucose uptake. These results indicate that simple cell culture models may be useful to help understand the bioactivity of phenolic compounds in relation to cardiovascular protection.

The acute effect of coffee on endothelial function and glucose metabolism following a glucose load in healthy human volunteers.

A diet rich in plant polyphenols has been suggested to reduce the incidence of cardiovascular disease and type 2 diabetes mellitus, in part, via improvements in endothelial function. Coffee is a rich source of phenolic compounds including the phenolic acid, chlorogenic acid (CGA). The aim of the study was to investigate the effect of coffee as a whole beverage on endothelial function, blood pressure and blood glucose concentration. Twelve healthy men and women were recruited to a randomised, placebo-controlled, cross-over study, with three treatments tested: (i) 18 g of ground caffeinated coffee containing 300 mg CGA in 200 mL of hot water, (ii) 18 g of decaffeinated coffee containing 287 mg CGA in 200 mL of hot water, and (iii) 200 mL of hot water (control). Treatment beverages were consumed twice, two hours apart, with the second beverage consumed simultaneously with a 75 g glucose load. Blood pressure was recorded and the finger prick glucose test was performed at time = 0 and then every 30 minutes up to 2 hours. Endothelial function, assessed using flow-mediated dilatation (FMD) of the brachial artery, was measured at 1 hour and a blood sample taken at 2 hours to measure plasma nitrate/nitrite and 5-CGA concentrations. The FMD response was significantly higher in the caffeinated coffee group compared to both decaffeinated coffee and water groups (P < 0.001). There was no significant difference in the FMD response between decaffeinated coffee and water. Blood glucose concentrations and blood pressure were not different between the three treatment groups. In conclusion, the consumption of caffeinated coffee resulted in a significant improvement in endothelial function, but there was no evidence for benefit regarding glucose metabolism or blood pressure. Although the mechanism has yet to be elucidated the results suggest that coffee as a whole beverage may improve endothelial function, or that caffeine is the component of coffee responsible for improving FMD.

Acute effects of quercetin-3-O-glucoside on endothelial function and blood pressure: a randomized dose-response study.

BACKGROUND: Epidemiologic studies have suggested that a flavonoid-rich diet can reduce the risk of developing cardiovascular disease. Certain flavonoids, in particular quercetin, have been shown to ameliorate endothelial dysfunction and reduce blood pressure (BP), possibly by increasing the bioavailability of the potent vasodilator nitric oxide (NO). Several studies have indicated that improvements in measures of cardiovascular health do not occur linearly, but rather, plateau or decrease with an increasing dose of flavonoids. OBJECTIVES: We determined whether the acute administration of increasing doses of a common quercetin glycoside (quercetin-3-O-glucoside) improves endothelial function and reduces BP in a dose-dependent manner. We also explored whether any effects were correlated with changes in plasma NO production. DESIGN: A randomized, controlled, crossover study was performed in 15 healthy volunteers who each completed 5 visits with a minimum washout period of 1 wk between testing days. Participants received each of the following 5 interventions in a random order: 1) 0, 2) 50, 3) 100, 4) 200, or 5) 400 mg quercetin-3-O-glucoside. Endothelial function and BP were assessed before and 60 min after intervention. A blood sample was taken before and 90 min after intervention for the analysis of plasma nitrate and nitrite as markers of NO production as well as of plasma quercetin metabolites. RESULTS: Although we observed a significant correlation between the dose of quercetin-3-O-glucoside and plasma concentrations of total quercetin (R(2) = 0.52, P < 0.001) and isorhamnetin (R(2) = 0.12, P = 0.005), we showed no improvements in endothelial function or BP and no changes in NO production after any dose. CONCLUSION: From these results, we conclude that there are no acute changes in BP or the NO-mediated endothelium-dependent relaxation of the brachial artery with doses of quercetin ranging from 50 to 400 mg in healthy men and women. This trial was registered at www.anzctr.org.au as ACTRN12615001338550.

Acute effects of chlorogenic acids on endothelial function and blood pressure in healthy men and women.

Coffee is a rich source of polyphenols, primarily chlorogenic acids (CGA). Certain polyphenols and polyphenol-rich foods and beverages have been shown to improve endothelial function and lower blood pressure (BP). The aim of the present study was to investigate the acute effect of two doses of CGA (5-CGA) on endothelial function and BP. In a cross-over study, 16 healthy men and women received: (i) 0 mg purified 5-CGA (control group); (ii) 450 mg purified 5-CGA; (iii) 900 mg purified 5-CGA; and (iv) 200 mg purified (-)-epicatechin (positive control) in random order one week apart. Peak and continuous mean (60 to 240 s post ischaemia) flow-mediated dilation (FMD) was measured at baseline, 1 h and 4 h. BP was measured at baseline and every 30 min to 4 h. Plasma CGA and epicatechin levels were significantly increased at both 1 h and 4 h post their respective treatments. Peak FMD was not significantly altered by either dose of 5-CGA or the epicatechin, relative to control (p > 0.05). Relative to control, effects on continuous mean FMD response following 450 mg 5-CGA and 900 mg of 5-CGA (0.47 ± 0.16%, p = 0.016 and 0.65 ± 0.16%, p < 0.001, respectively) at 1 h and (0.18 ± 0.17%, p = 0.99 and 0.44 ± 0.16%, p < 0.05, respectively) at 4 h. There was no significant effect of any of the treatments on BP. In conclusion, the present study has found no significant effect of 5-CGA, at 450 and 900 mg, on peak FMD response. However, there were significant improvements in mean post-ischaemic FMD response, particularly at the 1 h time point in this group of healthy individuals.

Absence of an effect of high nitrate intake from beetroot juice on blood pressure in treated hypertensive individuals: a randomized controlled trial.

BACKGROUND: Dietary nitrate, which is in green leafy vegetables and beetroot, decreases blood pressure through the enterosalivary nitrate-nitrite-nitric oxide pathway in healthy individuals. Whether similar effects would occur in individuals with treated hypertension and, therefore, at increased risk of cardiovascular disease is unclear. OBJECTIVE: We assessed whether increased dietary nitrate intake by using beetroot juice for 1 wk lowers blood pressure in treated hypertensive men and women. DESIGN: Participants (n = 27) were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effect of 1-wk intake of nitrate-rich beetroot juice was compared with 1-wk intake of nitrate-depleted beetroot juice (placebo). The primary outcome was blood pressure assessed by measuring home blood pressure during the intervention and 24-h ambulatory blood pressure on day 7 of the intervention. Other outcomes included nitrate metabolism assessed by measuring nitrate and nitrite in plasma, saliva, and urine. RESULTS: Relative to the placebo, 1-wk intake of nitrate-rich beetroot juice resulted in a 3-fold increase in plasma nitrite and nitrate, a 7-fold increase in salivary nitrite, an 8-fold higher salivary nitrate, and a 4-fold increase in both urinary nitrite and nitrate (P < 0.001). However, no differences in home blood pressure and 24-h ambulatory blood pressure were observed with 1-wk intake of nitrate-rich beetroot juice in comparison with the placebo. CONCLUSION: An increase in dietary nitrate intake may not be an effective short-term approach to further lower blood pressure in treated hypertensive subjects.

Effects of tea and coffee on cardiovascular disease risk.

Tea and coffee have been associated with risk of cardiovascular disease (CVD), both positively and negatively. Epidemiological data suggest that black and green tea may reduce the risk of both coronary heart disease and stroke by between 10 and 20%. Experimental and clinical trial data generally indicate either neutral or beneficial effects on risk factors and pathways linked to the development of CVD. Controversy still exists regarding the effects of coffee, where there have been concerns regarding associations with hypercholesterolaemia, hypertension and myocardial infarction. However, long term moderate intake of coffee is not associated with detrimental effects in healthy individuals and may even protect against the risk of developing type 2 diabetes. The detrimental effects of coffee may be associated with the acute pressor effects, most likely due to caffeine at high daily intakes, and lipids from boiled coffee can contribute to raised serum cholesterol. Genetic polymorphisms in enzymes involved in uptake, metabolism and excretion of tea and coffee compounds are also associated with differential biological effects. Potential mechanisms by which tea and coffee phytochemicals can exert effects for CVD protection include the regulation of vascular tone through effects on endothelial function, improved glucose metabolism, increased reverse cholesterol transport and inhibition of foam cell formation, inhibition of oxidative stress, immunomodulation and effects on platelet function (adhesion and activation, aggregation and clotting). The phytochemical compounds in tea and coffee and their metabolites are suggested to influence protective endogenous pathways by modulation of gene-expression. It is not known exactly which compounds are responsible for the suggestive protective effects of tea and coffee. Although many biologically active compounds have been identified with known biological effects, tea and coffee contain many unidentified compounds with potential bioactivity.

Chronic activation of AMP-activated protein kinase prevents 20-hydroxyeicosatetraenoic acid-induced endothelial dysfunction.

1. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoconstrictor involved in vascular dysfunction and blood pressure regulation. Studies have revealed strong associations between 20-HETE and endothelial dysfunction; however, the signalling mechanisms are largely unknown. Therefore, the aim of the present study was to investigate the effect of 20-HETE on the association between endothelial nitric oxide synthase (eNOS) and heat shock protein 90 (Hsp90). 2. In mouse aortic rings, 20-HETE significantly enhanced the constriction to phenylephrine and inhibited the relaxation to acetylcholine (P=0.05 vs control rings). In mice with chronic AMP-activated protein kinase (AMPK) activation, this protected against the negative effects of 20-HETE (P<0.05). Immunoprecipitation of eNOS in human umbilical vein endothelial cells treated with 20-HETE revealed a decrease in basal and vascular endothelial growth factor-stimulated Hsp90 association with eNOS (P<0.05). Pretreatment of cells with 5'-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR; a chronic activator of AMPK) prevented the loss of Hsp90 association with eNOS following 20-HETE treatment. Treatment with 20-HETE for 24 h induced an increase in eNOS phosphorylation that was not seen following acute treatment (30 min). The increased eNOS phosphorylation was accompanied by transient changes in Akt phosphorylation. 3. In conclusion, 20-HETE impairs eNOS-Hsp90 association, which can be reversed by chronic activation of AMPK. This provides a mechanism for reduced nitric oxide bioactivity and endothelial dysfunction in diseases with elevated 20-HETE levels, such as hypertension.

Effects of alpha-tocopherol and mixed tocopherol supplementation on markers of oxidative stress and inflammation in type 2 diabetes.

BACKGROUND: Vitamin E isomers may protect against atherosclerosis. The aim of this study was to compare the effects of supplementation with either alpha-tocopherol (alphaT) or mixed tocopherols rich in gamma-tocopherol (gammaT) on markers of oxidative stress and inflammation in patients with type 2 diabetes. METHODS: In a double-blind, placebo-controlled trial, 55 patients with type 2 diabetes were randomly assigned to receive (500 mg/day) (a) alphaT, (b) mixed tocopherols, or (c) placebo for 6 weeks. Cellular tocopherols, plasma and urine F(2)-isoprostanes, erythrocyte antioxidant enzyme activities, plasma inflammatory markers, and ex vivo assessment of eicosanoid synthesis were analyzed pre- and postsupplementation. RESULTS: Neutrophil alphaT and gammaT increased (both P <0.001) with mixed tocopherol supplementation, whereas alphaT (P <0.001) increased and gammaT decreased (P <0.005) after alphaT supplementation. Both alphaT and mixed tocopherol supplementation resulted in reduced plasma F(2)-isoprostanes (P <0.001 and P = 0.001, respectively) but did not affect 24-h urinary F(2)-isoprostanes or erythrocyte antioxidant enzyme activities. Neither alphaT nor mixed tocopherol supplementation affected plasma C-reactive protein, interleukin 6, tumor necrosis factor-alpha, or monocyte chemoattractant protein-1. Stimulated neutrophil leukotriene B(4) production decreased significantly in the mixed tocopherol group (P = 0.02) but not in the alphaT group (P = 0.15). CONCLUSIONS: The ability of tocopherols to reduce systemic oxidative stress suggests potential benefits of vitamin E supplementation in patients with type 2 diabetes. In populations with well-controlled type 2 diabetes, supplementation with either alphaT or mixed tocopherols rich in gammaT is unlikely to confer further benefits in reducing inflammation.

The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Oxidative stress has been suggested to play a role in the development of diabetes, hypertension and vascular dysfunction. Vitamin E, a major lipid-soluble dietary antioxidant, has two major dietary forms, alpha-tocopherol and gamma-tocopherol. The potential importance of gamma-tocopherol has largely been overlooked. Our aim was to investigate the effect of alpha-tocopherol and gamma-tocopherol supplementation on 24-h ambulatory blood pressure (BP) and heart rate, vascular function and oxidative stress in individuals with type 2 diabetes. METHOD: Fifty-eight individuals with type 2 diabetes were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 500 mg/day RRR-alpha-tocopherol, 500 mg/day mixed tocopherols (60% gamma-tocopherol) or placebo for 6 weeks. Primary endpoints were 24-h ambulatory BP and heart rate, endothelium-dependent and independent vasodilation and plasma and urinary F2-isoprostanes. RESULTS: Treatment with alpha-tocopherol significantly increased systolic BP [7.0 (5.2, 8.8) mmHg, P < 0.0001], diastolic BP [5.3 (4.0, 6.5) mmHg, P < 0.0001], pulse pressure [1.8 (0.6, 3.0) mmHg, P < 0.005] and heart rate [2.0 (0.6, 3.3) bpm, P < 0.005] versus placebo. Treatment with mixed tocopherols significantly increased systolic BP [6.8 (4.9, 8.6) mmHg, P < 0.0001], diastolic BP [3.6 (2.3, 4.9) mmHg, P < 0.0001], pulse pressure [3.2 (2.0, 4.4) mmHg, P < 0.0001] and heart rate [1.8 (0.5, 3.2) bpm, P < 0.01] versus placebo. Treatment with alpha-tocopherol or mixed tocopherols significantly reduced plasma F2-isoprostanes versus placebo, but had no effect on urinary F2-isoprostanes. Endothelium-dependent and independent vasodilation was not affected by either treatment. CONCLUSION: In contrast to our initial hypothesis, treatment with either alpha- or mixed tocopherols significantly increased BP, pulse pressure and heart rate in individuals with type 2 diabetes.

Supplementation with mixed tocopherols increases serum and blood cell gamma-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes.

BACKGROUND: Some studies have shown potential benefit of vitamin E on platelet function, but several clinical trials failed to show improved cardiovascular outcome with alpha-tocopherol supplementation. Gamma-tocopherol, a major dietary form of vitamin E, may have protective properties different from those of alpha-tocopherol. OBJECTIVE: We compared the effects of supplementation with alpha-tocopherol (500 mg) and a gamma-tocopherol-rich compound (500 mg, containing 60% gamma-tocopherol) on serum and cellular tocopherol concentrations, urinary tocopherol metabolite excretion, and in vivo platelet activation in subjects with type 2 diabetes. DESIGN: Fifty-eight subjects were randomly assigned to receive either 500 mg alpha-tocopherol/d, 500 mg mixed tocopherols/d, or matching placebo. Serum, erythrocyte, and platelet tocopherol and urinary metabolite concentrations were measured at baseline and after the 6-wk intervention. Soluble CD40 ligand, urinary 11-dehydro-thromboxane B2, serum thromboxane B2, soluble P-selectin, and von Willebrand factor were measured as biomarkers of in vivo platelet activation. RESULTS: Serum alpha-tocopherol increased with both tocopherol treatments. Serum and cellular gamma-tocopherol increased 4-fold (P < 0.001) in the mixed tocopherol group, whereas red blood cell gamma-tocopherol decreased significantly after alpha-tocopherol supplementation. Excretion of alpha-carboxyethyl-hydroxychroman increased significantly after supplementation with alpha-tocopherol and mixed tocopherols. Excretion of gamma-carboxyethyl-hydroxychroman increased significantly after supplementation with mixed tocopherols and after that with alpha-tocopherol, which may reflect the displacement of gamma-tocopherol by alpha-tocopherol due to incorporation of the latter into lipoproteins in the liver. Neither treatment had any significant effect on markers of platelet activation. CONCLUSIONS: Supplementation with alpha-tocopherol decreased red blood cell gamma-tocopherol, whereas mixed tocopherols increased both serum alpha-tocopherol and serum and cellular gamma-tocopherol. Changes in serum tocopherol closely reflect changes in cellular concentrations of tocopherols after supplementation.

The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: There is growing evidence that oxidative stress contributes to the pathogenesis of hypertension and endothelial dysfunction. Thus, dietary antioxidants may beneficially influence blood pressure (BP) and endothelial function by reducing oxidative stress. OBJECTIVE: To determine if vitamin C and polyphenols, alone or in combination, can lower BP, improve endothelial function and reduce oxidative stress in hypertensive individuals. DESIGN: A total of 69 treated hypertensive individuals with a mean 24-h ambulatory systolic blood pressure > or = 125 mmHg participated in a randomized, double-blind, placebo-controlled, factorial trial. Following a 3-week washout, participants received 500 mg/day vitamin C, 1000 mg/day grape-seed polyphenols, both vitamin C and polyphenols, or neither for 6 weeks. At baseline and post-intervention, 24-h ambulatory BP, ultrasound-assessed endothelium-dependent and -independent vasodilation of the brachial artery, and markers of oxidative damage, (plasma and urinary F2-isoprostanes, oxidized low-density lipoproteins and plasma tocopherols), were measured. RESULTS: A significant interaction between grape-seed and vitamin C treatments for effects on BP was observed. Vitamin C alone reduced systolic BP versus placebo (-1.8 +/- 0.8 mmHg, P = 0.03), while polyphenols did not (-1.3 +/- 0.8 mmHg, P = 0.12). However, treatment with the combination of vitamin C and polyphenols increased systolic BP (4.8 +/- 0.9 mmHg versus placebo; 6.6 +/- 0.8 mmHg versus vitamin C; 6.1 +/- 0.9 mmHg versus polyphenols mmHg, each P < 0.0001) and diastolic BP (2.7 +/- 0.6 mmHg, P < 0.0001 versus placebo; 1.5 +/- 0.6 mmHg, P = 0.016 versus vitamin C; 3.2 +/- 0.7 mmHg, P < 0.0001 versus polyphenols). Endothelium-dependent and -independent vasodilation, and markers of oxidative damage were not significantly altered. CONCLUSION: Although the mechanism remains to be elucidated, these results suggest caution for hypertensive subjects taking supplements containing combinations of vitamin C and polyphenols.

Supplementation with grape seed polyphenols results in increased urinary excretion of 3-hydroxyphenylpropionic Acid, an important metabolite of proanthocyanidins in humans.

Grape seed extract provides a concentrated source of polyphenols, most of which are proanthocyanidins. Polymeric proanthocyanidins are poorly absorbed in the small intestine of humans, and exposure may result from metabolism to phenolic acids by colonic bacteria. Any biological effects of proanthocyanidins may be due to the phenolic acid metabolites. Several phenolic acids have been identified as proanthocyanidin metabolites, but these may be derived from a range of other dietary sources. The aim of this study was to determine if 24-h urinary excretion of specific phenolic acids increased significantly and consistently following regular supplementation with grape seed extract. In a randomized, double-blind placebo-controlled trial, 69 volunteers received grape seed extract (1000 mg/day total polyphenols) or placebo for 6 weeks. Supplementation with grape seed polyphenols resulted in a consistent increase in the excretion of 3-hydroxyphenylpropionic acid (3-HPP, P < 0.001) and 4-O-methylgallic acid (P < 0.001) and a less consistent increase in the excretion of 3-hydroxyphenylacetic acid (P = 0.002). The observed increase in 3-HPP is in line with the suggestion that this compound is a major phenolic acid breakdown product of proanthocyanidin metabolism in vivo.

Phenolic acid metabolites as biomarkers for tea- and coffee-derived polyphenol exposure in human subjects.

Tea and coffee are rich in polyphenols with a variety of biological activities. Many of the demonstrated activities are consistent with favourable effects on the risk of chronic diseases. 4-O-methylgallic acid (4OMGA) and isoferulic acid are potential biomarkers of exposure to polyphenols derived from tea and coffee respectively. 4OMGA is derived from gallic acid in tea, and isoferulic acid is derived from chlorogenic acid in coffee. Our major objective was to explore the relationships of tea and coffee intake with 24 h urinary excretion of 4OMGA and isoferulic acid in human subjects. The relationships of long-term usual (111 participants) and contemporaneously recorded current (344 participants) tea and coffee intake with 24 h urinary excretion of 4OMGA and isoferulic acid were assessed in two populations. 4OMGA was related to usual (r 0.50, P<0.001) and current (r 0.57, P<0.001) tea intake, and isoferulic acid was related to usual (r 0.26, P=0.008) and current (r 0.18, P<0.001) coffee intake. Overall, our present results are consistent with the proposal that 4OMGA is a good biomarker for black tea-derived polyphenol exposure, but isoferulic acid may be of limited usefulness as a biomarker for coffee-derived polyphenol exposure.