Platelet reactivity in male smokers following the acute consumption of a flavanol-rich grapeseed extract.

Epidemiological studies suggest that a high dietary intake of flavanols, a subclass of flavonoids, is associated with reduced risk of vascular disease. Clinical studies have also shown that the consumption of certain flavanol-rich foods (e.g., cocoa, tea, red wine), as well as intake of the individual flavanol (-)-epicatechin, can result in improvement in a number of parameters associated with vascular disease, including improved endothelial function, reduced platelet reactivity, and reduced oxidative stress. The present study assessed the effects of a flavanol-rich supplement on platelet reactivity and plasma oxidant defense in a group of smokers, a population at an elevated risk for vascular disease. Male smokers were randomly assigned to a placebo (n = 10) or a flavanol-rich grapeseed extract (FRGSE; n = 13) group, and after an overnight fast, blood samples were collected before and at 1, 2, and 6 hours following consumption of the placebo or supplement. The FRGSE supplement, but not the placebo, significantly decreased ADP-stimulated platelet reactivity at 1, 2, and 6 hours following intake (P < .05) compared to baseline levels. Similarly, the supplement, but not the placebo, decreased epinephrine-stimulated platelet reactivity 2 hours following consumption. Plasma antioxidant capacity (total radical trapping antioxidant potential), lipid oxidation (plasma thiobarbituric acid-reactive substances), and serum uric acid concentrations were not affected in either group. Thus smokers may obtain some health benefits from the consumption of certain flavanol-rich foods, beverages, and supplements.

Cocoa flavanol-enriched snack bars containing phytosterols effectively lower total and low-density lipoprotein cholesterol levels.

BACKGROUND: Dietary intervention studies incorporating phytosterol-enriched margarine spreads have reported significant decreases in total and low-density lipoprotein (LDL) cholesterol in populations with both normal lipid levels and those with hypercholesterolemia. There is emerging support for more diverse and lower-fat phytosterol-enriched matrixes. Controversy exists, however, over whether phytosterol-enriched foods affect serum fat-soluble vitamins. OBJECTIVE: We investigated whether a flavanol-rich cocoa snack food containing phytosterols would decrease total and LDL cholesterol levels in subjects with hypercholesterolemia and significantly affect serum fat-soluble vitamins and carotenoids. DESIGN: A randomized, double-blind parallel arm study design was used. Subjects were randomized to one of two dietary treatments: a cocoa flavanol-enriched snack bar containing 1.5 g phytosterol (n=32), or a control product containing no phytosterols (n=35). Subjects consumed two servings per day. RESULTS: Consumption of the phytosterol-enriched snack bars but not control bars for 6 weeks was associated with significant reductions in plasma total (4.7%; P<0.01) and LDL cholesterol (6%; P<0.01), and the ratio of total to high-density lipoprotein cholesterol (7.4%; P<0.001). There were no changes in high-density lipoprotein cholesterol, triglycerides, or lipid-adjusted lycopene, beta-cryptoxanthin, lutein/zeaxanthin, alpha-carotene levels, or levels of serum vitamins A or E. A significant reduction in lipid-adjusted serum beta-carotene was observed in the phytosterol but not the no-phytosterol-added group (P<0.05). CONCLUSIONS: This study supports the use of a novel phytosterol-enriched snack bar to effectively reduce plasma total and LDL cholesterol levels in a population with hypercholesterolemia. The data suggest that the incorporation of this snack food into a balanced diet represents a practical dietary strategy in the management of serum cholesterol levels.

Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women.

Endothelial dysfunction characterizes many disease states including subclinical atherosclerosis. The consumption of flavanol-rich cocoa and cocoa-based products has been shown to improve endothelial function in both compromised and otherwise normal, healthy individuals when administered either acutely or over a period of several days, or weeks. Women experience increased risk for cardiovascular disease after menopause, which can be associated with endothelial dysfunction. Whether a flavanol-rich cocoa-based product can improve endothelial function in hypercholesterolemic postmenopausal women is not known. The purpose of the present study was to determine whether chronic dietary administration of flavanol-rich cocoa improves endothelial function and markers of cardiovascular health in hypercholesterolemic postmenopausal women. Thirty-two postmenopausal hypercholesterolemic women were randomly assigned to consume a high-flavanol cocoa beverage (high cocoa flavanols (CF)--446 mg of total flavanols), or a low-flavanol cocoa beverage (low CF--43 mg of total flavanols) for 6 weeks in a double-blind study (n=16 per group). Endothelial function was determined by brachial artery-reactive hyperemia. Plasma was analyzed for lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), hormones (follicle-stimulating hormone), total nitrate/nitrite, activation of cellular adhesion markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-Selectin, P-Selectin), and platelet function and reactivity. Changes in these plasma markers were then correlated to brachial reactivity. Brachial artery hyperemic blood flow increased significantly by 76% (P<0.05 vs. baseline) after the 6-week cocoa intervention in the high CF group, compared with 32% in the low CF cocoa group (P=ns vs. baseline). The 2.4-fold increase in hyperemic blood flow with high CF cocoa closely correlated (r2=0.8) with a significant decrease (11%) in plasma levels of soluble vascular cell adhesion molecule-1. Similar responses were not observed after chronic use of low CF. There were no significant differences between high and low CF in other biochemical markers and parameters measured. This study is the first to identify beneficial vascular effects of flavanol-rich cocoa consumption in hypercholesterolemic postmenopausal women. In addition, our results suggest that reductions in plasma soluble vascular cell adhesion molecule-1 after chronic consumption of a flavanol-rich cocoa may be mechanistically linked to improved vascular reactivity.

Effect of apple extracts on NF-kappaB activation in human umbilical vein endothelial cells.

The mechanisms by which foods, such as fruit, are able to reduce the risk of chronic disease are still unclear. Several fruit products, including apples and apple juice, that are flavonoid-rich are reported to increase antioxidant levels in human subjects. This is supported by the finding from our previous studies that the chronic consumption of apple juice by human subjects reduced ex vivo low-density lipoprotein (LDL) oxidation; we hypothesized that this was due to the flavonoid in the apple juice, which, as we reported earlier, reduced in vitro LDL oxidation. To further explore whether the mixture of flavonoids and other phytochemicals in apples are biologically relevant antioxidants, we tested the effects of this flavonoid-rich apple extract (AE) on oxidant-related pathways in a model of the endothelium: human umbilical vascular endothelial cells (HU-VECs). The effects of AE on oxidant-responsive (i.e., tumor necrosis factor [TNF]-alpha-induced) nuclear factor (NF)- kappaB signaling in cell culture were assessed in transfected HUVECs by using a construct that expressed luciferase under the control of NF-kappaB. Incubation of HUVEC for 24 hrs with up to 10 mM (as gallic acid equivalents) of AE demonstrated no cytotoxicity, as determined by lactate dehydrogenase release, caspase 3 activation, and apoptosis marker-based FACS analysis. AE after a 24-hr incubation period at either 200 or 2000 nM showed a complex pattern of decreased basal and TNF-alpha-stimulated NF-kappaB signaling (63% maximal decrease) as assessed by luciferase activity in the transfected HUVECs, as well as by reduced levels of IkappaBalpha protein phosphorylation detected by Western blot analysis. We suggest that AE downregulates NF-kappaB signaling and that this is indicative of an antioxidant effect of the flavonoids present in AE.

Food effects on the absorption and pharmacokinetics of cocoa flavanols.

Macronutrients in food and gastric acid are known to have a pronounced effect on the metabolism of many xenobiotics, an effect that impacts their efficacy as bioactive agents. In this investigation we assessed the impact of select food treatments and the histamine H(2)-receptor antagonist Famotidine (Pepcid-AC) on flavanol absorption and metabolism. Four crossover intervention studies were conducted with 6 subjects each. Volunteers consumed sugar-free, flavanol-rich cocoa (0.125 g/kg body wt) alone, with macronutrient-rich foods (8.75 or 17.5 kJ/kg subject body wt) or Famotidine (Pepcid-AC). Blood samples were drawn at 5 time points including baseline. Plasma samples were analyzed for epicatechin and catechin flavanols by HPLC. Pharmacokinetic parameters were assessed using non-compartmental methodology. When provided at 17.5 kJ/kg subject body weight (approximately 4 kcal/kg), sugar and bread test meals increased flavanol area under the curve (AUC) values to 140% of control values (P < 0.05). A corresponding tendency for plasma antioxidant capacity to increase was observed for the cocoa treatment at 1.5 and 2.5 h (P < 0.17, P < 0.06, respectively). The ability of treatment meals to affect AUC values was positively correlated with treatment carbohydrate content (r = 0.83; P< 0.02). In contrast to carbohydrate rich meals, lipid and protein rich meals and Famotidine treatment had minimal effects on flavanol absorption. Based on C(max) and AUC values, this data suggests that the uptake of flavanols can be increased significantly by concurrent carbohydrate consumption.

Effects of flavonoid-rich beverages on prostacyclin synthesis in humans and human aortic endothelial cells: association with ex vivo platelet function.

Diets rich in flavonoids have been associated with reduced risk for cardiovascular disease. This may be due, in part, to flavonoid-induced alterations in eicosanoid synthesis. Our objective was to identify plant-derived beverages that alter synthesis of prostacyclin in cultured human aortic endothelial cells (HAEC), and to determine if these beverages could alter in vivo 6-keto-prostaglandin F(1alpha) (a stable metabolite of prostacyclin) synthesis and platelet function. HAEC were treated with nine commonly consumed beverages to determine their effects on prostacyclin synthesis under acute and chronic treatment regimens. Orange, purple grape, and pomegranate juices and coffee (6-9 mL/kg) were then provided to 28 fasted, healthy adult subjects (eight men and 20 women) on five separate days. Plasma samples were collected immediately following juice consumption (baseline), and at 2 and 6 hours post-consumption. On an acute basis, administration of HAEC with pomegranate juice increased media prostacyclin. Chronic exposure to purple grape and pomegranate juice increased aortic endothelial cell prostacyclin synthesis (38% and 61%, respectively; P <.05). The consumption of purple grape, pomegranate, and orange juice prolonged epinephrine/collagen-induced clotting time (P <.05). Purple grape juice increased plasma 6-keto-prostaglandin F(1alpha) (20%; P <.05) at 2 hours; pomegranate and orange juice did not significantly influence plasma prostacyclin concentrations. Consistent with the in vitro data, coffee consumption did not influence clotting time or plasma prostacyclin concentrations. These results indicate that the HAEC model system can provide a qualitative means to screen food and food-derived products for biologic activity related to cardiovascular health.