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(-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans.

Proceedings of the National Academy of Sciences of the United States of America

Time Factors, Administration, Oral, Adult, Animals, Aorta, pathology, Cacao, metabolism, Cardiovascular Physiological Phenomena, Cardiovascular System, Catechin, chemistry, physiology, Diet, Endothelium, Flavones, Humans, Kinetics, Male, Models, Statistical, Multivariate Analysis, Nitric Oxide, Nitric Oxide Synthase, Rabbits, Regression Analysis, Risk, Signal Transduction

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      Abstract

      Epidemiological and medical anthropological investigations suggest that flavanol-rich foods exert cardiovascular health benefits. Endothelial dysfunction, a prognostically relevant key event in atherosclerosis, is characterized by a decreased bioactivity of nitric oxide (NO) and impaired flow-mediated vasodilation (FMD). We show in healthy male adults that the ingestion of flavanol-rich cocoa was associated with acute elevations in levels of circulating NO species, an enhanced FMD response of conduit arteries, and an augmented microcirculation. In addition, the concentrations and the chemical profiles of circulating flavanol metabolites were determined, and multivariate regression analyses identified (-)-epicatechin and its metabolite, epicatechin-7-O-glucuronide, as independent predictors of the vascular effects after flavanol-rich cocoa ingestion. A mixture of flavanols/metabolites, resembling the profile and concentration of circulating flavanol compounds in plasma after cocoa ingestion, induced a relaxation in preconstricted rabbit aortic rings ex vivo, thus mimicking acetylcholine-induced relaxations. Ex vivo flavanol-induced relaxation, as well as the in vivo increases in FMD, were abolished by inhibition of NO synthase. Oral administration of chemically pure (-)-epicatechin to humans closely emulated acute vascular effects of flavanol-rich cocoa. Finally, the concept that a chronic intake of high-flavanol diets is associated with prolonged, augmented NO synthesis is supported by data that indicate a correlation between the chronic consumption of a cocoa flavanol-rich diet and the augmented urinary excretion of NO metabolites. Collectively, our data demonstrate that the human ingestion of the flavanol (-)-epicatechin is, at least in part, causally linked to the reported vascular effects observed after the consumption of flavanol-rich cocoa.

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      Dietary polyphenols and the prevention of diseases.

      Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.
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        The clinical implications of endothelial dysfunction.

        Defining new approaches for the prevention and treatment of atherosclerosis is an important priority. Recently, measurement of endothelial function in patients has emerged as a useful tool for atherosclerosis research. Risk factors are associated with impaired endothelial function, and clinical syndromes relate, in part, to a loss of endothelial control of vascular homeostasis. Recent studies have shown that the severity of endothelial dysfunction relates to cardiovascular risk. A growing number of interventions known to reduce cardiovascular risk have been shown to improve endothelial function. This work suggests that studies of endothelial function could be used in the care of patients and as a surrogate marker for the evaluation of new therapeutic strategies. This article will review this growing literature in an effort to evaluate the current clinical utility of endothelial dysfunction.
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          Fruit and vegetable intake and risk of major chronic disease.

          Studies of fruit and vegetable consumption in relation to overall health are limited. We evaluated the relationship between fruit and vegetable intake and the incidence of cardiovascular disease and cancer and of deaths from other causes in two prospective cohorts. A total of 71 910 female participants in the Nurses' Health study and 37,725 male participants in the Health Professionals' Follow-up Study who were free of major chronic disease completed baseline semiquantitative food-frequency questionnaires in 1984 and 1986, respectively. Dietary information was updated in 1986, 1990, and 1994 for women and in 1990 and 1994 for men. Participants were followed up for incidence of cardiovascular disease, cancer, or death through May 1998 (women) and January 1998 (men). Multivariable-adjusted relative risks were calculated with Cox proportional hazards analysis. We ascertained 9329 events (1964 cardiovascular, 6584 cancer, and 781 other deaths) in women and 4957 events (1670 cardiovascular diseases, 2500 cancers, and 787 other deaths) in men during follow-up. For men and women combined, participants in the highest quintile of total fruit and vegetable intake had a relative risk for major chronic disease of 0.95 (95% confidence interval [CI] = 0.89 to 1.01) times that of those in the lowest. Total fruit and vegetable intake was inversely associated with risk of cardiovascular disease but not with overall cancer incidence, with relative risk for an increment of five servings daily of 0.88 (95% CI = 0.81 to 0.95) for cardiovascular disease and 1.00 (95% CI = 0.95 to 1.05) for cancer. Of the food groups analyzed, green leafy vegetable intake showed the strongest inverse association with major chronic disease and cardiovascular disease. For an increment of one serving per day of green leafy vegetables, relative risks were 0.95 (95% CI = 0.92 to 0.99) for major chronic disease and 0.89 (95% CI = 0.83 to 0.96) for cardiovascular disease. Increased fruit and vegetable consumption was associated with a modest although not statistically significant reduction in the development of major chronic disease. The benefits appeared to be primarily for cardiovascular disease and not for cancer.
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            Author and article information

            Journal
            10.1073/pnas.0510168103
            1327732
            16418281

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