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      Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials

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          Abstract

          The beneficial effects of flavonoid consumption on cardiovascular risk are supported by mechanistic and epidemiologic evidence. We aimed to systematically review the effectiveness of different flavonoid subclasses and flavonoid-rich food sources on cardiovascular disease (CVD) and risk factors--ie, lipoproteins, blood pressure, and flow-mediated dilatation (FMD). Methods included a structured search strategy on MEDLINE, EMBASE, and Cochrane databases; formal inclusion or exclusion, data extraction, and validity assessment; and meta-analysis. One hundred thirty-three trials were included. No randomized controlled trial studied effects on CVD morbidity or mortality. Significant heterogeneity confirmed differential effects between flavonoid subclasses and foods. Chocolate increased FMD after acute (3.99%; 95% CI: 2.86, 5.12; 6 studies) and chronic (1.45%; 0.62, 2.28; 2 studies) intake and reduced systolic (-5.88 mm Hg; -9.55, -2.21; 5 studies) and diastolic (-3.30 mm Hg; -5.77, -0.83; 4 studies) blood pressure. Soy protein isolate (but not other soy products or components) significantly reduced diastolic blood pressure (-1.99 mm Hg; -2.86, -1.12; 9 studies) and LDL cholesterol (-0.19 mmol/L; -0.24, -0.14; 39 studies). Acute black tea consumption increased systolic (5.69 mm Hg; 1.52, 9.86; 4 studies) and diastolic (2.56 mm Hg; 1.03, 4.10; 4 studies) blood pressure. Green tea reduced LDL (-0.23 mmol/L; -0.34, -0.12; 4 studies). For many of the other flavonoids, there was insufficient evidence to draw conclusions about efficacy. To date, the effects of flavonoids from soy and cocoa have been the main focus of attention. Future studies should focus on other commonly consumed subclasses (eg, anthocyanins and flavanones), examine dose-response effects, and be of long enough duration to allow assessment of clinically relevant endpoints.

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          Most cited references49

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          Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study.

          To determine whether flavonoid intake explains differences in mortality rates from chronic diseases between populations. Cross-cultural correlation study. Sixteen cohorts of the Seven Countries Study in whom flavonoid intake at baseline around 1960 was estimated by flavonoid analysis of equivalent food composites that represented the average diet in the cohorts. Mortality from coronary heart disease, cancer (various sites), and all causes in the 16 cohorts after 25 years of follow-up. Average intake of antioxidant flavonoids was inversely associated with mortality from coronary heart disease and explained about 25% of the variance in coronary heart disease rates in the 16 cohorts. In multivariate analysis, intake of saturated fat (73%; P = 0.0001), flavonoid intake (8%, P = .01), and percentage of smokers per cohort (9%; P = .03) explained together, independent of intake of alcohol and antioxidant vitamins, 90% of the variance in coronary heart disease rates. Flavonoid intake was not independently associated with mortality from other causes. Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality.
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            (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans.

            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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              Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women.

              Dietary flavonoids may have beneficial cardiovascular effects in human populations, but epidemiologic study results have not been conclusive. We used flavonoid food composition data from 3 recently available US Department of Agriculture databases to improve estimates of dietary flavonoid intake and to evaluate the association between flavonoid intake and cardiovascular disease (CVD) mortality. Study participants were 34 489 postmenopausal women in the Iowa Women's Health Study who were free of CVD and had complete food-frequency questionnaire information at baseline. Intakes of total flavonoids and 7 subclasses were categorized into quintiles, and food sources were grouped into frequency categories. Proportional hazards rate ratios (RR) were computed for CVD, coronary heart disease (CHD), stroke, and total mortality after 16 y of follow-up. After multivariate adjustment, significant inverse associations were observed between anthocyanidins and CHD, CVD, and total mortality [RR (95% CI) for any versus no intake: 0.88 (0.78, 0.99), 0.91 (0.83, 0.99), and 0.90 (0.86, 0.95)]; between flavanones and CHD [RR for highest quintile versus lowest: 0.78 (0.65, 0.94)]; and between flavones and total mortality [RR for highest quintile versus lowest: 0.88 (0.82, 0.96)]. No association was found between flavonoid intake and stroke mortality. Individual flavonoid-rich foods associated with significant mortality reduction included bran (added to foods; associated with stroke and CVD); apples or pears or both and red wine (associated with CHD and CVD); grapefruit (associated with CHD); strawberries (associated with CVD); and chocolate (associated with CVD). Dietary intakes of flavanones, anthocyanidins, and certain foods rich in flavonoids were associated with reduced risk of death due to CHD, CVD, and all causes.
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                Author and article information

                Journal
                The American Journal of Clinical Nutrition
                Oxford University Press (OUP)
                0002-9165
                1938-3207
                July 2008
                July 01 2008
                July 2008
                July 01 2008
                : 88
                : 1
                : 38-50
                Affiliations
                [1 ] From the School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, United Kingdom (LH, IH, KALC, JJR, and AC); the Institute of Food Research, Norwich, United Kingdom (PAK); the Harvard School of Public Health, Boston, MA (EBR); the Heart Research Institute, Sydney, Australia (JSC); and Kings College London, United Kingdom (WLH)
                Article
                10.1093/ajcn/88.1.38
                18614722
                ba198224-d0b8-453a-ac44-e0910fd20517
                © 2008

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