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Flavonoids and cardiovascular health: which compounds, what mechanisms?

2008; Elsevier BV; Volume: 88; Issue: 1 Linguagem: Inglês

10.1093/ajcn/88.1.12

1938-3207

Johanna M. Geleijnse, P.C.H. Hollman,

Free Radicals and Antioxidants

In the 1930s, the Hungarian scientists Rusznyak and SzentGyorgi identified a substance from lemon peels that reduced capillary permeability and that was an effective treatment in purpura patients who were resistant to vitamin C therapy (1). They called this substance “vitamin P” (P for permeability). Later, Bruckner and Szent-Gyorgyi (2) reported that this “vitamin P” (or citrin) was not a pure substance but that it consisted of a mixture of the flavonoids hesperidin and eriodictyol glucoside. Flavonoids are water-soluble plant pigments that are characterized by an aromatic ring structure with one or more hydroxyl groups. They belong to the larger group of plant (poly)phenols, which can be divided into 10 different subclasses, including flavonols, catechins, (pro)anthocyanidins, lignans, and lignins (3). Polyphenols occur in all plant foods and may contribute to the beneficial health effects of vegetables and fruit. Their contribution to the antioxidant capacity of the human diet is much larger than that of vitamins. More than 6000 different flavonoids in plants have been described, and their total intake could amount to 1 g/d, whereas combined intakes of -carotene, vitamin C, and vitamin E from food most often are 100 mg/d (4). Important dietary sources of flavonoids in Western societies are onions (flavonols); cocoa (proanthocyanidins); tea, apples, and red wine (flavonols and catechins); citrus fruit (flavanones); berries and cherries (anthocyanidins); and soy (isoflavones). Flavonoids lost their vitamin status in the 1950s and became suspected of carcinogenicity (mainly, quercetin) in the 1970s. In the late 1980s, however, their tainted reputation was repaired and they were considered to be anticarcinogenic. It was only in the 1990s that the Dutch research group led by Kromhout reported a strong protective effect of several flavonols—ie, quercetin, kaempferol, and myricitin—against mortality due to coronary heart disease in the Zutphen Elderly Study (5). The risk of coronary death in this cohort was reduced by as much as 70% in men who consumed 30 mg flavonols/d. A later analysis in the Rotterdam Study among 4807 older Dutch men and women confirmed these findings, with a 65% lower risk for fatal myocardial infarction in subjects whose flavonol intake was 33 mg/d, mainly from tea (6). In the cohort of Dutch men in the Zutphen Study, flavonol intake was also related to a 70% lower risk of incident stroke (7). Epidemiologic studies of flavonoids and cardiovascular mortality have also been performed in other countries, and in most, although not all, studies, a protective association was found (3, 8). The strong risk reductions that were observed in the Dutch cohorts, however, could not be reproduced. The meta-analysis by Huxley and Neil in 2003 that comprised 7 cohort studies from the United Kingdom, United States, Finland, and the Netherlands yielded a pooled relative risk for incidence of coronary heart disease of 0.80 (95% CI: 0.69, 0.93); the relative risks varied between 0.6 and 1.6 for high and low flavonol intake, respectively, in non-Dutch cohorts (8). The discrepancy in the strength of the associations may be due to measurement error for true flavonol exposure, because dietary assessment methods and major dietary sources of flavonols (with large variations in bioavailability) differ between countries. Most epidemiologic studies used the tables published by Hertog et al (5) that showed flavonol content of foods and drinks in the Netherlands, which may not be directly applicable to other countries. In addition, confounding by differences in socioeconomic status, other dietary compounds, and lifestyle factors among populations could have played a role. After the reports by Kromhout’s group, research into possible biological pathways that could underlie the vasoprotective properties of dietary flavonoids in humans got a boost. A wealth of flavonoid studies using biomarkers of cardiovascular risk appeared in the literature in the past decade. In this issue of the Journal, Hooper et al (9) provide a sorely needed comprehensive review of 133 flavonoid trials, which they attempted to include in a meta-analysis. They aimed at determining the optimal doses of flavonoids and food sources for cardiovascular risk reduction and at setting priorities for future research. The main outcomes would not surprise researchers in the field—namely, that polyphenol-rich cocoa reduces blood pressure by 6 (systolic) and 3 (diastolic) mm Hg and that soy protein, which is rich in isoflavones, reduces LDL cholesterol by 0.2 mmol/L. Similar findings, although somewhat smaller, have also been reported by Taubert et al (10) in a meta-analysis of randomized controlled trials of cocoa polyphenols and blood pressure and by Taku et al (11) in a meta-analysis of soy isoflavones and blood lipids. Hooper et al also showed that black tea acutely raises blood pressure by 6 (systolic) and 3 (diastolic) mm Hg, whereas chocolate acutely increases flow-mediated dilation by 4%. Although the latter findings are interesting from a physiologic point of view, such