Editorial

See corresponding article on page 38.

Flavonoids and cardiovascular health: which compounds, what mechanisms?1,2

Johanna M Geleijnse and Peter CH Hollman
In the 1930s, the Hungarian scientists Rusznyak and SzentGyrgi 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-Gyrgyi (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 flavonolsie, quercetin, kaempferol, and myricitinagainst 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 Kromhouts 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 fieldnamely, 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
From the Division of Human Nutrition, Wageningen University, Wageningen, Netherlands. 2 Reprints not available. Address correspondence to JM Geleijnse, Division of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV Wageningen, Netherlands. E-mail: marianne.geleijnse@wur.nl.
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Am J Clin Nutr 2008;88:123. Printed in USA. 2008 American Society for Nutrition

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changes could be reversible, and acute effects are not easily translated into long-term risks of disease. Meta-analysis of chronic tea intake did not show significant effects on blood pressure (9, 10). Acute effects of tea may also be due to other substances, eg, caffeine, rather than flavonoids. This brings us to a drawback of the review by Hooper et alnamely, that a distinction between trials with isolated flavonoids and those with flavonoid-rich products cannot be made easily (if at all). Most of the trials included flavonoid-rich products, whereas only 10 trials were based on isolated flavonoids. Thus, it remains unclear whether the measured effect on cardiovascular biomarkers could actually be attributed to the targeted flavonoid(s). Chocolate and cocoa contain a rich mixture of (poly)phenols such as the flavonoid class of proanthocyanidins, which itself contains many different compounds. Apart from that, plant-derived foods such as tea and cocoa also contain other substances that could exert an effect on the cardiovascular system, such as theobromine, tryptophan, caffeine, and minerals such as potassium and magnesium. This meta-analysis shows the state of the art in flavonoid and cardiovascular research. As Hooper et al stated, no randomized controlled trials have studied the effects of flavonoids on clinical cardiovascular endpoints. However, a number of trials of acceptable quality with flavonoid-rich foods provide evidence for a beneficial effect on flow-mediated dilation, blood pressure, and lipid profile, which are relevant indicators of cardiovascular health. Substantial evidence for a vasoprotective effect of specific flavonoids is, however, still lacking. Optimal doses of specific flavonoids for cardiovascular protection, one of the aims of the review, are still beyond the horizon. Flavonoid research has

made large progress since the days of Szent-Gyrgi, but, to really advance the field, the step to individual flavonoids must be made now.
Neither of the authors had a personal or financial conflict of interest.

REFERENCES
1. Rusznyak S, Szent-Gyrgyi A. Vitamin P: flavonols as vitamins. Nature 1936;138:27. 2. Bruckner V, Szent-Gyrgyi A. Chemical nature of citrin. Nature 1936; 138:1057 (letter). 3. Arts ICW, Hollman PCH. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 2005;81(suppl):317S25S. 4. Scalbert A, Johnson IT, Saltmarsh M. Polyphenols: antioxidants and beyond. Am J Clin Nutr 2005;81(suppl):215S7S. 5. Hertog MGL, Feskens ElM, Hollman PCH, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease. The Zutphen Elderly Study. Lancet 1993;342:100711. 6. Geleijnse JM, Launer LJ, Van der Kuip DA, Hofman A, Witteman JC. Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study. Am J Clin Nutr 2002;75:880 6. 7. Keli SO, Hertog MGL, Feskens EJ, Kromhout D. Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the Zutphen study. Arch Intern Med 1996;156:637 42. 8. Huxley RR, Neil HA. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr 2003;57:904 8. 9. Hooper L, Kroon PA, Rimm EB, et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008;88:38 50. 10. Taubert D, Roesen R, Schmig E. Effect of cocoa and tea intake on blood pressure: a meta-analysis. Arch Intern Med 2007;167:626 34. 11. Taku K, Umegaki K, Sato Y, Taki Y, Endoh K, Watanabe S. Soy isoflavones lower serum total and LDL cholesterol in humans: a metaanalysis of 11 randomized controlled trials. Am J Clin Nutr 2007;85: 1148 56.

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