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 Szent-
Györgi 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-Györgyi (2) reported that this “vita-
min 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 character-
ized 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 쏜10 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 con-
tribution 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 쏝100 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 cor-
onary death in this cohort was reduced by as much as 70% in men
who consumed 쏜30 mg flavonols/d. A later analysis in the Rot-
terdam Study among 4807 older Dutch men and women con-
firmed these findings, with a 65% lower risk for fatal myocardial
infarction in subjects whose flavonol intake was 쏜33 mg/d,
mainly from tea (6). In the cohort of Dutch men in the Zutphen
Study, flavonol intake was also related to a 쏜70% lower risk of
incident stroke (7). Epidemiologic studies of flavonoids and car-
diovascular mortality have also been performed in other coun-
tries, and in most, although not all, studies, a protective associ-
ation was found (3, 8). The strong risk reductions that were
12 Am J Clin Nutr 2008;88:12–3. Printed in USA. © 2008 American Society for Nutrition
observed in the Dutch cohorts, however, could not be repro-
duced. The meta-analysis by Huxley and Neil in 2003 that com-
prised 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 dis-
Downloaded from www.ajcn.org by on August 22, 2010
crepancy in the strength of the associations may be due to mea-
surement error for true flavonol exposure, because dietary as-
sessment 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 coun-
tries. 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 prop-
erties of dietary flavonoids in humans got a boost. A wealth of
flavonoid studies using biomarkers of cardiovascular risk ap-
peared 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 isofla-
vones, 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 find-
ings are interesting from a physiologic point of view, such
1
From the Division of Human Nutrition, Wageningen University,
Wageningen, Netherlands.
2
Reprints not available. Address correspondence to JM Geleijnse, Divi-
sion of Human Nutrition, Wageningen University, PO Box 8129, 6700 EV
Wageningen, Netherlands. E-mail: marianne.geleijnse@wur.nl.
 EDITORIAL
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 pres-
sure (9, 10). Acute effects of tea may also be due to other sub-
stances, eg, caffeine, rather than flavonoids.
This brings us to a drawback of the review by Hooper et
al—namely, that a distinction between trials with isolated fla-
vonoids and those with flavonoid-rich products cannot be made
easily (if at all). Most of the trials included flavonoid-rich prod-
ucts, whereas only 앒10 trials were based on isolated flavonoids.
Thus, it remains unclear whether the measured effect on cardio-
vascular 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 sys-
tem, 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 accept-
able 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 spe-
cific flavonoids is, however, still lacking. Optimal doses of spe-
cific flavonoids for cardiovascular protection, one of the aims of
the review, are still beyond the horizon. Flavonoid research has
13
made large progress since the days of Szent-Györgi, 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-Györgyi A. Vitamin P: flavonols as vitamins. Nature
1936;138:27.
2. Bruckner V, Szent-Györgyi 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):317S–25S.
4. Scalbert A, Johnson IT, Saltmarsh M. Polyphenols: antioxidants and
beyond. Am J Clin Nutr 2005;81(suppl):215S–7S.
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;342:1007–11.
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
Downloaded from www.ajcn.org by on August 22, 2010
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, Schömig 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 meta-
analysis of 11 randomized controlled trials. Am J Clin Nutr 2007;85:
1148 –56.