Dietary flavonoids : effects on endothelial function and blood pressure

Journal of the Science of Food and Agriculture
J Sci Food Agric 86:2492– 2498 (2006)
Review
Dietary ?avonoids: effects on endothelial
function and blood pressure
Jonathan M Hodgson? and Kevin D Croft
University of Western Australia, School of Medicine and Pharmacology at Royal Perth Hospital, and the Western Australian Institute for
Medical Research, Perth, Western Australia, Australia
Abstract: Several population studies have found an inverse association between ?avonoid intake and risk of
cardiovascular disease. These studies have resulted in the hypothesis that dietary ?avonoids protect against
cardiovascular disease. Many in vitro studies, studies using animal models and human intervention trials have
been carried out to investigate how ?avonoids might provide protection. Emerging and largely consistent evidence
suggests that ?avonoids can improve endothelial function and may reduce blood pressure. In vitro studies show
that a variety of ?avonoids cause vasorelaxation of isolated arteries from rats. In human intervention trials,
?avonoids derived from tea and cocoa or dark chocolate – both rich sources of catechins – have been found to
improve endothelial function acutely and with regular ingestion. The evidence for bene?ts of ?avonoids from
other dietary sources is less clear. Improvements in endothelial function could contribute to lower blood pressure.
Population studies have associated higher intake of tea and chocolate with lower blood pressure. Short-term
intervention studies in humans have shown blood pressure lowering with cocoa or dark chocolate, but short-term
regular ingestion of tea has not been found to lower blood pressure. The long-term effects of regular ingestion of
a ?avonoid-enriched diet on endothelial function and blood pressure have yet to be assessed. In addition, there is
evidence that ?avonoid metabolism is an important factor in?uencing the biological activity and effects of dietary
?avonoids, but further studies are needed to investigate this area.
? 2006 Society of Chemical Industry
Keywords: ?avonoids; endothelial function; blood pressure; metabolism
INTRODUCTION
or 3,4,5-hydroxylated (Fig. 1). The six major classes
Over the past two decades there has been considerable
of ?avonoids include ?avonols, ?avones, ?avanols,
research interest in the potential health bene?ts of
?avanones, anthocyanins and iso?avones (Table 1).
?avonoids. Results of population studies suggest that
The structures of four of the ?avonoids which have
dietary ?avonoids provide modest protection against
been of considerable research interest are presented
cardiovascular disease.1,2 There is also a growing
in Fig. 1. A great deal of the available data on health
body of evidence from controlled trials that dietary
effects of ?avonoids relates primarily to foods and
?avonoids can improve endothelial function and
beverages rich in ?avonols, ?avanols or iso?avones.
reduce blood pressure in humans,3 and inhibit the
development of atherosclerosis in animal models.4
These effects may be at least partly responsible for
CARDIOVASCULAR DISEASE IN POPULATION
any reduction in the risk of cardiovascular disease.
STUDIES
The relationship between ?avonoid intake and risk
of cardiovascular disease has been investigated in
DEFINITIONS AND DIETARY SOURCES
a number of epidemiological studies.2,3 There have
Many thousands of polyphenolic compounds are
now been 12 prospective studies on ?avonoid intake
produced as secondary plant metabolites. Within the
and coronary heart disease and ?ve prospective
plant they have a diverse range of functions. When
studies on ?avonoid intake and stroke.2 Seven studies
ingested by humans they may provide health bene?ts.
suggest a protective effect on coronary events and
Flavonoids are a major class of polyphenols. They
or death: six for ?avonols and/or ?avones and one
have a C6 –C3 –C6 structure consisting of two aromatic
for ?avanols. Two studies suggest a protective effect
rings that are linked together by a three-carbon unit
of ?avonols and ?avones against stroke. Huxley and
to form an oxygenated heterocycle. The A ring is
Neil5 performed a meta-analysis of seven prospective
characteristically of the phloroglucinol or resorcinol
studies of ?avonoids in relation to coronary heart
hydroxylation pattern and the B ring usually 4-, 3,4-
disease. The highest tertile of ?avonoid intake was
? Correspondence to: Jonathan M Hodgson, School of Medicine & Pharmacology, GPO Box X2213, Perth, WA, 6001, Australia
E-mail: jonathan@cyllene.uwa.edu.au
(Received 8 May 2006; accepted 31 July 2006)
Published online 4 October 2006; DOI: 10.1002/jsfa.2675
? 2006 Society of Chemical Industry. J Sci Food Agric 0022–5142/2006/$30.00

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Effects of ?avonoids on blood pressure
Table 1. Flavonoid classes, representative ?avonoids and food and beverages sources
Class
Representative ?avonoids
Main food and beverage sources
Flavonols
Quercetin; kaempferol; myricetin
Tea; apples; onions
Flavones
Apigenin; luteolin
Herbs; vegetables
Flavanols
Catechins; procyanidins
Tea; red wine; red grapes; grape seeds; cocoa
Flavanones
Hesperidin; naringenin
Citrus fruits
Anthocyanins
Cyanidin
Berries
Iso?avones
Genistein; daidzein
Soy protein-containing foods
(OH)
greater cardiovascular bene?ts than similar alcohol
3?
intake from beer.9 This may be related to the
2?
4? (OH)
high ?avonoid content of wine but could also be
8
B
HO
O
5? (OH)
due to other confounding lifestyle factors such as
1 2
diet, socioeconomic status or pattern of alcohol
A
3
consumption.10 Iso?avone intake can be linked closely
6
OH
to the intake of foods containing soy protein. To date,
OH
O
one prospective study has investigated the link between
Flavonol
soy protein intake and coronary heart disease events
OH
and found a protective relationship.11
OH
OH
Although these studies do not establish a causative
OH
HO
O
link, the overall evidence from population studies does
HO
O
suggest that a higher ?avonoid intake may provide
OH
OH
modest protection against cardiovascular disease.2,3
OH
OH O
Quercetin
(?)-Epicatechin
ANIMAL MODELS OF ATHEROSCLEROSIS
OH
OH
OH
OH
The effects of ?avonoid-rich foods or extracts on the
HO
O
HO
O
development of atherosclerosis have been studied in
OH
OH
the apoE de?cient mouse and in hamsters. These
OH
OH
O
studies are consistent in demonstrating favourable
OH
OH
C
OH
effects. In the apoE de?cient mouse, which devel-
O
OH
ops human-like atherosclerotic plaques, inhibition
(?)-Epigallocatechin
(?)-Epigallocatechin gallate
of lesion development has been demonstrated with
tea,12 red wine-derived polyphenols4,13 – 15 and isolated
Figure 1. Structures of four ?avonoids that have been of
quercetin or catechin.13 Oral supplementation with
considerable research interest.
a pure phenolic acid derivative from honey, caffeic
acid phenethyl ester, also attenuates atherosclerosis
associated with a 20% reduction in the risk of fatal
in the apoE de?cient mouse.16 Similar inhibition has
coronary heart disease in comparison the lowest tertile
been found with tea17 and red-grape extracts18 in the
of intake. The lack of bene?t observed in some studies
cholesterol-fed hamster. Some studies have suggested
could be explained by either a uniformly very low or
a dissociation of the anti-atherosclerosis activity with
high ?avonoid intake within these populations.6
oxidative damage.4,15 This suggests that the bioactiv-
Cross-sectional and prospective population studies
ity of the polyphenols may not be due to antioxidant
have also investigated the relationship of polyphenol-
activity in vivo.
rich foods and beverages with cardiovascular disease.
Results of more than ten prospective studies suggest
that three cups of tea per day (rich in catechins)
FLAVONOIDS AND CARDIOVASCULAR DISEASE
can reduce coronary heart disease risk by about
RISK FACTORS
10%.7 Data from cross-sectional studies would also
Intervention studies in humans have explored the
suggest a similar protective effect of tea.7 A recent
effects of ?avonoids and ?avonoid-rich foods on a
cross-sectional study from the Zutphen Elderly
range of cardiovascular disease-related endpoints.19
Study suggests that cocoa (rich in catechins and
These have included processes involved in the
procyanidins) intake is inversely associated with
pathogenesis of vascular disease such as oxidative
blood pressure and all-cause mortality.8 The available
damage and in?ammation, cardiovascular disease risk
data from population studies on red wine (rich
factors such as blood lipids, homocysteine, blood
in procyanidins) consumption are more dif?cult
pressure and body weight, and markers of vascular
to interpret because of the confounding effect
disease such as arterial compliance and endothelial
of alcohol. There is some suggestion that light-
function. For many of these endpoints, the results are
to-moderate consumption of red wine may have
mixed and a consistent picture has yet to emerge.
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J Hodgson and KD Croft
There has been considerable research interest in
The effect of dietary ?avonoids on endothelial
?avonoids as antioxidants. Flavonoids possess potent
function in humans has been an area of major
antioxidant activity in vitro. However, despite many
interest in recent years.3,23 Accumulating data suggest
investigations, there remains limited evidence to
that ?avonoids can improve endothelial function.40 – 53
suggest that ?avonoids can actually inhibit oxidative
These studies can be broadly categorised based on
damage in vivo.4,20 – 22 Manach et al.23 in a review
the dietary source of ?avonoids used into tea, cocoa
of the most recent human intervention trials with
and dark chocolate, red wine and related sources,
antioxidant/oxidant endpoints highlight the large
and soy iso?avones.19 In controlled intervention trials
discrepancies in this area. In addition, studies showing
chronic40,41 and acute41 – 43 ingestion of tea has been
inhibition of atherosclerosis in animal models point to
shown to improve endothelial function. Similarly,
mechanisms other than antioxidant effects.4,15,18
improved endothelial function has been demonstrated
Results of in vitro studies, studies in animal models
in several studies with ?avonoid-rich cocoa or dark
and population studies suggest that ?avonoids could
chocolate.44 – 48 The results of Schroeter et al.48 suggest
reduce blood cholesterol concentrations. However,
that epicatechin in cocoa is primarily responsible
many human intervention studies have found little
for the vascular effects. Oral administration of pure
or no change in blood lipid and lipoproteins with
(?)-epicatechin showed similar acute vascular effects
increased ?avonoid intake.23,24 Overall, the available
as ?avanol-rich cocoa. These effects were likely due
data suggest that ?avonoids may have a small bene?cial
to augmentation of NO synthesis by ?avanols. Tea
effect on blood cholesterol concentrations in individ-
also contains epicatechin, but at lower concentrations,
uals with elevated blood cholesterol concentrations.
and contains high concentrations of other catechins
For a variety of other cardiovascular disease-
with a similar structure.54 The data on red wine
related endpoints, the data are limited to only a
and related sources is mixed. A controlled trial with
few investigations. Additional studies are needed
very small numbers by Cuevas et al.49 did suggest
to con?rm suggested bene?ts of ?avonoids on
bene?t of red wine, whereas other controlled trials
platelet function,25 in?ammation,26 body fatness27
have shown no effect.55 – 58 Several uncontrolled trials
and homocysteine.28
using de-alcoholised red wine or purple grape juice
have shown a signi?cant improvement in endothelial
function.50 – 52 Many randomised controlled trials have
FLAVONOIDS AND ENDOTHELIAL FUNCTION
now investigated the effect of isolated iso?avones59 – 63
In vitro studies
or soy protein containing iso?avones53,64 – 66
on
Isolated vessels from animals can be used to assess
endothelial function in the brachial artery. The results
of these studies suggest that iso?avones do not
the effects of potentially vasoactive substances in vitro.
signi?cantly improve endothelial function. However,
The effects of individual ?avonoids on the relaxation
studies with endothelial or vascular function outcomes
of isolated arteries from rats have been investigated in
other than ?ow-mediated dilatation are suggestive
many studies. The relaxation responses of ?avonols,
of bene?ts,67 – 69 indicating that different mechanisms
?avones, ?avanols, ?avanones, anthocyanins and
could be involved.
iso?avones have all been assessed in this model.
These
studies
show
that
?avonoids
can
cause
vasorelaxation at physiological concentrations. The
FLAVONOIDS AND BLOOD PRESSURE
relaxation observed is largely endothelium-dependent
Effects of ?avonoids to improve endothelial function
and nitric oxide (NO)-dependent, although other
may be at least partially responsible for any reduction
mechanisms also appear to be involved.29 – 34
in risk of cardiovascular disease. Acute and sustained
improvement in endothelial function could contribute
Human intervention trials
to lower blood pressure. Dietary ?avonoids can reduce
Consistent bene?ts of ?avonoids from some dietary
blood pressure in the spontaneously hypertensive rat.70
sources (catechin-rich foods and beverages) have
Studies of the effects on blood pressure of short-term
been observed on endothelial function. In humans,
regular ingestion of ?avonoids in humans provide
one of the main methods to investigate endothelial
mixed results.47,57,58,71 – 73 Three short-term studies
function has been to use ultrasonography focusing on
have shown blood pressure lowering with ?avonoid-
conduit vessels, such as the brachial artery.35 This is
rich cocoa or dark chocolate.47,72,73 In contrast, short-
a non-invasive technique that measures vasodilation
term regular ingestion of tea for up to 4 weeks appears
of the artery in response to shear stress induced by
not to signi?cantly alter blood pressure.40,71 Studies
increased blood ?ow. This is known as ?ow-mediated
showing that soy protein containing iso?avones can
dilatation and is largely NO-dependent.36 The validity
reduce blood pressure74,75 are likely to be confounded
of this technique is supported by observations showing
by an effect of protein per se to reduce blood pressure.76
that abnormalities in the peripheral circulation are
Isolated iso?avones appear to have little or no effect
associated with a range of cardiovascular risk factors,37
on blood pressure, at least in the short term.77
with abnormal vasotonic responses in the coronary
Investigations of the possible longer-term effects
circulation38 and with increased risk of coronary
of regular ingestion of ?avonoids on blood pres-
events.39
sure are limited to cross-sectional studies assessing
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Effects of ?avonoids on blood pressure
tea intake78 – 81 and chocolate intake.8 Inverse rela-
who methylated fewer of the ?avonoids had more of
tionships of tea intake78,79 and a marker of tea
an improvement in endothelial function. There were
?avonoid exposure79 with blood pressure, and of
similar ?ndings during acute tea consumption. That
tea intake with prevalence of hypertension80,81 have
is, any improvement in ?ow-mediated dilatation fol-
been reported. Recent cross-sectional data from the
lowing ingestion of tea may be enhanced in individuals
Zutphen Elderly Study suggest an inverse association
who O-methylate fewer of the absorbed ?avonoids.85
between cocoa intake and blood pressure and cardio-
Thus, differences in ?avonoid metabolism could be
vascular mortality.8 Relationships of red wine intake
related to the level of bene?t of dietary ?avonoids
with blood pressure are in?uenced by the more potent
on the risk of cardiovascular disease, but additional
effect of alcohol to raise blood pressure.58
studies are needed to investigate this hypothesis.
In vitro activities of ?avonoid metabolites
FLAVONOID METABOLISM: BIOLOGICAL
The available data on the effects of O-methylation
ACTIVITY AND EFFECTS
of ?avonoids on in vitro activities are limited.86 – 88
Absorbed ?avonoids are often rapidly metabolised.
Most data from the many hundreds of in vitro studies
This may be relevant to biological activity and effects of
are based on the use of ?avonoids present in foods,
dietary ?avonoids. An important pathway of ?avonoid
and not as they exist in the circulation. This may
metabolism following absorption is O-methylation by
limit the validity of the studies in extrapolating
catechol-O-methyltransferase (COMT ).82 It appears
the data to human physiology.89 We have shown
that much of the absorbed ?avonoids are methy-
that O-methylation of a phenolic compound can
lated, but the degree of ?avonoid metabolism may
signi?cantly reduce its antioxidant activity.86 Koga
vary between individuals. Flavonoids can act as accep-
and Meydani87 found that catechin metabolites were
tors of methyl groups, becoming O-methylated via the
more effective than catechin in inhibiting monocyte
action of COMT during metabolism of methionine
adhesion to endothelial cells. Spencer et al.88 found
to homocysteine. Therefore, dietary polyphenols have
that the protection against cell death induced by
the potential to raise total plasma homocysteine con-
hydrogen peroxide elicited by 3 -O-methyl epicatechin
centrations (tHcy).28 In addition, the O-methylation of
is not signi?cantly different from that of epicatechin.
?avonoids reduces endothelial exposure to unaltered
Further studies are clearly needed to investigate in vitro
compounds and may alter vasodilator activity. There-
activities of ?avonoids as they occur in the circulation.
fore, differences in ?avonoid metabolism have the
potential to in?uence biological activities and effects.
The activity of COMT can vary as much as three-fold
CONCLUSIONS AND FUTURE RESEARCH
between individuals,83 which could contribute to the
Population and intervention studies indicate that
variability in observed ?avonoid methylation.84 The
a higher intake of ?avonoids protects against car-
COMT activity is related to genetic variation in the
diovascular disease. Accumulating evidence suggests
COMT gene. There are two main genotypes: low
that ?avonoid-rich foods and beverages can improve
activity COMT and high activity COMT.83 This is
endothelial function and may reduce blood pressure.
likely to be a major factor, but not the only factor
This may at least partly explain any bene?t on car-
in?uencing ?avonoid methylation.
diovascular disease risk. However, several questions
have yet to be adequately addressed. The effects
Biological effects
on endothelial function, blood pressure and other
We have previously investigated the potential impor-
cardiovascular disease risk factors of long-term regu-
tance
of
?avonoid
methylation
in
intervention
lar ingestion of a high ?avonoid diet have not been
trials.28,85 In individuals drinking ?ve cups per day
assessed in a controlled trial. Long-term studies are
of black tea for 4 weeks, we assessed the relationship
important to con?rm the bene?ts suggested by results
between degree of O-methylation of the tea-derived
of acute and short-term intervention studies, and for
polyphenols and the change in tHcy. Overall, regular
the translation of ?ndings into appropriate public
ingestion of black tea did not alter tHcy. How-
health advice. It is also uncertain whether changes
ever, the degree to which individuals O-methylated
in blood pressure follow improvements in endothelial
tea-derived ?avonoids was positively associated with
function, and the extent to which any changes in blood
change in tHcy.28 These results suggest that individ-
pressure are due to acute vasoactive effects. Another
ual differences in O-methylation may in?uence the
unanswered question relates to whether or not a range
ultimate effects of black tea on tHcy. More recently
of ?avonoids of similar structure elicit the same vas-
we have investigated whether changes in endothe-
cular effects. The recent studies with cocoa suggest
lial function following chronic and acute ingestion of
that epicatechin is primarily responsible for the effects
tea were related to the O-methylation of tea-derived
of cocoa/dark chocolate to improve endothelial func-
?avonoids.85 During chronic ingestion of tea, the
tion. It remains uncertain whether a range of catechins
degree to which individuals O-methylated tea-derived
as well as other classes of ?avonoids have the same
?avonoids was negatively associated with change in
activity. These investigations will help to establish if
?ow-mediated dilatation responses. Those individuals
cardiovascular bene?ts are likely to be limited to a
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J Hodgson and KD Croft
small number or a wider range of foods and beverages.
20 Hodgson JM, Croft KD, Mori TA, Burke V, Beilin LJ and
Finally, results of recent trials with tea suggest that
Puddey IB, Regular ingestion of tea does not inhibit lipid
peroxidation in vivo. J Nutr 132:55–58 (2002).
?avonoid metabolism could be an important determi-
21 Hodgson JM, Puddey IB, Croft KD, Mori TA, Rivera J and
nant of biological effects. The importance of ?avonoid
Beilin LJ, Iso?avonoids do not inhibit in vivo lipid peroxida-
O-methylation requires further investigation.
tion in subjects with high-normal blood pressure. Atheroscle-
rosis 145:167–172 (1999).
22 Halliwell B, Rafter J and Jenner A, Health promotion by
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