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Anthocyanins in Cardiovascular Disease Prevention

Authors:

Abstract

Anthocyanins are a group of abundant and widely consumed flavonoid constituents that occur ubiquitously in the plant kingdom, providing the bright red-orange to blue-violet colors present in many fruit- and vegetable-based food products. Their intake has been estimated to be up to 9-fold higher than that of other dietary flavonoids. Anthocyanins have become increasingly important to the food industry as their use as natural alternatives to artificial colors has become widespread and knowledge of their health-promoting properties has become more evident. Epidemiological studies suggest that increased consumption of anthocyanins lowers the risk of cardiovascular disease (CVD), the most common cause of mortality among men and women. Anthocyanins frequently interact with other phytochemicals, exhibiting synergistic biological effects but making contributions from individual components difficult to decipher. Over the past 2 decades, many peer-reviewed publications have demonstrated that in addition to their noted in vitro antioxidant activity, anthocyanins may regulate different signaling pathways involved in the development of CVD. This review summarizes the latest developments on the bioavailability/bioactivity and CVD preventative activities of anthocyanins, including results from in vitro cell culture and in vivo animal model systems as related to their multiple proposed mechanisms of action. Limited yet promising data from epidemiological studies and human clinical trials are also presented. Future studies aimed at enhancing the absorption of anthocyanins and characterizing their metabolic and/or breakdown products are necessary to ultimately evaluate their use for protection/prevention against the development of CVD.
REVIEW
Anthocyanins in Cardiovascular Disease
1
Taylor C. Wallace*
Developing Solutions, LLC, Washington, DC 20008
ABSTRACT
Anthocyanins are a group of abundant and widely consumed avonoid constituents that occur ubiquitously in the plant kingdom, providing the
bright red-orange to blue-violet colors present in many fruit- and vegetable-based food products. Their intake has been estimated to be up to 9-
fold higher than that of other dietary avonoids. Anthocyanins have become increasingly important to the food industry as their use as natural
alternatives to articial colors has become widespread and knowledge of their health-promoting properties has become more evident.
Epidemiological studies suggest that increased consumption of anthocyanins lowers the risk of cardiovascular disease (CVD), the most common
cause of mortality among men and women. Anthocyanins frequently interact with other phytochemicals, exhibiting synergistic biological effects
but making contributions from individual components difcult to decipher. Over the past 2 decades, many peer-reviewed publications have
demonstrated that in addition to their noted in vitro antioxidant activity, anthocyanins may regulate different signaling pathways involved in the
development of CVD. This review summarizes the latest developments on the bioavailability/bioactivity and CVD preventative activities of
anthocyanins, including results from in vitro cell culture and in vivo animal model systems as related to their multiple proposed mechanisms of
action. Limited yet promising data from epidemiological studies and human clinical trials are also presented. Future studies aimed at enhancing
the absorption of anthocyanins and characterizing their metabolic and/or breakdown products are necessary to ultimately evaluate their use for
protection/prevention against the development of CVD. Adv. Nutr. 2: 17, 2011.
Introduction
In 2004, an estimated 17.1 million people died from cardiovascular
disease (CVD),
2
mainly from heart disease (7.2 million) and stroke
(5.7 million). This number is expected to increase to 23.6 million
people in 2030 (1). According to the WHO, CVD is caused by dis-
orders of the heart and blood vessels and includes coronary heart
disease (CHD), cerebrovascular disease, peripheral artery disease,
rheumatic heart disease, congenital heart disease, deep vein throm-
bosis, and pulmonary embolism. Atherosclerosis is a chronic in-
flammatory disease caused by plaque rupture or erosion, which
leads to acute formation of platelet-rich thrombi that occlude or
partially occlude the arterial lumen and causes CVD clinical events
such as myocardial infarction, unstable angina, or cerebrovascular
accident (2). Behavioral risk factors such as smoking, lack of phys-
ical inactivity, and an unhealthy diet account for ~80% of CVD (1).
Behavioral risk factors may promptly lead to intermediate risk fac-
tors of developing CVD, including obesity, as well as elevated blood
pressure, glucose, and lipid levels (1).
Consumption of fruits and vegetables has been inversely associ-
ated with a decreased risk of CVD (3), most likely due to the abun-
dance and variety of bioactive compounds present. As an
alternative to pharmaceutical medications, consumption of diets
rich in natural bioactive components and their contribution to
maintaining or improving cardiovascular health has been a subject
of considerable interest to researchers. Dietary avonoids, a large,
w6000-member group of polyphenols, have emerged as potential
candidates to protect against CVD, because epidemiological studies
associate regular consumption of flavonoid-rich foods and bever-
ages with a decreased risk of CVD mor tality. Many published co-
hort studies suggest that high intakes of flavonoids may be
associated with a decreased risk of CVD; however, others find little
to no sig nificant association (4). An analysis of 16 cohort studies
revealed that as mean flavonoid intake increased, age-adjusted
CHD mortality decreased significantly (5). Recently, a 16-y fol-
low-up study of 34,489 CVD-free postmenopausal women in the
Iowa Womens Health Study showed that dietary intakes of certain
classes of flavonoids, including flavanones and anthocyanidins and
certain foods rich in flavonoids, were associated with a reduced risk
of death due to CVD and CHD (6).
Anthocyanins are glycosylated polyhydroxy and polymethoxy
derivatives of avilium salts and are members of the avonoid fam-
ily, possessing a characteristic C
3
C
6
C
3
carbon structure. Plants
typically produce anthocyanins as a protective mechanism against
environmental stress factors, including UV light, cold tempera-
tures, and drought (7). The chromophore of 8 conjugated double
bonds carrying a positive charge on the heterocyclic oxygen ring
is responsible for the intense red-orange to blue-violet color pro-
duced by anthocyanins under acidic conditions. Anthocyanins
1
Author disclosure: T. C. Wallace, no conflicts of interest.
* To whom correspondence should be addressed. E-mail: taylor.wallace@me.com.
2
Abbreviations used: CHD, coronary heart disease; CVD, cardiovascular disease; eNOS,
endothelial nitric oxide synthase; GI, gastrointestinal; MCP-1, monocyte chemotactic protein
1; MMP, matrix metalloproteinase; NOS, NO synthase.
ã2011 American Society for Nutrition. Adv. Nutr. 2: 1–7, 2011; doi:10.3945/an.110.000042.
1
show a l
max
between 465 and 550 nm, as well as significant absorp-
tion in the UV range between 270 and 280 nm (8). Over 635 antho-
cyanins have been identified (9). Six anthocyanidins, cyanidin,
delphinidin, malvidin, pelargonidin, peonidin, and petunidin, oc-
cur ubiquitously in nature, accounting for over 90% of the antho-
cyanins cur rently identified (9). Anthocyanidins are rarely found in
nature because of their poor stability, whereas glycosylated forms
predominate with and/or without additional aromatic and/or ali-
phatic acid conjugation(s). Anthocyanin-rich extracts are increas-
ingly attractive to the food industry as natural alternatives to
synthetic FD&C dyes and lakes.
Daily intake of polyphenols has been estimated to be ~1000 mg/d,
which is signicant when compared with the estimated daily con-
sumption of other phytonutr ients such as carotenoids, vitamin E,
and vitamin C (estimated at 5, 12, and 90 mg/d, respectively)
(10). The daily estimated intake of anthocyanins is high (estimated
at 180 and 215 mg/d) compared with the intake of other dietary a-
vonoids such as genistein and quercetin (estimated at 2025 mg/d)
(11). Anthocyanins are among the few plant polyphenols that can
be detected in the plasma in their native intact forms (glycosides).
Until very recently, anthocyanins were thought to have a very low
bioavailability, with <1% of the ingested amount reaching the
plasma; however, some studies reveal that the bioavailability of
these compounds may be underestimated, because the metabolites
and breakdown products of anthocyanins have not yet been iden-
tified (12).
In this review, recent studies on the CVD preventative activities
of anthocyanins, including results from in vitro cell culture and in
vivo animal model systems as well as data from human epidemio-
logical studies, are presented. Current knowledge of the bioavaila-
bility of anthocyanins as well as their breakdown products and
metabolites is also presented. Many in vitro laboratory studies pro-
vide insight on the multiple mechanisms by which anthocyanins
may help maintain a healthy vascular system. The abundance of
in vivo animal and human studies is low ; furthermore, the rele-
vance of the high concentrations of anthocyanins used in many
in vitro studies as related to the in vivo situation needs to be
conrmed.
Current status of knowledge
Bioavailability
The biological activities of anthocyanins are closely linked to their
absorption and metabolism. A recent study reiterates that anthocy-
anins are rapidly absorbed in the stomach and intestine of rats (13).
An intense red color was present in the acidic extract of all gastric
and small intestinal tissue samples, indicating uptake of anthocya-
nins into the gastrointestinal (GI) tissues. Anthocyanins in the tis-
sues of the rat stomach were identied by their spectral changes at
pH 1.0, 4.5, and 10.0 but could not be quantied by HPLC, because
they seem to have bound to an unidentied protein. This may be
attributed to nonspecic binding or specic binding to a trans-
porter protein (14). Uptake of black raspberry anthocyanins
reached 7.5% of the administered dose in the small intestinal tissue,
which is much higher than the reported bioavailability of these
compounds based on plasma and urine concentrations (13). This
suggests that intact anthocyanins may be taken up into the GI tract
tissues efciently but not transported into the circulation. Trans-
port across the apical membrane using an in vitro epithelial
Caco-2 cell model occurred to a much larger extent than further
translocation of intact black currant anthocyanins across the baso-
lateral membrane (15). Glycosylation and acylation patterns de-
crease the bioavailability of an anthocyanin; however, glycosidases
present in the GI tract may hydrolyze anthocyanins into
anthocyanidins, thereby increasing their biological potential but
decreasing their stability. The presence of a g lucose moiety com-
pared with a galactose or arabinose on the cyanidin and peonidin
anthocyanidins present in cranberry juice seems to make them
more bioavailable as a percentage of the delivered dose (16).
Anthocyanins exist in the circulation and urine as intact, meth-
ylated, glucuronide derivatives and/or sulfoconjugated forms (17
19), reaching peak plasma concentrations between 1 and 3 h after
consumption and depending on the individual compound and the
food matrix. The metabolites persist in the ur ine for up to 24 h and
may retain their basic anthocyanin structure (19,20). Pharmacoki-
netic evidence implies that parent glycosides and glucuronide de-
rivatives are prominent in the bloodstream between 0 and 5 h
but become increasingly methylated over time (624 h), which sug-
gests that the bioactivity of anthocyanins are likely altered over time
as a result of metabolic transformation (21).
Several in vivo studies suggest that the food matrix has a signif-
icant effect on the absorption and metabolism of anthocyanins.
Ohnishi et al. (22) recovered 5% of administered cranberry juice
anthocyanins in the urine of humans (22), whereas other re-
searchers recovered between 1.8 and 2% of strawberry anthocya-
nins (18,23). A recent study of 15 patients w ith coronary artery
disease showed that the total urinary recovery of administered
cranberry juice anthocyanins was variable (between 0.078 and
3.2%) among the participants, which is consistent with other berry
anthocyanin bioavailability studies (16). The degree of individual
variation in anthocyanin bioavailability may result from differences
in xenobiotic metabolism in the GI tract, liver, and other tissues.
Human polymorphisms have been reported in the genes for cate-
chol-O-methyltransferase, glutathione S-transferases, and UDP
glucuronosyl transferase (24). The variation of human gut micro-
flora may also play a prominent role in the bioavailability of antho-
cyanins. Microbiota present in the GI tract may metabolize
anthocyanins, producing smaller, more bioavailable end-products.
The predominance of the colorless carbinol (7580%) and chal-
cone (1520%) forms of anthocyanins present in the blood and
urine at neutral pH levels may give rise to rapid degradation of
the compounds into smaller phenolic derivatives. As seen in the
stomach, intact anthocyanins, their metabolic forms, and decretory
products may escape analytical detection by chemically binding to
other components such as proteins present in the bloodstream.
Shortcomings such as this can be overcome by using labeled antho-
cyanins in animal and human studies for identification of all me-
tabolites generated.
Gut microora have the ability to metabolize anthocyanins;
however, the literature in this area is limited. Using a bacterial prep-
aration imitating the normal human microbiota population, it is
possible to demonstrate the conversion of larger polyphenols to
phenolic acids, which demonstrate similar antiin ammatory effects
as the parent compounds (25). Microbial deglycosylation and deg-
radation of 6 anthocyanins were investigated in vitro using HPLC-
DAD and GC-MS (26). Anthocyanin glycosides in this study were
hydrolyzed into anthocyanidins (aglycons) by the microbiota
within 20 min to 2 h of incubation depending on the sugar moiety
present (26). Because liberated anthocyanidins are very unstable in
a neutral pH environment, degradation of the pigments was expe-
rienced within 20 min of incubation. Cy-3-rut was first hydrolyzed
into cy-3-glu and then into the cyanidin aglycon, which rapidly de-
graded into protocatechuic acid (3,4-dihydroxybenzoic acid) as a
product of human colonic microflora (26). Porcine gut microflora
metabolized anthocyanins in vitro into products such as syringic
acid (3,5-dimethoxy-4-hydroxybenzoic acid), vanillic acid (3-
methoxy-4hydroxybenzoic acid), phloroglucinol aldehyde (2,4,6-
2 Wallace
trihydr o xyben zoic acid), phloroglucinol acid (2,4,6-trihydr o xyb enzoic
acid), and gallic acid (3,4,5-trihydroxybenzoic acid), depending on
the individual anthocyanin (26). Smaller phenolic acids and other
anthocyanin metabolites have greater chemical and microbial sta-
bility, suggesting that they may play an important role in the noted
physiological effects and increase in antioxidant activity observed in
many studies (26). It should also be noted that degradation-meth-
ylated anthocyanins by the gut microbiota may yield de-methylated
products.
Epidemiological data
Epidemiological studies have examined the relationship between
foods rich in anthocyanins (such as red wine and several species
of berries) and CVD as well as the relationship between total antho-
cyanin intake and risk of developing CVD. Postmenopausal women
(n = 34,489) participating in the Iowa Womens Health Study
showed a significant reduction in CVD mortalit y associated with
strawberry intake during a 16-y follow-up period (6). Blueberries
also showed a significant decrease in CHD mortality using an
age- and energy-adjusted model. A significant reduction in RR
was associated with the consumption of strawberries and blue-
berries at least once per week. This cohort study reported that a
mean intake of 0.2 mg/d of anthocyanins was associated with re-
duced risk of CVD in postmenopausal women (6). Female health
professionals enrolled in the Womens Health Study (n = 38,176)
showed a borderline significant risk reduction of C-reactive protein
(CRP) levels among women consuming higher amounts of straw-
berries. A decreasing trend for CVD was observed in this study for
participants who consumed higher amounts of strawberries (27).
Several epidemiological studies have shown that CVD mortality
can be decreased by moderate consumption of red wine (28,29).
A meta-analysis of wine consumption in relation to CVD risk sug-
gests a consistent dose-response cardiovascular preventative effect
(30). Numerous human studies suggest that red wine has more fa-
vorable effects on lipid metabolism than white wine (31), possibly
due to its increased phytochemical content. The French Paradox
first drew attention to the CVD protective effects of red wine after
epidemiological data collected by the WHO revealed a discord in
CVD mortality in a cohort of participants from Toulouse, France,
compared with other cohorts from 17 Western countries, including
the United States and United Kingdom (3234). The French cohort
had a lower risk of CVD mortality despite a higher consumption of
saturated fat (32).
Mechanisms
Mechanistic studies support the benecial effects of avonoids, in-
cluding anthocyanins, on the established biomarkers of CVD risk
such as NO, inammation, and endothelial dysfunction (3537).
Inflammation defined by calor (heat), rubor (redness), and tumor
(swelling) plays a major role in the development of CVD. The role
of anthocyanins in CVD prevention is strongly linked to protection
against oxidative stress. Several mechanisms of action have been
proposed to explain the in vivo antiinflammatory actions of flavo-
noids. Anthocyanin isolates and anthocyanin-rich mixtures of fla-
vonoids may provide protection from DNA cleavage, estrogenic
activity (altering the development of hormone-dependent disease
symptoms), enzyme inhibition, increased cytokine production
(thus regulating immune responses), antiinflammatory activity,
lipid peroxidation, decreased capillary permeability and fragility,
and membrane strengthening (3842). The chemical structure (po-
sition, number, and types of substitutions) of an anthocyanin plays
an important role in the biological activity exerted. Dietary antho-
cyanins have been shown to accumulate in the tissues of pigs
during long-term feeding and have a longer residence time in tis-
sues than in the bloodstream (43). Whether anthocyanins accumu-
late in the cardiac or vascular tissues dur ing long-term feeding is
still unknown; however, data from animal studies have
shown that anthocyanins affect vascular reactivity (44). Relatively
low-dose anthocyanin interventions with patients clinically diag-
nosed with vascular diseases have been associated with signifi-
cant reductions in ischemia (45), blood pressure (46), lipid levels
(47), and inflammatory status (48). Commercial grape juice
(10 mL/kg) has been shown to significantly inhibit platelet activity
and experimental coronary thrombosis in vivo (49). Corn-derived
anthocyanins made the myocardium less susceptible to ischemia-
reperfusion injury ex vivo and in vivo compared with the
anthocyanin-free control (50). Clinical studies show little effect
of proinflammatory markers on healthy human par ticipants; how-
ever, a recent study by Karlsen et al. (51) showed significant im-
provement of plasma risk biomarkers after supplementation with
anthocyanins (51).
NO. The endothelium regulates vascular homeostasis by produc-
ing factors that act locally in the vessel wall and lumen, including
NO. NO is a signaling molecule that inuences the development
of atherosclerosis and many aspects of inammation, ranging
from its own production to immunocompetent cells to the recruit-
ment of leukocytes (52). NO is produced from
L-arginine by 3 NO
synthase (NOS) enzymes: endothelial NOS (eNOS), neuronal
NOS, and inducible NOS. NO is a potent vasodilator with antihy-
pertensive, antithrombotic, antiatherogenic, and antismooth mus-
cle proliferative properties (53). The eNOS protein has been shown
to be impaired in conditions associated with atherosclerosis, hyper-
tension, diabetes, and ischemia-reperfusion injury (54). These con-
ditions are also associated with the production of reactive oxygen
species, which can chemically quench NO and/or damage the en-
dothelium and thus impair NO production.
Anthocyanin concentrations in the bloodstream are too low to
directly contribute to in vivo quenching of reactive oxygen species
even though they exhibit superior antioxidant potential to classic
antioxidants such as but ylated hydroxyanisole. They may, how-
ever, be adequate to improve endothelial function by inuencing
NO levels. Chokeberry and bilberry anthocyanin-rich extracts
have the ability to prevent loss of endothelium-dependent, NO-
mediated relaxation in porcine arteries in vitro at a level that
roughly reects that seen in several studies to exist in the human
plasma after consumption of these compounds (55).
In a study by Youdim et al. (56), 4 anthocyanins isolated from
elderberries were incorporated into the plasma, lemma, and cytosol
of endothelial cells in vitro to directly examine their role. The re-
sults from this study indicate that anthocyanins can be directly
incorporated into endothelial cells and produce signicant oxida-
tive stress protection (56). Delphinidin provided endothelium-
dependent vaso-relaxation in the rat aorta comparable to that of
red wine polyphenols (57). A similar nding with black currant
concentrate was reported in rat aorta rings in vitro (58). Upregula-
tion of eNOS in bovine endothelial cells after a 6-h exposure to
0.1 mmol/L cy-3-glu has been reported. In addition, 12-min expo-
sure of bovine endothelial cells to cy-3-glu phosphorylates NOS
and enhances NOS activity (59). Pelargonidin inhibits inducible
NOS and mRNA expression as well as the production of NO in
a dose-dependent manner in macrophages exposed to the inflam-
matory stimulus LPS (60). Other fruit pigment preparations have
been shown to produce endothelium-dependent relaxation of the
arteries; however, these effects have largely been confined to the
pigments of red wine and grapes (57,6164). Protection from heart
Anthocyanins in cardiovascular disease 3
attacks through administration of grape juice and red wine has
been strongly tied to the ability of anthocyanins to reduce inflam-
mation, inhibit platelet formation, and enhance NO release (65).
Mazza et al. (17), using the oxygen radical absorbance capacity
assay, found that the concentration of anthocyanins in the serum
was directly correlated to the serum antioxidant capacity when
adult males were supplemented with 1.2 g of anthocyanins from
freeze-dried blueberries. This change in antioxidant capacity sug-
gests that anthocyanins and their decretory products may play an
important role in decreasing the production of superoxide by
NADPH oxidase in addition to other possible mechanisms. A de-
crease in NADPH oxidase activity can lead to an increase in serum
antioxidant capacity. It has been proposed that eNOS metabolism,
rather than general antioxidant activity, is a major target of flavo-
nols, a similar class of flavonoids, and that NADPH oxidase activity
is a crucial site of action (66). The same theory could hold true for
anthocyanins because of their similarity in chemistry.
Cytokines and chemokines. Cytokines are mediators of local and
intercellular communications required for an integrated response
to a variety of stimuli in immune and inammatory processes. Dif-
ferent cytokines are associated with inammatory disease, with a
clinical outcome partially determined by the balance between
proinammatory and antiinammatory cytokines (67). The analy-
sis of structure-activity relationships among avonoids suggests
that 4 hydroxylations at positions 5, 7, 3
1
, and 4
1
, together with a
bond at the C
2
C
3
and the B-ring attachment at the C
2
position,
seem necessary for the highest proinflammatory cytokine expres-
sion (68). Chemokines are small cytokines that play a significant
role in controlling leukocyte migration. Monocyte chemotactic
protein 1 (MCP-1) is a chemokine secreted by activated macro-
phages and endothelial cells whose production is upregulated in
both acute and chronic inflammatory diseases. MCP-1 is known
to mediate the signaling of macrophages to sites of inflammation
in the body and is directly involved in the development of athero-
genesis. Anthocyanins may protect against TNFainduced MCP-
1 secretion in human endothelial cells (69). Rats administered
4% freeze-dried whole blueberries in a high-fat diet showed a sig-
nificant decrease in the proinflammatory TNFa, MCP-1, and IL-10
molecules. These results were not demonstrated in rats fed a low-
fat diet (24). The level of MCP-1 released by adipocytes is signifi-
cantly greater in obese mice than in nonobese mice and when
adipocytes are co-cultured with macrophages (70). Treatment of
endothelial cells with cy-3-glu and pel-3-glu has been reported to
inhibit the production of cyt okines and matrix metalloproteinases
(MMP), including MMP-1 and MMP-9 (71).
NF-kB and other signal transduction pathways. In several stud-
ies, the suppression of proinammatory chemokines, growth fac-
tors, and adhesion molecules was associated with an inhibition of
NF-kB activation (7274). NF-kB, an oxidative stress-sensitive
transcription factor that controls expression of genes involved in
the inflammatory response, is the most widely studied inflamma-
tory mediator. Several NF-kBrelated proinflammatory chemo-
kines, cytokines, and mediators of inflammatory responses were
shown to decrease in the plasma of healthy adult participants after
supplementation with anthocyanins in parallel-designed, placebo-
controlled, clinical trials, suggesting mediated inhibition of NF-
kB activation by anthocyanins in vivo (51,75,76). Direct inhibition
of LPS-induced NF-kB transactivation by anthocyanins was ob-
served in human monocytes (51). Similarly, red wine has been re-
ported to inhibit NF-kB production of proinflammatory factors in
endothelial cells and inflammatory cells (77,78). In humans,
treatment with lyophilized grape powder for 4 wk was associated
with a reduction in NF-kB (79).
Treatment of human umbilical vein endothelial cells with an-
thocyanins regulated cholesterol distribution by interfering with
the recruitment of TNF receptor-associated factors-2 in lipid rafts,
thereby inhibiting CD40-induced proinammatory signaling (71).
The anthocyanin delphinidin has been shown to decrease the ex-
tent of apoptotic and necrotic cell death in cultured cardiomyocytes
and to reduce infarct size after ischemia in rats. This process is me-
diated by the inhibition of signal transducers and activators of tran-
scription 1 activation (80).
Adhesion molecules. Vascular endothelial cells line the luminal
side of blood vessels and mediate interactions among the blood ves-
sels, blood, and tissue (81). Endothelial cells recruit leukocytes by
selectively expressing adhesion molecules on their surface as a re-
sponse to proinammatory stimuli such as TNFa and LPS. Flavo-
noids, including anthocyanins, seem to modulate this type of
monocyte adhesion during the inflammatory process by decreasing
their expression by endothelial cells.
Anthocyanins suppress the induced secretion of several mole-
cules related to inammatory modulation, specically vascular en-
dothelial growth factor and intracellular adhesion molecule-1 in
cellular models (56,73,82). In a study of 9 major red wine polyphe-
nols, only the anthocyanins delphinidin and cyanidin inhibited the
platelet-derived growth factor AB-induced expression of vascular
endothelial growth factor by preventing activation of redox-sensi-
tive p38 MAPK and c-Jun N-terminal kinase pathways (83). This
study suggested a crucial role of the hydroxyl residue at position
3 of the B-ring, because significant inhibitory effects were not
shared by other anthocyanin compounds such as malvadin and
peonidin, which contain a methoxyl residue at position 3 (83).
Anthocyanins may also protect against adhesion molecule pro-
duction induced by activated platelets. An investigation of optimal
platelet function showed that anthocyanins and their colonic me-
tabolites inhibit thrombin receptor-activating peptideinduced
platelet aggregation but did not influence platelet reactivity when
strong agonists such as collagen and ADP were present (84). An-
tithrombotic properties were exhibited by 10 mmol/L dihydro-
ferulic acid and 3-(3-hydroxyphenyl) propionic acid (colonic
metabolites) as well as 1 mmol/L del-3-rut and a mixture of all
compounds (84).
CRP. Low-grade chronic inammation signaled by increased levels
of CRP has been recognized as an independent risk factor for CVD
(25). CRP is an acute phase reactant whose elevation in the serum is
considered an indicator of chronic inammation and whose inter-
action with endothelial cells may be one mechanistic link to ather-
osclerosis because it induces adhesion molecule expression (85).
Analyses of NHANES data show a signicant inverse association
between serum CRP and anthocyanin intakes among adults in
the United States (86). Data from the USDA avonoid databases
matched with a 24-h dietary recall indicate that anthocyanidin in-
takes were inversely associated with serum CRP concentration (86).
A recent clinical study using anthocyanin-rich sweet cherries
showed a decrease in serum CRP after 4 wk of intervention (76).
Conclusion
Knowledge of anthocyanin metabolism, absorption, and bioa-
vailability as related to CVD has increased tremendously over the
last decade; however, much work remains to achieve denitive con-
clusions about the potential of anthocyanins in CVD protection.
The need for future research in this area is clearly evident. Although
4 Wallace
experimental studies seem to demonstrate the potential of anthocy-
anins to inuence many CVD-related biomarkers, epidemiological
evidence remains promising but insufcient. A large prospective
study of the cardio-protective effects of anthocyanins should be
conducted with comprehensive information about their dietary in-
take. Anthocyanins seem to have a clear effect on endothelial func-
tion and proinammatory markers, even if most of the effects are
reported using in vitro assays. The relevance of many in vitro stud-
ies to the in vivo situation needs to be conrmed, because many in
vitro studies apply high concentrations of anthocyanins that far ex-
ceed the level observed in vivo; however, some studies do achieve
results at comparable levels.
Isotopic labeling of anthocyanins would generate better knowl-
edge about the way these phytonutr ients are metabolized and ab-
sorbed in the gut and/or in which tissues they accumulate
throughout the body. Increased studies involving metabolism of
anthocyanins by the gut microbiota are needed to better under-
stand the bioactivity and bioavailabilit y of these compounds. Inter-
vention studies of participants at risk for CVD or related
pathologies compared with healthy human participants are needed
to properly determine the effect of anthocyanins on CVD-related
biomarkers. Large-scale, long-term, randomized, placebo-con-
trolled human trials are needed to validate the amount of anthocy-
anins required to achieve optimal vascular health.
Acknowledgment
The sole author had responsibility for all parts of the manuscript.
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Anthocyanins in cardiovascular disease 7
... A number of studies including clinical tests, epidemiological data, as well as in vitro and in vivo investigations with animals have found a cause-effect relationship between a diet rich in polyphenols and its favorable impact on health [42,43]. At present, polyphenols are considered potential therapeutic agents possessing antioxidant properties, which can be used in the management of cardiovascular diseases [44][45][46][47]. Due to their treatment efficacy, they have been designated as anti-ageing molecules [48]. ...
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... Considerable interest has been shown in diets enriched with natural bioactive substances and their capacity for preserving or improving cardiovascular health [13,14]. High consumption of vegetables and fruits has been directly connected with a reduced incidence of CVD [15], mostly due to the abundance and variability of bioactive composites within. ...
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... From previous study, supplementation of anthocyanins has demonstrated to modulate the expression of both IL-6 and VCAM-1. Feeding anthocyanin-rich bilberry and strawberry beverages to human participants with elevated risk of CVD reported reduced plasma concentrations of IL-6 and C-reactive protein [61]. The effect of cyanidins 3 glycoside metabolites on OxLDL-induced IL-6 production in in vitro suggests its anti-inflammatory effect [62]. ...
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... The biological activity of isolated anthocyanins and anthocyanidins, or foods rich in anthocyanins, can be manifested in the prevention of cardiovascular disease [42], influence on cholesterol distribution, protection of endothelial cells from CD40-induced proinflammatory signaling [43], anticancer, antitumor, and antimutagenic activity [44], beneficial effects in diabetes [45], protective effects against oxidative liver damage [46], protective effects on gastric inflammation and damage [47], antimicrobial and antiviral activity [48,49], slowing down neuronal and behavioral aging [50], and protection from some neurodegenerative diseases such as Alzheimer's disease [51]. Anthocyanins and anthocyanidins also effectively induce insulin secretion when tested in pancreatic cell lines [11]. ...
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... Several plant foods common in PBDs, notably dark colored fruits and vegetables, tea, coffee, and cocoa, are high in polyphenolic compounds, including flavonoids, phenolic acids, lignans, and stilbenes [1 •]. Within the flavonoid family, anthocyanins found in orange-red and blue-purple colored fruits and vegetables have estimated intakes of almost ninefold higher than other flavonoid-rich foods and have been shown in cell culture and animal studies to improve measures of endothelial cell function and of oxidant-stress [45], providing another mechanism by which PBDs may improve CVD outcomes. A 2017 systematic review and meta-analysis was the first to pool the human evidence examining the effects of anthocyanin-rich foods on vascular health. ...
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Purpose of Review The number of published studies on the health effects of plant-based diets has increased dramatically in the last decade. The purpose of this narrative review is to update the most recent evidence from large prospective cohort studies and meta-analyses on the effects of plant-based dietary patterns on cardiovascular outcomes and risk factors and total mortality. Recent Findings Most new data from large prospective cohort studies carried out in the USA, Europe, and Asia continue to show inverse associations between plant-based diets and the incidence of ischemic heart disease and stroke, while less data exist for heart failure incidence. New analyses suggest that only some components of plant-based diets are associated with cardiovascular benefit. Recent meta-analyses show inverse associations between plant–protein intake and all-cause mortality, although heterogeneity exists, and small mortality risks from some animal proteins, notably processed meats. New studies continue to demonstrate small but favorable effects of plant-based diets on traditional risk factors and suggest other emerging mechanisms by which plant-based diets exert cardiovascular benefits. Summary The recommendation to consume a plant-based diet to reduce cardiovascular risk remains an evidence-based strategy based on observational studies. New data highlight the importance of ensuring that these diets are nutrient-rich and low in plant foods associated with signals of harm. For this reason, assessment of diet quality is important even in patients who report adherence to plant-based diets. Large randomized trials with hard cardiovascular endpoints might strengthen this evidence-base, but feasibility is limited.
... Furthermore, the usage of anthocyanins (ANCs) is supposed to be related to a reduced risk of degenerative diseases, such as cardiovascular diseases [23], cancer [24], atherosclerosis [25], and diabetes [26]. Also, in another research, it was reported that the compounds are responsible for the inhibition of α-amylase and α-glucosidase, included flavonoids, flavonol, phenolic acid, and anthocyanins [27]. ...
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... Mulyawanti et al. (2018) encontraram teores menores, de 114,23 mg 100 g -1 em batata-doce de polpa roxa. Os compostos fenólicos são antioxidantes naturais e têm sido associados à redução do risco de doenças degenerativas (Lim et al., 2013;Charepalli et al., 2015), à proteção contra certas formas de câncer Stoner, 2008) e à redução do risco de doença coronariana (Wallace, 2011). As antocianinas são uma classe importante de flavonoides que representam um grande grupo de metabólitos secundários das plantas. ...
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In most countries, high intake of saturated fat is positively related to high mortality from coronary heart disease (CHD). However, the situation in France is paradoxical in that there is high intake of saturated fat but low mortality from CHD. This paradox may be attributable in part to high wine consumption. Epidemiological studies indicate that consumption of alcohol at the level of intake in France (20-30 g per day) can reduce risk of CHD by at least 40%. Alcohol is believed to protect from CHD by preventing atherosclerosis through the action of high-density-lipoprotein cholesterol, but serum concentrations of this factor are no higher in France than in other countries. Re-examination of previous results suggests that, in the main, moderate alcohol intake does not prevent CHD through an effect on atherosclerosis, but rather through a haemostatic mechanism. Data from Caerphilly, Wales, show that platelet aggregation, which is related to CHD, is inhibited significantly by alcohol at levels of intake associated with reduced risk of CHD. Inhibition of platelet reactivity by wine (alcohol) may be one explanation for protection from CHD in France, since pilot studies have shown that platelet reactivity is lower in France than in Scotland.
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Dr. Sketch: Dr. Loscalzo, a definition of endothelial dysfunction would be useful to all.Dr. Loscalzo: The normal endothelial cell expresses at least four different properties that become abnormal in a dysfunctional endothelial cell. Under normal circumstances, the endothelial cell maintains the basal state of vascular tone, inhibits platelet activation and platelet-dependent thrombosis; it maintains the antithrombotic milieu of the blood vessel. The normal endothelial cell is also resistant to association with leukocytes and last, the normal endothelial cell produces products that prevent the migration and proliferation of the underlying smooth muscle cells.There are many factors that can induce endothelial dysfunction and reverse the generally beneficial effects of endothelial activity. Many of these factors are the well-established risk factors for atherosclerotic disease including hypercholesterolemia, hypertension, diabetes mellitus and exposure to cigarette smoke. When a patient is exposed in sufficient quantities or amounts to such risk factors, the endothelium becomes progressively dysfunctional, is unable to maintain the normal state of vascular tone and is unable to inhibit platelet activation. In addition, the endothelium is unable to minimize the adhesion of leukocytes or the proliferation of smooth muscle cells. As a result of these changes the dysfunctional endothelial cell promotes atherothrombogenesis. Endothelial dysfunction is not or should not be viewed as a risk factor in itself for atherosclerotic disease, but rather as a final pathway in the progress of atherosclerosis through which the well-established risk factors exert their adverse effects.Dr. Sketch: What is the role of nitric oxide in this process?Dr. Loscalzo: Nitric oxide represents an endothelial product that, interestingly, can perform all the beneficial functions mentioned above. Nitric oxide in the normal state maintains the basal state of a vessel's tone. Nitric oxide impairs platelet activation and leukocyte adhesion and it inhibits smooth muscle proliferation. When the endothelium becomes dysfunctional these phenotypic properties of the endothelial cell change. The nitric oxide produced by the dysfunctional endothelial cell is no longer biologically active, largely because it reacts with superoxide and becomes inactivated in the process. In addition, the dysfunctional endothelial cell makes less prostacyclin and begins to make endothelin. The dysfunctional cell enhances the degree of vascular tone that is seen in that blood vessel. Therefore, nitric oxide is critical in the extent to which a normal endothelial cell maintains the basal state of vascular tone and when the endothelium becomes dysfunctional less bioactive nitric oxide is produced.Dr. Sketch: What is the clinical implication of these interactions?Dr. Loscalzo: The clinical implications of endothelial dysfunction and understanding of it is in its infancy. It is known that one can reverse endothelial dysfunction by improving the risk profile of an individual. There are several very good studies showing that cholesterol-lowering therapy improves endothelial function in terms of changes in blood vessel tone that are endothelium dependent. It is also clear that cessation of smoking or treatment of hypertension can effect the same results. Therefore, if one approaches the prevention of clinical atherothrombotic events in a patient in the usual fashion, one mechanism by which the treatment of these risk factors can provide benefit in clinical endpoints is a consequence of improvement in endothelial function. If one examines the regression trials in the context of our current knowledge of endothelial dysfunction one can, in fact, interpret them mechanistically much better than was originally believed. Those trials all showed an improvement in clinical endpoint, which exceeded the extent to which there was anatomic regression of the atheromatous lesions. We would argue that the improvement and outcome in that setting was more likely a consequence of improvements in vascular and endothelial function by reducing the risk factors to which the patients were exposed.Dr. Sketch: Is there anything on the horizon to lead us to think that there will be a direct therapeutic approach that we can offer patients to reverse this process?Dr. Loscalzo: At the current time the best way to improve endothelial dysfunction is to attack each of the specific abnormalities that one measures or is interested in. For example, if one wishes to improve the production of nitric oxide by the endothelium one can either reduce the risk factors and thereby improve nitric oxide production or one can add a nitrovasodilator. Nitrovasodilators may have a benefit per se or serve as a surrogate for endogenous nitric oxide and improvement in endothelial function may result.Dr. Sketch: Does endothelial dysfunction play a role in acute myocardial infarction?Dr. Loscalzo: I believe it does. In a setting of