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Anthocyanins in Cardiovascular Disease Prevention



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.
Anthocyanins in Cardiovascular Disease
Taylor C. Wallace*
Developing Solutions, LLC, Washington, DC 20008
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.
In 2004, an estimated 17.1 million people died from cardiovascular
disease (CVD),
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
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
Author disclosure: T. C. Wallace, no conflicts of interest.
* To whom correspondence should be addressed. E-mail:
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.
show a l
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
Current status of knowledge
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
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).
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
, and 4
, together with a
bond at the C
and the B-ring attachment at the C
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).
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.
The sole author had responsibility for all parts of the manuscript.
Literature Cited
1. WHO [internet]. Cardiovascular diseases (CVDs). Fact sheet no. 317.
2008 [cited 14 July 2010]. Available at:
2. Erdman JW Jr, Balentine D, Arab L, Beecher G, Dwyer JT, Folts J,
Harnley J, Hollman P, Keen CL, et al. Flavonoids and heart health:
proceedings of the ILSI North America Flavon oids Workshop, May
31-June 1, 2005, Washington, DC. J Nutr. 2007;137(3 Suppl 1):
3. Nöthlings U, Schulze M, Weikert C, Boeing H, van der Schouw YT,
Bamia C, Benetou V, Lagiou P, Krogh V, et al. Intake of vegetables, le-
gumes, and fruit, and risk of all-cause cardiovascular, and cancer mor-
tality in a European diabetic population. J Nutr. 2008;138:77581.
4. Mursu J, Voutilainen S, Nurmi T, Tuomainen TP, Kurl S, Salonen JT.
Flavonoid intake and the risk of ischaemic stroke and CVD mortality
in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease
Risk Factor Study. Br J Nutr. 2008;100:8905.
5. Hertog MGL, Kromhour D, Aravanis C, Blackburn H, Buzina R,
Fidanza F, Giapaoli S, Jansen A, Menotti A, et al. Flavonoid intake
and long-term risk of coronary heart disease and cancer in the Seven
Countries Study. Arch Intern Med. 1995;155:3816.
6. Mink PJ, Srafford CG, Barraj LM, Harnack L, Hong CP, Nettleton JA,
Jacobs DR. Flavonoid intake and cardiovascular disease mortality: a
prospective study in postmenopausal women. Am J Clin Nutr. 2007;
7. Chalker-Scott L. Environmental significance of anthocyanins in plant
stress responses. Photochem Photobiol. 1999;70:19.
8. Eder R. Pigments. In: Nollet LML, editor. Food analysis by HPLC.
Monticello (NY): Marcel Dekker; 2000. p. 84580.
9. Andersen OM, Jordheim M. The anthocyanins. In: Andersen OM,
Markham KR, editors. Flavonoids: chemistry, biochemistry, and appli-
cations. New York (NY): CRC Press; 2006. p. 471552.
10. Wallace TC, Wagner M, Leveille G, Keen CL, Woteki CE, Manley C,
Rizk SW, Heber D, Shrikhande AJ. Unlocking the benefits of cocoa fla-
vanols. Food Technol. 2009;63:3441.
11. Hertog MG, Hollman PC, Katan MB, Kromhout D. Intake of poten-
tially anticarcinogenic flavonoids and their determinants in adults in
the Netherlands. Nutr Cancer. 1993;20:219.
12. Manach C, Williamson G, Morand C, Scalbert A, Rémséy C. Bioavail-
ability and bioefficacy of polyphenols in humans. I. Review of 97 bio-
availability studies. Am J Clin Nutr. 2005;81:S23042.
13. He J, Wallace TC, Keatley KE, Failla ML, Giusti MM. Stability of black
raspberry anthocyanins in the digestive tract lumen and transport effi-
ciency into gastric and small intestinal tissues in the rat. J Agric Food
Chem. 2009;57:31418.
14. Passamonti S, Vrhovsek U, Mattivi F. The interaction of anthocyanins
with bilitranslocase. Biochem Biophys Res Commun. 2002;296:6316.
15. Steinert RE, Ditscheid B, Netzel M, Jahreis G. Absorption of black cur-
rant anthocyanins by monolayers of human intestinal epithelial Caco-2
cells mounted in ussing type chambers. J Agric Food Chem. 2008;56:
16. Milbury PE, Vita JA, Blumberg JB. Anthocyanins are bioavailable in
humans following an acute dose of cranberry juice. J Nutr. 2010;140:
17. Mazza G, Kay CD, Cottrell T, Holub BJ. Absorption of anthocyanins
from blueberries and serum antioxidant status in human subjects.
J Agric Food Chem. 2002;50:77317.
18. Felgines C, Talavera S, Gonthier MP, Texier O, Scalbert A, Lamaison JL,
Remesy C. Strawberry anthocyanins are recovered in urine as glucuro-
and sulfoconjugates in humans. J Nutr. 2003;133:1296301.
19. Kay CD, Mazza G, Holub BJ. Anthocyanins exist in the circulation pri-
marily as metabolites in adult men. J Nutr. 2005;135:25828.
20. Kay CD, Mazza G, Holub BJ, Wang J. Anthocyanin metabolites in hu-
man urine and serum. Brit. J Nutr. 2004;91:92333.
21. Mazza G, Kay CD. Bioactivity, absorption, and metabolism of anthocy-
anins. In: Daayf F, Lattanzio V, editors. Recent advances in polyphenols
research. Hoboken (NJ): Blackwell Publishing; 2008. p. 22862.
22. Ohnishi R, Ito H, Kasajima N, Kaneda M, Kariyama R, Kumon H,
Hatano T, Yoshida T. Urinary excretion of anthocyanins in humans
after cranberry juice ingestion. Biosci Biotechnol Biochem. 2006;70:
23. Carkeet C, Clevidence BA, Novotny JA. Anthocyanin excretion by hu-
mans increases linearly with increasing strawberry dose. J Nutr. 2008;
24. Lampe JW, Chang JL. Interindividual differences in phytochemical me-
tabolism and disposition. Semin Cancer Biol. 2007;17:34753.
25. Williamson G, Seis H, Heber D, Keen CL, Macdonald IA, Actis-Gorreta
L, Momma TY, Ottaviani JI, Holt RR, et al. Functional foods for health
promotion: state-of-the-science on dietary flavonoids. Nutr Rev. 2009;
26. Keppler K, Humpf H-U. Metabolism of anthocyanins and their pheno-
lic degradation products by the intestinal microflora. Bioorg Med
Chem. 2005;13:5195205.
27. Sesso HD, Gaziano JM, Jenkins DJ, Buring JE. Strawberry intake, lipids,
C-reactive protein, and the risk of cardiovascular disease in women.
J Am Coll Nutr. 2007;26:30310.
28. Rimm EB, Giovannucci EL, Willett WC, Colditz GA, Ascherio A, Ros-
ner B, Stampfer MJ. Prospective study of alcohol consumption and risk
of coronary disease in men. Lancet. 1991;338:4648.
29. Klatsky AL. Could abstinence from alcohol be hazardous to your
health? Int J Epidemiol. 2001;30:73942.
30. Di Castelnuovo A, Rotondo S, Iacoviello L, Donati MB, DeGaetano G.
Meta analysis of wine and beer consumption in relation to vascular
risk. Circulation. 2002;105:283644.
31. van Velden DP, Mansvelt EP, Troup GJ. Red wines good, white wines
bad? Redox Rep. 2002;7:3156.
32. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French par-
adox for coronary heart disease. Lancet. 1992;339:15236.
33. Keil U, Kuulasmaa K. WHO MONICA Project: risk factors. Int J Epi-
demiol. 1989;18:S4655.
34. Colling M, Weggemann S, Doring A, Keil U, Wolfram G. [Nutrition
survey of adults using a 7-day protocol- a pilot study in the Augsburg
MONICA project]. Offentl Gesundheitswes. 1989;51:947.
35. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft
KD. Pure dietary flavonoids quercetin and (-)-epicatechin augment ni-
tric oxide products and reduce endothelin-1 acutely in healthy men1.
Am J Clin Nutr. 2008;88:101825.
Anthocyanins in cardiovascular disease 5
36. Steffen Y, Gruber C, Schewe T, Sies H. Mono-o-methylated flavanols
and other flavonoids as inhibitors of endothelial NADPH oxidase.
Arch Biochem Biophys. 2008;469:20919.
37. Pergola C, Rossi A, Dugo P, Cuzzocrea S, Sautebin L. Inhibition of ni-
tric oxide biosynthesis by anthocyanin fraction of blackberry extract.
Nitric Oxide. 2006;15:309.
38. Acquav iva R, Russo A, Galvano F, Galvano G, Barcellona ML, Li Volti
G, Vane lla A. Cyanidin an d cyanidin 3-O-beta-D-glucoside as DNA
cleavage protectors and antioxidants. Cell Biol Toxicol. 2003;19:
39. Lazzé MC, Pizzala R, Savio M, Stivala LA, Prosperi E, Bianchi L. Antho-
cyanins protect against DNA damage induced by tert-butyl-hydroper-
oxide in rat smooth muscle and hepatoma cells. Mutat Res. 2003;
40. Lefevre M, Howard L, Most M, Ju Z, Delany J. Microarray analysis of
the effects of grape anthocyanins on hepatic gene expression in mice.
FASEB J. 2004;18:A851.
41. Ramirez-Tortosa C, Andersen ØM, Gardner PT, Morrice PC, Wood SG,
Duthie SJ, Collins AR, Duthie GG. Anthocyanin-rich extract decreases
indices of lipid peroxidation and DNA damage in vitamin E-depleted
rats. Free Radic Biol Med. 2001;31:10337.
42. Rossi A, Serraino I, Dugo P, Di Paola R, Mondello L, Genovese T,
Morabito D, Dugo G, Sautebin L, et al. Protective effects of anthocya-
nins from blackberry in a rat model of acute lung inflammation. Free
Radic Res. 2003;37:891900.
43. Kalt W, Blumberg JB, McDonald JE, Vinqvist-Tymchuk MR, Fillmore
SA, Graf BA, OLeary JM, Milbury PE. Identification of anthocyanins
in the liver, eye, and brain of blueberry-fed pigs. J Agric Food Chem.
44. Kalea AZ, Clark K, Schuschke DA, Klimis-Zacas DJ. Vascular reactivity
is affected by dietary consumption of wild blueberries in the Sprague-
Dawley rat. J Med Food. 2009;12:218.
45. Sumner MD, Elliott-Eller M, Weidner G, Daubenmier JJ, Chew MH,
Marlin R, Raisin CJ, Ornish D. Effects of pomegranate juice consump-
tion on myocardial perfusion in patients with coronary heart disease.
Am J Cardiol. 2005;96:8104.
46. Aviram M, Rosenblat M, Gaitini D, Nitecki S, Hoffman A, Dornfeld L,
Volkova N, Presser D, Attias J, et al. Pomegranate juice consumption for
3 years by patients with carotid artery stenosis reduces common carotid
intima-media thickness, blood pressure and LDL oxidation. Clin Nutr.
47. Gorinstein S, Caspi A, Libman I, Lerner HT, Huang D, Leontowicz H,
Leontowicz M, Tashma Z, Katrich E, et al. Red grapefruit positively in-
fluences serum triglyceride level in patients suffering from coronary
atherosclerosis: studies in vitro and in humans. J Agric Food Chem.
48. Naruszewicz M, Laniewska I, Millo B, D1uzniewski M. Combination
therapy of statin with flavonoids rich extract from chokeberry fruits en-
hanced reduction in cardiovascular risk markers in patients after myo-
cardial infarction (MI). Atherosclerosis. 2007;194:e17984.
49. Demrow HS, Sllane PR, Folts JD. Administration of wine and grape
juice inhibits in vivo platelet activity and thrombosis in stenosed canine
coronary arteries. Circulation. 1995;91:11828.
50. Toufektsian MC, de Lorgeril M, Nagy N, Salen P, Donati MB, Giordano
L, Mock HP, Peterek S, Matros A, et al. Chronic dietary intake of plant-
derived anthocyanins protects the rat heart against ischemia-reperfu-
sion injury. J Nutr. 2008;138:74752.
51. Karlsen A, Retterstol L, Laake P, Paur I, Kjolsrud-Bohn S, Sandvik L,
Blomhoff R. Anthocyanins inhibit nuclear factor-kB activation in mon-
ocytes and reduce plasma concentrations of pro-inflammatory media-
tors in healthy adults. J Nutr. 2007;137:19514.
52. Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001;
53. Vallence P. Vascular nitric oxide in health and disease. In: Ignarro L, ed-
itor. Nitric oxide biology and pathobiology. San Diego (CA): Academic;
2000. p. 92130.
54. Dillon GA, Vito JA. Nitric oxide and endothelial dysfunction. In:
Loscalzo J, Vito JA. Nitric oxide and the cardiovascular system. Totawa
(NJ): Humana; 2000. p. 20725.
55. Bell DR, Gochenaur K. Direct vasoactive and vasoprotective properties
of anthocyanin-rich extracts. J Appl Physiol. 2006;100:116470.
56. Youdim KA, McDonald J, Kalt W, Joseph JA. Potential role of dietary
flavonoids in reducing microvascular endothelium vulnerability to ox-
idative and inflammatory insults (small star, filled). J Nutr Biochem.
57. Andriambeloson E, Magnier C, Haan-Archipoff G, Lobstein A, Anton
R, Beretz A, Stoclet JC, Andriantsitohaina R. Natural dietary polyphe-
nolic compounds cause endothelium-dependent vasorelaxation in rat
thoracic aorta. J Nutr. 1998;128:232433.
58. Nakamura Y, Matsumoto H, Todoki K. Endothelium-dependent vaso-
relaxation induced by black currant concentrate in rat thoracic aorta.
Jpn J Pharmacol. 2002;89:2935.
59. Xu JW, Ikeda K, Yamori Y. Upregulation of endothelial nitric oxide syn-
thase by cyanidin-3-glucoside, a typical anthocyanin pigment. Hyper-
tension. 2004;44:21722.
60. Hamalainen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E.
Anti-inflammatory effects of flavonoids: genistein, kaempferol, querce-
tin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas
flavones, isorhamnetin naringenin, and pelargonidin inhibit only NF-
kappaB activation along with their inhibitory effect on iNOS expression
and NO production in activated macrophages. Mediators Inflamm.
61. DellAgli M, Busciala A, Bosisio E. Vascular effects of wine polyphenols.
Cardiovasc Res. 2004;63:593602.
62. Mendes A, Desgranges C, Cheze C, Vercauteren J, Freslon JL. Vasore-
laxant effects of grape polyphenols in rat isolated aorta. Possible in-
volvement of a purinergic pathway. Fundam Clin Pharmacol. 2003;
63. Ndiaye M, Chataigneau T, Andriansitohaina R, Stocelt JC, Schini-Kerth
VB. Red wine polyphenols cause endothelium-dependent EDHF-medi-
ated relaxations in porcine coronary arteries via a redox-sensitive
mechanism. Biochem Biophys Res Commun. 2003;310:3717.
64. Stein JH, Keevil JG, Weibe DA, Aeschlimann S, Folts JD. Purple grape
juice improves endothelial function and reduces susceptibility of LDL
cholesterol to oxidation in patients with coronary artery disease. Circu-
lation. 1999;100:10505.
65. Schewe T, Steffen Y, Sies H. How do dietary flavanols improve vascular
function? A position paper. Arch Biochem Biophys. 2008;476:1026.
66. Choi JS, Choi YJ, Shin SY, Li J, Kang SW, Bae JY, Kim DS, Ji GE, Kang
JS, et al. Dietary flavonoids differentially reduce oxidized LDL-induced
apoptosis in human endothelial cells: role of MAPK- and JAK/STAT-
signaling. J Nutr. 2008;138:98390.
67. Comalada M, Ballester I, Bailon E, Sierra S, Xaus J, Galvez J, de Medina
FS, Zarzuelo A. Inhibition of pro-inflammatory markers in primary
bone marrow-derived mouse macrophages by naturally occurring fla-
vonoids: analysis of the structure-activity relationship. Biochem Phar-
macol. 2006;72:101021.
68. Garcia-Alonso M, Minihane AM, Rimbach G, Rivas-Gonzalo JC, de
Pascual-Teresa S. Red wine anthocyanins are rapidly absorbed in hu-
mans and affect monocyte chemoattractant protein 1 levels and antiox-
idant capacity of plasma. J Nutr Biochem. 2009;20:5219.
69. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes
and macrophages aggravates inflammatory changes: role of free fatty
acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc
Biol. 2005;25:20628.
70. Xia M, Ling W, Zhu H, Wang Q, Ma J, Hou M, Tang Z, Li L, Ye Q. An-
thocyanin prevents CD40-activated proinflammatory signaling in en-
dothelial cells by regulating cholesterol distribution. Arterioscler
Thromb Vasc Biol. 2007;27:51924.
71. Atalay M, Gordillo G, Roy S, Rovin B, Bagchi D, Bagchi M, Sen CK.
Anti-angiogenic property of edible berry in a model of hemangioma.
FEBS Lett. 2003;544:2527.
72. Bagchi D, Sen CK, Bagchi M, Atalay M. Anti-angiogenic, antioxidant,
and anti-carcinogenic proper ties of a novel anthocyanin-rich berry ex-
tract formula. Biochemistry (Mosc). 2004;69:75
73. Cimino F, Ambra R, Canali R, Saija A, Virgili F. Effect of cyanidin-3-O-
glucoside on UVB-induced response in human keratinocytes. J Agric
Food Chem. 2006;54:40417.
6 Wallace
74. Hollands W, Brett GM, Dainty JR, Teucher B, Kroon PA. Urinary excre-
tion of strawberry anthocyanins is dose dependent for physiological
oral doses of fresh fruit. Mol Nutr Food Res. 2008;52:1097105.
75. Kelley DS, Rasooly R, Jacob RA, Kader AA, Mackey BE. Consumption
of Bing sweet cherries lowers circulating concentrations of inflamma-
tion markers in healthy men and women. J Nutr. 2006;136:9816.
76. Carluccio MA, Siculella L, Ancora MA, Massaro M, Scoditti E, Storelli
C, Visioli F, Distante A, De Caterina R. Olive oil and red wine antiox-
idant polyphenols inhibit endothelial activation: antiatherogenic prop-
erties of Mediterranean diet phytochemicals. Arterioscler Thromb Vasc
Biol. 2003;23:6229.
77. Blanco-Colio LM, Valderrama M, Alvarez-Sala LA, Bustos C, Ortego
M, Hernandez-Presa MA, Cancelas P, Gomez-Gerique J, Millan J.
Red wine intake prevents nuclear factor-kappa beta activation in pe-
ripheral blood mononuclear cells of healthy volunteers during post-
prandial lipemia. Circulation. 2000;102:10206.
78. Zern TL, West KL, Fernandes ML. Grape polyphenols decrease plasma
triglycerides and cholesterol accumulation in the aorta of ovariecto-
mized guinea pigs. J Nutr. 2003;133:226872.
79. Scarabelli TM, Mariotto S, Abdel-Azeim S, Shoji K, Darra E, Stephanou
A, Chen-Scarabelli C, Marechal JD, Knight R, et al. Targeting STAT1 by
myricetin and delphinidin provides efficient protection of the heart from
ischemia/reperfusion-induced injury. FEBS Lett. 2009;583:53141.
80. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver
RP, Pober JS, Wick TM, Konkle BA, et al. Endothelial cells in physiol-
ogy and in the pathophysiology of vascular disorders. Blood. 1998;91:
81. Roy S, Khanna S, Alessio HM, Vider J, Bagchi D, Bagchi M, Sen CK.
Anti-angiogenic property of edible berries. Free Radic Res. 2002;36:
82. Oak MH, Bedoui JE, Maderia SVF, Chalupsky K, Schini-Kerth VB. Del-
phinidin and cyanidin inhibit PDGF
-induced VEGF release in vascu-
lar smooth muscle cells by preventing activation of p38 MAPK and
JNK. Br J Pharmacol. 2006;149:28390.
83. Rechner AR, Kroner C. Anthocyanins and colonic metabolites of die-
tary polyphenols inhibit platelet function. Thromb Res. 2005;116:
84. Liang YJ, Shyu KG, Wang BW, Lai LP. C-reactive protein activates the
nuclear factor-kB pathway and induces vascular cell adhesion mole-
cule-1 expression through CD32 in human umbilical vein endothelial
cells and aortic endothelial cells. J Mol Cell Cardiol. 2006;40:41220.
85. USDA. Economic Research Service: Agriculture Information Bulletin
792.7. Washington (DC): USDA; 2004.
86. Chun OK, Chung SJ, Claycombe KJ, Song WO. Serum C-reactive pro-
tein concentrations are inversely associated with dietary flavonoid in-
take in U.S. adults. J Nutr. 2008;138:75360.
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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The aim of the study is to evaluate the effect of Aronia melanocarpa fruit juice (AMJ) supplementation on age-related coronary arteries remodeled in aged rat hearts. Male Wistar rats (n = 24) were divided into three groups: (1) young controls (CY), aged 2 months, without AMJ supplementation; (2) old controls (CO), aged 27 months, without AMJ supplementation; and (3) the AMJ group (A), which used 27-month old animals, supplemented orally with AMJ for 105 days. AMJ supplementation did not influence the wall-to-diameter parameter (Kernohan index) of the coronary arteries of test animals. Aged rats supplemented with AMJ showed a significant decrease in the amount of collagen fibers in their coronary tunica media, as compared with the old controls. The intensity of the immunoreaction for alpha smooth muscle actin (αSMA) in the coronary tunica media was significantly lower in the supplemented group than in the old controls. The intensity of the angiotensin-converting enzyme 2 (ACE2) immunoreaction in the coronary tunica media of the supplemented group was significantly higher than the one observed in the old controls. These results indicate the positive effects of AMJ supplementation on the age-dependent remodeling of coronary arteries and support for the preventive potential of antioxidant-rich functional food supplementation in age-related diseases.
... Black rice is considered as a panacea for health and longevity in China [10]. Red rice can delay aging and protect against noncommunicable diseases [13], including cancer, cardiovascular disease, diabetes, and metabolic syndrome [14]. Therefore, it is beneficial to analyze the composition of the seed metabolome of landrace varieties and discover the genes that determine their nutritional quality, improving the overall nutritional value of rice. ...
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Rice (Oryza sativa L.) is one of the most globally important crops, nutritionally and economically. Therefore, analyzing the genetic basis of its nutritional quality is a paramount prerequisite for cultivating new varieties with increased nutritional health. To systematically compare the nutritional quality differences between landraces and cultivated rice, and to mine key genes that determine the specific nutritional traits of landraces, a seed metabolome database of 985 nutritional metabolites covering amino acids, flavonoids, anthocyanins, and vitamins by a widely targeted metabolomic approach with 114 rice varieties (35 landraces and 79 cultivars) was established. To further reveal the molecular mechanism of the metabolic differences in landrace and cultivated rice seeds, four cultivars and six landrace seeds were selected for transcriptome and metabolome analysis during germination, respectively. The integrated analysis compared the metabolic profiles and transcriptomes of different types of rice, identifying 358 differentially accumulated metabolites (DAMs) and 1982 differentially expressed genes (DEGs), establishing a metabolite–gene correlation network. A PCA revealed anthocyanins, flavonoids, and lipids as the central differential nutritional metabolites between landraces and cultivated rice. The metabolite–gene correlation network was used to screen out 20 candidate genes postulated to be involved in the structural modification of anthocyanins. Five glycosyltransferases were verified to catalyze the glycosylation of anthocyanins by in vitro enzyme activity experiments. At the same time, the different mechanisms of the anthocyanin synthesis pathway and structural diversity in landrace and cultivated rice were systematically analyzed, providing new insights for the improvement and utilization of the nutritional quality of rice landrace varieties.
... 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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Obesity is a risk factor for cardiovascular diseases, frequently related to oxidative stress and inflammation. Dietary antioxidant compounds improve heart health. Here, we estimate the oxidative grade and inflammation in the heart of dietary-induced obese (DIO) rats after exposure to a high-fat diet compared to a standard diet. The effects of tart cherry seed powder and seed powder plus tart cherries juice were explored. Morphological analysis and protein expressions were performed in the heart. The oxidative status was assessed by the measurement of protein oxidation and 4-hydroxynonenal in samples. Immunochemical and Western blot assays were performed to elucidate the involved inflammatory markers as proinflammatory cytokines and cellular adhesion molecules. In the obese rats, cardiomyocyte hypertrophy was accompanied by an increase in oxidative state proteins and lipid peroxidation. However, the intake of tart cherries significantly changed these parameters. An anti-inflammatory effect was raised from tart cherry consumption, as shown by the downregulation of analyzed endothelial cell adhesion molecules and cytokines compared to controls. Tart cherry intake should be recommended as a dietary supplement to prevent or counteract heart injury in obese conditions.
... 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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C-reactive protein (CRP) is a well-established biochemical marker for atherosclerosis. Modification of LDL inside the artery wall favors the elevation of this acute phase protein. Hence, this mechanism is considered an important factor to trigger the monocyte to macrophages differentiation which results in the formation of foam cells. Therefore, this key event should be targeted and focused on how this complex (OxLDL + CRP) proceeds to endothelial dysfunction. Oligomeric proanthocyanidins (OPC) is a well-known cardioprotective flavon-3-ols. The present study is challenged between the cardioprotective roles of OPC against the deleterious effect of OxLDL + CRP complex upon endothelial cells. Protein–protein docking was carried out between CRP and LOX-1. This docked protein complex was again docked with OPC to show the inhibitory mechanism of CRP binding with LOX-1. OPC showed a promising inhibitory mechanism against OxLDL + CRP complex. Docking studies showed that in the absence of ligands (OPC), binding of CRP and LOX-1 was greater and vice versa in the presence of ligands. Based on these molecular docking results, in vitro studies have been carried out. The monolayer of endothelial cells was incubated with THP-1 monocytes for 48 h, induced with OxLDL (10 μg/ml) + CRP (15 μg/ml) and cotreated with OPC (100 μg/ml). Morphological changes, cell migration assay, and capillary tube forming assay were carried out. Myeloperoxidase levels were estimated to determine the adhesion of monocytes onto EC monolayer. RT-PCR analysis of L-Selectin was also done. The quantification of NO levels and analysis of mRNA expressions of eNOS was to determine the nitric oxide demand caused due to OxLDL + CRP complex. LOX-1, scavenger receptor levels were analyzed by mRNA expression. Proinflammatory markers such as IL-6, MCP-1, and IL-1β were studied. Accumulation of ROS levels was measured fluorimetrically using DCF-DA staining. Mitochondrial membrane potential was determined by JC-1 dye and cell cycle analysis was done by FACS analysis. To emphasis the results, the OPC-treated group showed decreased levels of proinflammatory markers, LOX-1 and L-selectin levels. Endothelial nitric oxide levels were increased upon OPC treatment and reduction in the ROS levels was also observed. Endothelial cells apoptosis was prevented by OPC. To conclude, OxLDL + CRP complex inhibitory effects of OPC could maintain the normal homeostasis.
... 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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Flowers have always accompanied people thanks to their manifold aesthetic properties. Some species have also become a component of the human diet. Recent years have seen an increased interest in edible flowers and, consequently, research has been undertaken to determine their chemical composition. Dyes that are abundantly contained in flowers, whose role is to attract pollinating animals, are recognized substances with health-promoting properties. Anthocyanins are a group of dyes that are very common in petals and other parts of flowers. Studies carried out in the twentieth and twenty-first century on flowers growing in temperate climates have found very strong antioxidant and anti-inflammatory properties of anthocyanins. Therefore, flowers used by humans for centuries to decorate their surroundings may become an easily available source of nutrients and health-promoting substances. This paper discusses the health-promoting properties of anthocyanins and collects literature on anthocyanin content in edible flowers commonly grown on balconies, terraces, and roofs in countries of temperate climate.
... 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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Anthocyanins are components of the flavonoid group with different properties, such as antidiabetic properties. This study aimed to isolate anthocyanin from Berberis integerrima Bunge fruits and evaluate α-amylase and α-glucosidase inhibition by this mentioned anthocyanin. The anthocyanin of Berberis integerrima fruit was isolated using column chromatography, and the antidiabetic properties of the anthocyanin were determined by the levels of α-amylase and α-glucosidase inhibition. Km and Vmax were also evaluated using the GraphPad Prism 7. The results of this study showed that the anthocyanin content of the fruit extract was 14.36 ± 0.33 mg/g, and following purification, this amount increased to 34.51 ± 0.42 mg/g. The highest of α-glucosidase inhibition was observed in the purified anthocyanin with IC50 = 0.71 ± 0.085 mg/ml, compared to acarbose as the baseline with IC50 = 8.8 ± 0.14 mg/ml, p < 0.0001 . Purified anthocyanin of the mentioned fruit with IC50 = 1.14 ± 0.003 mg/ml had the greatest α-amylase inhibition, which was similar to acarbose as the standard with IC50 = 1 ± 0.085 mg/ml, p < 0.05 . The inhibition of α-glucosidase and α-amylase by purified anthocyanin showed uncompetitive inhibition, and the enzyme inhibition by unpurified anthocyanin showed mixed inhibition. The obtained findings showed that Berberis integerrima fruit can be mentioned as a source of anthocyanin with antidiabetic properties.
... 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. ...
Platelet chemokines play well-established roles in the atherosclerotic inflammation. Cyanidin-3-O-β-glucoside (Cy-3-g) is one of the main bioactive compounds in anthocyanins, but its effects on chemokines during atherosclerosis have not been determined yet. In the present study, ApoE-/- mice were fed on the chow diet, high-fat diet (HFD), and HFD-supplemented Cy-3-g at 200, 400, and 800 mg/kg diet. After 16 weeks, Cy-3-g significantly alleviated the atherosclerotic lesion and inhibited platelet aggregation and activation. Moreover, Cy-3-g significantly reduced inflammatory chemokines CXCL4, CXCL7, CCL5, CXCL5, CXCL12, and CCL2 in plasma and downregulated CXCR4, CXCR7, and CCR5 on platelets and peripheral blood mononuclear cells. Besides, Cy-3-g decreased the mRNA of TNFα, IFNγ, ICAM-1, VCAM-1, CD68, MMP7, CCL5, CXCR4, and CCR5 in the aorta of mice. Therefore, it suggests that Cy-3-g plays important preventive roles in the process of atherosclerosis via attenuating chemokines and receptors in ApoE-/- mice.
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Objective The previous evidence shows that there is an association between total dietary polyphenols intake (DPI) and its subclasses and lower risk of metabolic Syndrome (MetS). This cross-sectional study aims to evaluate associations between DPI and cardiometabolic factors in Iranian women. Methods A total of 404 Iranian women were included in this study. Dietary intakes and polyphenols intakes were measured using a validated semi-quantitative food frequency questionnaire (FFQ) and the Phenol-Explorer database, respectively. Biochemical variables and blood pressure were evaluated using Pars Azmoon kits and mercury sphygmomanometer. Results The mean intake of total polyphenol was 2533.96 ± 1223.67 g. While there were significant negative associations between stilbenes and lignans intake and body mass index (BMI) (P-value = 0.04; P-value = 0.02, respectively), beverages containing phenolic acids and hip circumference (HC) (P-value = 0.02), total polyphenols intake and weight to hip ratio (WHR) (P-value = 0.04). Also there was significant negative associations between stilbenes intake and cholesterol (CHOL) level (P-value = 0.03), other polyphenols intake and triglyceride (TG) ((P-value = 0.01), lignan intake and homeostasis model assessment insulin resistance (HOMA-IR) (P-value = 0.03). Conclusion These findings demonstrated that dietary polyphenols were associated with cardiometabolic factors in Iranian women. Prospective and interventional studies in both genders, different populations and ethnicities need to be conducted to further the knowledge about examine associations between consumption of polyphenols and metabolic component.
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Anthocyanins are water-soluble pigments found in all plant tissues throughout the plant kingdom. Our under- standing of anthocyanin biosynthesis and its molecular control has greatly improved in the last decade. The adaptive advantages of anthocyanins, especially in non- reproductive tissues, is much less clear. Anthocyanins of- ten appear transiently at specific developmental stages and may be induced by a number of environmental fac- tors including visible and UVB radiation, cold tempera- tures and water stress. The subsequent production and localization of anthocyanins in root, stem and especially leaf tissues may allow the plant to develop resistance to a number of environmental stresses. This article reviews the environmental induction of anthocyanins and their proposed importance in ameliorating environmental stresses induced by visible and UVB radiation, drought and cold temperatures.
Serum C-reactive protein (CRP) is a biomarker for chronic inflammation and a sensitive risk factor for cardiovascular diseases. Though CRP has been reported to be related to food intake, there is no documentation of a direct association with flavonoid intake, We aimed to test the associations between dietary flavonoid intake and serum CRP concentrations among U.S. adults after adjusting for dietary, sociodemographic, and lifestyle factors. Data from the NHANES 1999-2002 were used for this cross-sectional study. Subjects were >= 19-y-old adults (n = 8335), and did not include pregnant and/or lactating women. Flavonoid intake of U.S. adults was estimated by the USDA flavonoid databases matched with a 24-h dietary recall in NHANES 1999-2002. The serum CRP concentration was higher in women, older adults, blacks, and smokers, and in those with high BMI or low exercise level, and in those taking NSAID, than in their counterparts (P < 0.01). Intakes of apples and vegetables were inversely associated with serum CRP concentrations after adjusting for covariates (P < 0.05). Total flavonoid and also individual flavonol, anthocyanidin, and isoflavone intakes were inversely associated with serum CRP concentration after adjusting for the covariates (P < 0.05). Among the flavonoid compounds investigated, quercetin, kaempferol, malvidin, peonidin, daidzein, and genistein had inverse associations with serum CRP concentration (P < 0.05). These associations did not change even after the additional adjustment for fruit and vegetable consumption. Our findings demonstrate that intake of dietary flavonoids is inversely associated with serum CRP concentrations in U.S. adults. Intake of flavonoid-rich foods may thus reduce inflammation-mediated chronic diseases.
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.
Carotenoids are of widespread occurrence as natural pigments in plants and animals; they contribute the natural yellow, orange, and red colors of many plants as well as being used extensively as nontoxic natural or nature-identical colorants in foodstuffs (1). Their name is derived from -carotene, the main representative of their group, which was first isolated from carrots (Daucus carota) by Wackenroder in 1831 (2). Carotenoids are isoprenoid polyenes which are formed by head-to-tail linkage of C5 isoprene units, except for one tail-to-tail linkage in the center of the molecule, which makes it symmetrical (3). The C40 carotenoids can be divided into carotenes, which are hydrocarbons (e.g., -carotene, Fig. 1a) and their oxygenated derivates, the xanthophylls (e.g., zeaxanthin, Fig. 1b). Fruit xanthophylls are often acylated with fatty acids (4). Besides the C40 carotenoids there are also apocarotenoids, a degraded form with less than 40 carbon atoms in the skeleton, and higher carotenoids where the carbon skeleton contains 45 or 50 carbon atoms, respectively (5). The characteristic absorption spectrum of each carotenoid is determined by the chromophore, a series of conjugated double bounds. Usually the spectrum shows three absorption bands, which are affected by the length of the chromophore, the nature of the double bound and the taking out of conjunction
Understanding cocoa flavanols and their mechanisms for health may drive development of the next generation of functional food products. The bioavailability and bioactivity of flavanols, and their oligomers (procyanidins) differ depending on their chemical composition, isomeric form and chain length, their interactions with other components present in the food matrix, and their breakdown products following gut metabolism. While the consumption of a flavonoid-rich cocoa does not change the antioxidant capacity of the plasma, it can modulate circulation and decrease tissue inflammation. The consumption of flavonoid-rich diets is associated with decreased risk of hypertension and decreased mortality from cardiovascular disease. The effects observed with experimental animal models and studies with healthy human adult subjects support the concept that consumption of flavanol-rich foods can result in acute (1-30 days) improvements in vascular health and blood flow.
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.
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