Cardiovascular disease (CVD) is one of the leadingcauses of death in many economically developed nations aswell as in emerging economies. Although some of the majorrisk factors for CVD are not “modifiable”—age, sex, geneticpredisposition—diet and lifestyle issues are recognized asthe major modifiable risk factors. For instance, the negativeeffects of excessive dietary intake of saturated fats andcholesterol in the development of CVD via changes inplasma low-density lipoprotein–cholesterol (LDL-c) are
well established [1]. It is noteworthy however that certainnonlipid risk factors too can influence the development ofCVD including coronary heart disease because about onehalf of all coronary heart disease deaths occur in individualswith normal cholesterol levels [2]. Accordingly, currentknowledge favors the notion that risk factors other thanraised plasma cholesterol play an important role in thedevelopment of CVD [3].
Indeed, recent findings have highlighted the importanceof oxidative stress, vascular inflammation, and endothelialdysfunction (as central) to the development of CVD (Fig. 1)[4]. Such advancements in the knowledge of the diseaseprocess have also provided new avenues to develop novelpharmaceutical and/or dietary strategies to curb the devel-opment of vascular diseases. On this point, the recent
Fig. 1. Grape and wine polyphenols may exert their cardioprotective actions via some of the physiological processes shown in the schematic. See Table 1 for amore complete summary of effects.
expansion and the growing popularity of functional foodsand nutraceuticals aimed at promoting heart health can beviewed as specific examples. It is of interest to note thatepidemiological observations have played a significant partin the development of such products, with the most notableexamples being the findings in relation to the lowerischemic heart disease incidences in the Eskimos and thebetter vascular health and lower cardiac mortality rates inthe French [5]. In both instances, research based on theoriginal epidemiological observations have progressedrapidly and resulted in the identification and confirmationof respective dietary protective agents, namely, the long-chain n-3 polyunsaturated fatty acids (Eskimos) and thepolyphenols of Vitis vinifera in the case of the French. Forthe latter, Renaud and de Lorgeril [5] suggested wineintake as one possible explanation for the lower thanexpected coronary heart disease mortality rates in France(the “French Paradox”). Many studies to date haveinvestigated the French paradox, and recent evidencedemonstrates that consuming alcohol in the form of (red)wine might confer a protection against coronary heartdisease above that expected from its alcohol content alone,with the benefit being attributed to the presence ofpolyphenols. Similarly, grape seed and red wine extractsare also known to contain high levels of polyphenols, andthe beneficial health effects have been attributed toconsumption of these compounds [6-13].
Some of the potential mechanisms of preventing CVDafter consumption of grape polyphenols could be related totheir antioxidant activity [14]. The protective effect ofpolyphenols is in part due to their ability to retard thedevelopment and progression of early atherosclerotic lesionsto advanced atherosclerotic plaques. Antioxidant flavonoidsfound in red wine for example can reduce the oxidation ofLDL-c, which is a key and early event of the atherogenicprocess [15]. Other potential mechanisms by which grapepolyphenols may exert cardioprotective effects include areduction in oxidative stress, modulation of the inflamma-tory cascade, improvement in vascular endothelial function(eg, flow-mediated dilatation [FMD]), and protection againstatherothrombotic episodes including myocardial ischemiaand inhibition of platelet aggregation [14,16-22]. In thisreview, we discuss the beneficial cardiovascular effects ofgrape polyphenols.
2. Grape composition
Products such as red wine extract, grape seed, and grapeskin extracts as well as grape juice are all known to contain adiverse array of potent antioxidants in the form ofpolyphenols, which include phenolic acids (eg, gallic acid),anthocyanins, and simple and complex flavonoids (eg,proanthocyanidins). The quantity, structure, and degree ofpolymerization of grape proanthocyanidins differ, dependingon their localization in the grape tissues [23]. For example,grape seeds contain higher concentrations of monomeric,oligomeric, and polymeric flavan-3-ols compared with grapeskins [23]. In a study by Monagas et al [23], grape seedswere reported to contain approximately 2.3 to 8.2 mg/g ofmonomeric, oligomeric, and polymeric flavan-3-ols such as(+)-catechin, (−)-epicatechin and their gallates. However,grape skin proanthocyanidins have a higher degree ofpolymerization than those from the seeds and as a resultare more easily transferred to wine [23,24]. Grape skinscontain approximately 20-fold less (on a milligram per grambasis) monomeric, oligomeric, and polymeric flavan-3-olscompared with grape seeds [23]. It is also well known thatgrape polyphenol composition and content varies betweendifferent cultivars and is influenced by geographic locationand the climatic conditions [25].
Although the skin and seeds of grapes have been reportedto contain “cardioprotective” polyphenolic antioxidants, arecent animal study demonstrated that extracts from the fleshof grapes possessed cardioprotective actions [21]. The totalpolyphenolic index was lower in the grape flesh comparedwith the grape skin; however, the anthocyanins wereexclusively in the grape skin, whereas the reactive oxygenscavenging activities were similar in the 2 groups. Theresults suggested that the flesh of grapes may be equallycardioprotecive despite the fact that the grape flesh does notcontain anthocyanin activity.
As mentioned above, there is mounting evidence toindicate the potential cardioprotective effects of red wine andred grape juice consumption, and this has been attributed tospecific polyphenolic constituents of the grapes (see othersections below and Table 1) [25]. One of the activecomponents of red wine is resveratrol (trans-3,5,4′-trihy-droxystilbene), a naturally occurring phytoalexin originatingmainly from the skin of grapes. Phytoalexins including
Purple grape juice Human subjects 5-7 mL kg−1 day−1 orally 1 wk ↓ platelet aggregation [7]Purple grape juice Human subjects 7 mL kg−1 day−1 orally 14 d ↓ platelet aggregation, ↑ NO release and [6]
↓ superoxide productionGrape extract Sprague-Dawley rat ≥100 mg kg−1 day−1 orally 3 wk ↑ cardiac free radical scavenging [14]Concord grape juice Hypertensive patients 5.5 mL kg−1 day−1 orally 8 wk ↓ systolic BP 7.2 mm Hg and diastolic
BP 6.2 mm Hg[39]
Grape powder ApoEo mice 150 μg total polyphenolsper day orally
Red grape juice HepG2 and HL60 cells ≈5 mL/L in culture medium Up to 20 h Disrupt LDL trafficking in cells [66]Red grape juice Hemodialysis patients 100 mL/d orally 14 d ↓ MCP1, LDL, and ApoB [17]Polyphenolic
grape extractHuman platelets in vitro Incubation of platelets
in PGE up to 50 μg/mLUp to 60 min ↓ platelet aggregation,
Resveratrol Isolated platelets Up to 1.2 μg/L Minutes ↓ platelet aggregation 42% [48]Resveratrol Rat aortic smooth
muscle cells50 μmol/L in medium 30 min ↓ angiotensin II–induced vascular
smooth muscle cell hypertrophy[60]
↓ phosphorylation of PI3K and p70S6K
Resveratrol Isolated rat heart 10 μmol/L in perfusate Minutes ↓ myocardial infarct size/apoptosis/NO dependent
[35]
Improved aortic flow↑ iNOS mRNA
Resveratrol,oleanolic acid
COX enzyme 100 μg/mL in medium 5 min ↓ COX-1 activity 98% (resveratrol) [62]↓ COX-2 activity 10% (oleanolic acid)
Resveratrol tsA201 cells 77 μmol/L in medium Minutes Blocked cardiac Na+ and Ca2+ ion channels [55]↓ stimulated-diastolic [Ca2+]i
Resveratrol Rat and guinea pigs Up to 45 mg/kg intravenous Minutes ↓ arrhythmia duration, VT, and mortality [51]Isolated cardiomyocytes Up to 100 μmol/L in medium Minutes ↓ APD, inhibit ICa
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resveratrol are antibacterial and antifungal chemicals pro-duced by plants as a defense against infection by pathogens[26]. The amount of resveratrol found in grape skins alsovaries with exposure to fungal infection and its geographicorigin. The resveratrol levels in the final “product,” forexample, for wine, can also be affected by the vinificationprocess (eg, the amount of fermentation time a wine spends in
contact with grape skins) and the grape cultivar and can be ashigh as 5.87 mg/L in merlot wines [27].
3. Oxidative stress/LDL oxidation
Oxidation of lipoproteins such as LDL-c is an importantstep in the development of atherosclerosis, and therefore, a
sufficiently high plasma antioxidant status may be protec-tive. Oxidized LDLs stimulate endothelial cells to producechemokines and other factors that have direct chemotacticactivity for monocytes to adhere to the endothelium.Oxidized LDL is preferentially taken up by macrophagecells via scavenger receptors, and they consequently becomeloaded with lipids and convert into “foam cells” [28]. Thesefoam cells that tend to accumulate in fatty streaks are earlyindicators of atherosclerosis. Therefore, LDL oxidation hasbeen identified as a key event in atherosclerosis, thussuggesting that it may be possible to reduce the risk ofatherosclerosis by dietary supplementation with antioxidantpreparations enriched in polyphenols such as red wine, grapeseed, and grape skin extracts. Indeed, short-term ingestion ofpurple grape juice decreased LDL susceptibility to oxidationin coronary artery disease patients [29] and in hypercholes-terolemic human subjects supplemented with grape seedproanthocyanidin extract [9,30]. In addition, it was shownthat the skin and flesh of grapes contain similar andsignificant reactive oxygen species (ROS) scavengingactivity, suggesting that grape flesh may be equallycardioprotective as grape skin [21].
4. Atherosclerosis
High blood levels of cholesterol, particularly LDL-c,contribute to the development of atherosclerosis [15].Apolipoprotein Eo (ApoEo)-deficient mice are characterizedby accelerated development of atherosclerosis and anincrease in “oxidative state” (ie, more susceptible tooxidative stress) and represent a good model for athero-sclerosis. Fuhrman et al [31] investigated atheroscleroticlesions using ApoEo-deficient mice following the dietarysupplementation of freeze-dried extracts of fresh grapes. ForApoEo-deficient mice that consumed 150 μg total poly-phenolics per day for 10 weeks, a 41% reduction in theatherosclerotic lesion area was observed compared withcontrol (no supplements) or placebo (glucose and fructosesupplementation) groups. This effect was associated with asignificant reduction in serum oxidative stress as indicatedby an 8% reduction in plasma lipid peroxide concentrationand an increase in antioxidant capacity (16%-20%) as well asa reduction (33%) in macrophage uptake of oxidized LDL[31]. In addition, a study by Frederiksen et al [32] usingWatanabe heritable hyperlipidemic rabbits demonstrated thatconsumption of a red grape skin extract was associated witha retardation of the development of aortic atherosclerosis inmale rabbits but not females, as determined by cholesterolcontent within the abdominal aorta [32].
Oxidized LDLs favor the transformation of macrophagesinto foam cells (containing large amounts of cholesterolester), and therefore, the development of foam cells in theaorta is a good model and indicator of atherosclerotic lesions[16]. Using a hamster model of atherosclerosis, Vinson et al[33] found that grape seed proanthocyanidins induced apronounced reduction in plasma cholesterol (25%) and
triglyceride levels (up to 34%). Accompanying thesechanges was a reduction in the percentage of aorta coveredin foam cells. The latter was reduced by 50% and 63% aftersupplementation of the animals with 50 and 100 mg/kg grapeseed proanthocyanidins, respectively [33]. Furthermore,these beneficial effects were associated with a significantdecrease in plasma lipid peroxidation levels.
In a randomized, double-blind, placebo-controlled study,grape seed proanthocyanidin extract was given to 40hypercholesterolemic patients for 8 weeks [9]. There was asignificant reduction in LDL-c levels and total cholesterollevels for the grape seed proanthocyanidin group, but onlywhen this group was additionally supplemented with niacin-bound chromium, suggesting the mechanisms of action arecomplex andmay require other “factors” for nutritional benefit.
5. Vascular relaxation/ flow
Awealth of data in the literature show that grape and winepolyphenols possess strong vasorelaxant actions both in thelarge conductance (aorta) and smaller resistance (mesenteric)vessels ex vivo [13,29,34]. The primary mode of action hasbeen reported to be inhibition of the release of nitric oxide(NO), and supporting data are also available to suggestinduction of endothelial NO synthase by polyphenols isreduced [35,36].
Soares De Moura et al [20] demonstrated that oraladministration of grape skin extract significantly reducedsystolic, mean, and diastolic arterial pressure in a hyperten-sive rat model. In addition, red wine polyphenols adminis-tered in drinking water (150 mg kg−1 day−1) preventedincreases in systolic blood pressure (BP) but not heart rate inmale Wistar rats after infusion with the potent vasoconstric-tor, angiotensin II [37].
Grape skin extract was shown to concentration-depen-dently inhibit lipid peroxidation and induce endothelium-dependent vasodilation in norepinephrine-induced con-tracted mesenteric vessels ex vivo [20]. The resultsdemonstrated that the beneficial effect of moderate redwine consumption could be partly due to antioxidant actions.However, a recent study [38] using cholesterol-fed hamstersdemonstrated that the beneficial effects of grape seed extractwere independent of the antioxidant effects (the plasmaantioxidant capacity was measured by the Randox method),that is, a 11% decrease in plasma cholesterol and 77%increase in endothelium-dependent relaxation of aortic ringsand 68% reduction of atherosclerosis.
A study by Stein et al [29] involved administering purplegrape juice (Welch's 100% Concord Grape) to 15 adults withdocumented coronary artery disease, for 14 days. Flow-mediated vasodilation was calculated from various para-meters after ultrasound of the brachial artery and was foundto be significantly increased above baseline values. Althoughthe effects of the flavonoids from the grape juice productsincluding red wine have been known to exert anti-inflammatory, antioxidant, platelet inhibitory, and arterial
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relaxing effects, Concord grape juice was also shown toreduce systolic BP by 7.2 mm Hg and diastolic BP by 6.2mm Hg in a study involving 40 hypertensive patients [39].Other cardiovascular parameters after consumption of grapeseed proanthocyanidins or grape extract have been shown tobe altered, including improvement in coronary flow, aorticflow, and developed pressure [8,14]. Furthermore, theseresults were associated with a significant reduction of thegeneration of oxygen free radicals.
Interestingly, Clifton [19] reported no differences insystolic and diastolic BP, serum lipids, oxidized LDL, andother cardiovascular measures after daily consumption ofgrape seed extract by 36 adults for a 4-week treatmentperiod. However, there was a significant difference in FMDas measured by ultrasound in subjects who had aboveaverage cardiovascular risk factors, which included highcholesterol, smoking, or high BP. Therefore, sufficient grapeseed antioxidant polyphenols from grape seed extract wereabsorbed to influence FMD [19]. It is conceivable that“bioavailability” of the polyphenols may have been adeterminant in the failure of grape seed extract to reduceBP despite improvement in FMD in this study [19]. Reportedbioavailabilities of the flavonoids range from about 10% to50% [40]. A recent in vitro study confirmed the limitedbioavailability of dietary polyphenols when the polyphenolswere in a complex with carbohydrate polymers and lipids[41]. In this regard, a recent pharmacokinetic study withhealthy volunteers demonstrated that only high doses of oralresveratrol, tha is, 5 g, led to peak plasma concentrations ofresveratrol of 2.4 μmol/L after 1.5 hour postdose [42]. Inaddition, urinary excretion was rapid, with approximately77% of all resveratrol species excreted within 4 hours (of thelowest dose tested). Therefore, consumption of very highdoses of resveratrol may be required to elicit changes inphysiological parameters such as BP. Finally, the type ofpolyphenol as well as the nature and extent of its glycosidicconjugation may also influence its bioavailability [40,43,44].
6. Platelet aggregation
It has been previously suggested that the inhibition ofplatelet reactivity by wine may partly explain some of itscardioprotective effects, for example, the French paradox asmentioned earlier [5]. Red wine and grape juice, but notwhite wine, when infused intravenously or intragastricallyinto anesthetized dogs improved coronary artery blood flowparameters and inhibited platelet aggregation [45]. This earlystudy suggested that the protective cardiovascular effectsobserved could be related to the phenolic flavonoids in thered wine and grape juice. In a study involving only 10subjects, the effects of drinking purple grape juice, grapefruitjuice, or orange juice for 1 week were examined [7]. Plateletaggregation responses to collagen were significantly reducedin the grape juice group only and appear to reflect the totalphenolic contents of the test components. For instance, thetotal phenolics (gallic acid equivalents) were 2.26, 0.75, and
0.86 g/L for purple grape juice, orange juice, and grapefruitjuice, respectively. In addition, purple grape juice containedflavonols, anthocyanidins, and proanthocyanidins, but therewas no detectable levels of these components in the orangeor grapefruit juices. Another (human) study demonstrated adecrease in platelet aggregation, increase in platelet-derivedNO release, and a decrease in superoxide formation, both invitro and after oral supplementation with purple grape juice,confirming the absorption and bioavailability of thebioactives from purple grape juice [6].
Platelet endothelial cell adhesion molecule-1 (PECAM-1)is a tyrosine phosphoprotein highly expressed in endothelialcells. It is an important component in the regulation ofneutrophil transendothelial migration [46]. A recent studyshowed that a possible mechanism involved in the beneficialeffects of grape extracts containing polyphenols on plateletactivation involves the activation of PECAM-1 [47]. There-fore, activation of PECAM-1 by grape polyphenols may partlyexplain the positive effects of red wine consumption, and thishas been proposed to further explain the French paradox [47].Shanmuganayagam et al [22] compared the effects ofcombining grape seed and grape skin extracts on plateletactivity in dogs in an ex vivo feeding study or using an in vitrohuman platelet incubation study protocol. The major findingwas that the concentrations of grape seed extract (5 mg/kgbody weight) and grape skin extract (20 mg/kg body weight)had little effect on ex vivo platelet activity in dogs. In humans,only the highest test dose of grape seed extract (100 mg/Lblood) inhibited platelet aggregation.However in bothmodels,a greater antiplatelet effect was observed when a combinationof grape seed and grape skin extract was used [22].
The antiaggregating effects of resveratrol have beenobserved at concentrations as low as 1.2 μg/L (of red winediluted 1000-fold), which inhibited platelet aggregation by41.9% [48]. Therefore, reducing the level of plateletaggregation may be a contributing factor associated withthe cardioprotective effects of polyphenols.
7. Myocardial ischemia/reperfusion
Ventricular arrhythmias remain an important cause ofdeath in ischemic heart disease, and ROS have beenimplicated in the pathogenesis of ischemic heart disease[49]. Agents known to scavenge free radicals could preventthe deleterious effects of reperfusion-induced arrhythmiasand/or improve the recovery of the myocardium afterischemia. Recent studies in experimental animal modelshave demonstrated protective actions of grape and winepolyphenols against experimentally induced myocardialischemia and reperfusion [8,21,35,50-54]. For instance,both the grape and wine polyphenols have been reported toreduce the mortality and the severity of cardiac arrhythmiaafter myocardial ischemia/reperfusion, both after acuteinfusion and after oral administration [53,54]. Using theLangendorff isolated rat heart preparation, Sato et al [50]identified grape seed proanthocyanidins (in a 3-week
prefeeding dietary intervention trial) to be cardioprotectiveagainst myocardial ischemia and reperfusion as evidenced byreduced infarct size and improved recovery of postischemiccontractile functions [50]. The grape seed proanthocyanidinsupplemented group had a significant reduction in themyocardial infarct size as well as a relatively higher aorticflow compared with controls, and this was associated with asignificant increase in the hydroxyl radical scavengingactivity. A more recent study reported both grape flesh andgrape skin extracts (oral administration) improved aortic flowand protected hearts from ischemic reperfusion, and bothdietary interventions reduced myocardial infarction sizesuggesting both grape flesh and grape skin are equallycardioprotective [21]. In another study investigating thepotential cardioprotective effects of grape seed proanthocya-nidins, the extent of ischemia/reperfusion-induced cardiacarrhythmias were measured [8]. After 3 weeks on the grapeseed proanthocyanidin–supplemented diets, the incidence ofreperfusion-induced arrhythmias was 25% in the supple-mented group compared with 92% in the control group.Furthermore, resveratrol has also been also shown topharmacologically precondition the heart. For example,Hattori et al [35] demonstrated preconditioning of isolated,perfused working rat hearts with 10 μmol/L resveratrol, andthis provided cardioprotection against postischemic ventri-cular recovery, reduced myocardial infarct size, and apopto-sis. The results also showed that the action of resveratrolinvolved a cardioprotective mechanism that was NOdependent, which was supported by an increase in inducibleNO synthase mRNA expression in the heart at only 30minutes after reperfusion [35].
In more recent studies, resveratrol decreased experimen-tally induced arrhythmia duration, incidence of ventriculartachycardia, and animal mortality [51,52]. Results ofelectrophysiological studies revealed that resveratrol dose-dependently (up to 100 μmol/L) decreased the action
Fig. 2. Effects of grape extract (skin, seed, juice, resveratrol, and so on) on some ofand a negative (−) indicates an inhibitory effect. oxLDL indicates oxidized LDL;
potential duration and inhibited the L-type calcium currentsin isolated ventricular cardiomyocytes, thus partly explain-ing the mechanisms(s) of action [51]. In rat heartcardiomyocytes isolated from the right ventricle, resveratrolwas shown to block the peak voltage gated sodium currentswith an IC50 of 77 μmol/L [55]. Resveratrol was also shownto reduce toxin-induced increases in diastolic calciumconcentrations leading to a reversal of contractile dysfunc-tion. Therefore, apart from resveratrol being well known forits antioxidant activity in vivo, it appears that resveratrolplays a more direct role on ion channels, controlling theexcitability of the myocardium, which have been shown forother bioactives [56,57] and may partly explain thecardioprotective activity of resveratrol.
8. Cellular signaling
Sato et al [58] demonstrated that grape seed proanthocya-nidins may offer cardioprotection by inhibiting the regulatorygenes cJUN and JNK1 [58]. In addition, grape seed extracts atlow concentrations could inhibit agonist-induced vascularcell adhesion molecule-1 expression, a marker for celladhesion that has been reported to be involved in chronicinflammatory conditions [59]. Resveratrol was shown toinhibit the release of chemokines such as interleukin-6 andother biochemical parameters involved in inflammatoryprocesses, which have been reviewed elsewhere [16].
Because angiotensin II–induced hypertrophy of vascularsmooth muscle cells is a key step in the development ofCVD, Haider et al [60] investigated the potential beneficialeffects of resveratrol on this process in vitro. Resveratrol at50 μmol/L decreased phosphorylation of phospahtidylinosi-tol 3-kinase (PI3K) and p70 ribosomal protein S6 kinase(p70S6K) proteins, both of which are implicated inangiotensin II–induced protein synthesis (and vascularsmooth muscle cell hypertrophy). The 2 proteins PI3K and
the early steps of atherosclerosis. A positive (+) indicates an increase in effectPGE2, prostaglandin E2.
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p70S6K are involved in the ERK 1/2 signaling pathway,downstream from ligand-activated G-protein–coupledreceptors. Therefore, it is possible that resveratrol in additionto its effect on angiotensin II–induced hypertrophy couldplay an important role in other G-protein–coupled receptorsignaling pathways that are involved in CVD.
Because different isoforms of cyclooxygenase (COX)enzymes have been strongly implicated in inflammatoryprocesses (such as atherosclerosis [61]), this class ofenzymes may also provide useful targets for resveratrol.Indeed, resveratrol isolated from grape skin was shown toinhibit the COX-1 enzyme by 98% at 100 μg/mL, butresveratrol was without effect against the closely relatedCOX-2 enzyme [62]. In addition, viniferin and catechin (alsofrom grape skin) inhibited COX-1 and COX-2 [62] and aretherefore somewhat comparable to the pharmacologicalagents aspirin, naproxen, and ibuprofen in terms of theirselectivity for inhibition of different isoforms of COX.
Peroxisome proliferator-activated receptors regulate tran-scription of various genes involved in cholesterol metabo-lism in the liver and other organs [63,64]. In a study by Ma etal [65], the grape seed proanthocyanidins were anti-inflammatory in human umbilical vein endothelial cells bya mechanism involving activation of PPARγ expression[65]. Thus, in addition to their cardioprotective effects, grapeseed proanthocyanidins appear to reduce the inflammatoryprocesses (see Fig. 2), which might partly explain themechanism(s) for the amelioration of other chronic inflam-matory conditions such as inflammatory bowel disease,cancer, and diabetes.
9. Summary
There is mounting evidence that crude grape extracts andred wine products contain bioactive ingredients that affordsome protection against CVD. This is supported by data fromin vitro, ex vivo, and in vivo animal studies and, albeitlimited, human trials. The beneficial effects of thesebioactive products appear to be mediated via a plethora ofbiochemical pathways and signaling mechanisms actingeither independently or synergistically. The pleiotropicnature of the reported benefits of these polyphenols tendsto suggest the modulation of multiple mechanisms and mayexplain their physiological efficacy. These properties renderthe polyphenols attractive candidates for nutraceutical andfunctional foods. Therefore, supplementation with grapeseed, grape skin, or red wine products may be a usefuladjunct to consider for a dietary approach in the preventionof CVDs, although additional research is required to supportsuch a strategy.
Acknowledgment
This work was funded by the Preventative HealthNational Research Flagship of the Commonwealth Scientificand Industrial Research Organisation.
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