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Review Article
Cardioprotective effects of moderate red wine consumption: Polyphenols vs. ethanol
Marcello Iriti
a,*, Elena M. Varoni
baDepartmentofAgriculturalandEnvironmentalSciences,MilanStateUniversity,Milan,Italy
bDepartmentofBiomedical,SurgicalandDentalSciences,MilanStateUniversity,Milan,Italy
Introduction
Mediterraneandietincludesanumberofdifferentnutritional habits,althoughsomecommonkeyelementscanberecognized indietarypatternsofMediterraneanpopulations:highconsump- tionoffruit,bothfreshanddried(e.g.figs,raisin);rawandcooked seasonalvegetables; whole-cerealproducts;fishand seafood;
dairyproducts,goatandewemilkinfermentedformsofcheese andyoghurt;nuts;leanmeatsuchasrabbitandchicken;aromatic herbsandspices;extra-virginolive oilasmaindressing;moderate
alcoholdrinking,particularlybasedonredwine.However,inthe southern Mediterranean region,due to cultural andreligious reasons,wineisusuallyreplacedwithblackteaasamainsource ofphytochemicals,mainlypolyphenols.Theparticularstructure andcompositionoftraditionalMediterraneandiets,besidestheir varietyandassortment,havebeenproposedtoexplainthelow prevalence of cardiovascular diseases and the improved life expectancy in some countrieswhich face Mediterraneansea basin(IritiandVitalini,2012).
Even if wine is an alcoholic beverage, a plethora of beneficialbiologicalandpharmacologicalactivitieshasbeen journalofappliedbiomedicine 12(2014) 193–202
article info
Articlehistory:
Received26May2014 Receivedinrevisedform 9September2014
Accepted11September2014 Availableonline20September2014
Keywords:
Polyphenols Melatonin Phytosterols
Coronaryheartdisease Spirits
De-alcoholizedwine
abstract
Sincedecades,ithasbeensuggestedthatregular,moderateconsumptionofredwine,a major componentofMediterraneandiet,atmainmeals,maycontributetoexplainthe healthypropertiesattributedtothistraditionaldietarystyle.Despitepreclinicalinvitro/
invivodatahave shownasignificantcardioprotectiveactivityofgrapephytochemicals, mostlypolyphenols,evidenceinhumansisstilldebated.Thislackofconsensusmaybedue totheequilibriumbetweenthetwomaincomponentsofwinerelevantforhealth:ethanol andbioactivecompoundsorphytochemicals,whichincludenotonlypolyphenols,butalso newlydetectedmolecules,suchasmelatoninandphytosterols.Thestateofartrelatedto thisdelicateequilibriumrepresentsthestartingpointfordesigningfutureclinicaltrials,in perspectiveofclinicalrecommendations.Abettercomprehensionofthewinechemistry complexitywithitsmajorcomponentsembodiesapivotalissueinbiomedicine,involving thefieldsofdiet-relatedenvironmentalmedicineaswellaschronomedicine.Inthispaper, webrieflyreviewedputativebeneficial effectsofmoderateredwineintake inhumans, focusingonthereductionofcardiovascularrisk.
#2014FacultyofHealthandSocialStudies,UniversityofSouthBohemiainCeske Budejovice.PublishedbyElsevierUrban&PartnerSp.zo.o.Allrightsreserved.
* Correspondingauthorat:viaG.Celoria2,20133Milan,Italy.Tel.:+390250316766;fax:+390250316781.
E-mailaddress:marcello.iriti@unimi.it(M.Iriti).
Availableonlineatwww.sciencedirect.com
ScienceDirect
journalhomepage:http://www.elsevier.com/locate/jab
1214-021X/$–seefrontmatter#2014FacultyofHealthandSocialStudies,UniversityofSouthBohemiainCeskeBudejovice.Published byElsevierUrban&PartnerSp.zo.o.Allrightsreserved.
http://dx.doi.org/10.1016/j.jab.2014.09.003
ascribed, in the past decades, to some grape and wine metabolites,underthe name of ‘‘bioactivecompounds’’. In particular, polyphenols, a large group of phenylalanine derivatives,have beenextensivelyinvestigated.Thesephy- tochemicals,dividedintoflavonoids(includinganthocyanins), stilbenes (e.g. resveratrol) and proanthocyanidins (or con- densedtannins)(Figs. 1and2),possessdifferentmolecular andbiochemical targetsbothin healthyanddiseasedcells (Iriti and Faoro, 2009). Their main mechanisms of (cardio) protection include high antioxidant and antiinflammatory activities; resveratrol, in particular, has been reported to stimulate endothelial production of nitric oxide, reducing oxidativestress, decreasingvascularinflammationand pre- venting platelet aggregation (Li and Förstermann, 2012).
Furthermore,thediversityofgrapeandwinechemistryhas been recently improved by the discovery of new bioactive moleculesintheseproducts,i.e.melatoninandphytosterols (Figs. 2 and 3). Melatonin is an indoleamine traditionally considered a vertebrate neurohormone, secreted from the pinealglandwithacircadianrhythm,andsignificantlypresent ingrapevineproducts(Vitalinietal.,2013).Itplaysapivotal roleinhumanchronobiology,sinceitregulatesthebiological clockandcircadianphysiologicalfunctions,suchassleepand appetite(Rodellaetal.,2013).Onwhatconcerncardiovascular protection, melatonin has been shown to improve blood pressureparametersassuggestedbytheresultsof ameta- analysis(Grossmanetal.,2011),notonlyactingonheartwitha
central effect, but also byreducing vesseloxidation, nitric oxidemetabolismandimprovingendothelialfunctions(Cicero andBorghi,2013).
In addition to melatonin, three phytosterols, i.e. b- sitosterol,stigmasteroland campesterol,effectivehypocho- lesterolizingagents,havebeendetectedingrapesandwine (Ruggieroetal.,2013).Phytosterolshavebeenreportedtoplay a key role againstdyslipidemias,withhypocholesterolemic effects:dailyintakeofplantsterolsorstanolsof1.6–2.0g/day isabletodecreaseintestinalcholesterolabsorptionfromthe gutbyabout30%,aswellasplasmatotalandLDLcholesterol levels,thusreducingthecardiovascularrisk(Marangoniand Poli,2010).Therefore,itcanbehypothesizedthattheseand, possibly, other phytochemicals may maximize the healthy properties of polyphenols by additive and/or synergistic effects.
Despitepolyphenolsareconsideredthearchetypeofhealth benefitsattributedtoamoderateredwineconsumption,as demonstratedbyahugeamountofinvitro/invivoexperimental models(IritiandFaoro,2009),theinhumanevidenceisstill inconclusive,possiblybecauseofthepresenceofethanolin wine, which cancounteract ornullify, to someextent,the protective effectsof polyphenols in conditionsof heavy or binge (episodic heavy) wine intake (Barbero-Becerra et al., 2011).Asanexample,despiteavastpreclinicalliteratureon resveratrol,clinicalevidenceonitscardioprotectivepotential isstilllargelyopentodoubt(CiceroandBorghi,2013).
Fig.1–Typicalbioactivepolyphenolspresentinredwineincludeanthocyanidins(malvidin),stilbenes(resveratrol),flavonols (quercetin),flavan-3-ols[(+)-catechin]andproanthocyanidinsorcondensedtannins,oligo-andpolymericderivativesof flavan-3-olunits.
In this perspective, to date, the equilibrium between ethanolandbioactivephytochemicals containedin wineis underdiscussion,involvingthosebiomedicine-relatedstudies exploringeffectsofdietondiseasedevelopmentandpreven- tion(Berger,2011).
Inthisreview,webrieflyexaminedthehealth-promoting effectsofmoderateredwineintakeinhumans,focusingon thesuggestedassociationwithcardiovascularprotection.We focusedonstudieswhichcomparedwineandspiritconsump- tion,withstrongly differentethanol/phytochemicals ratios.
Meta-analysesonwineandcardiovasculardiseasewerealso
considered.Ourworkaimstoprovideanupdatedknowledge on this issue in order to stimulate and encourage future biomedical research, mainly in the field of diet-related environmentalmedicineandofchronobiologyaswell.
Interventional studies
Severalinhumansstudieshavebeenrecentlycarriedoutto elucidatetherelationamongtypesofalcoholicbeverage(wine, spirit,beer),underdifferentdrinkingpatterns,andcardiovas- cular risk. Interventional studies investigated effects on surrogateoutcomes,mainlyserumbiomarkersandfunctional changes.
Variationofserumbiomarkers
The different effectsof red wine and gin consumptionon inflammatorybiomarkersofatherosclerosiswereinvestigated inarandomized,crossover,single-blindedclinicaltrial.Forty healthymen(meanage37.6years)consumed30gofethanol perday,for28days,aseitherredwine(two160mLglasses)or gin(100mL),thelatterabeveragewithaverylowpolyphenol content.Bloodsampleanalysesindicatedthatbothwineand gin drinking had anti-inflammatory effects by reducing plasma fibrinogen (by9and 5%,respectively) and cytokine interleukin-1a (IL-1a) (by 21 and 23%, respectively) levels.
However, only wine had two additional effects: (i) a 21%
decrease in C-reactive protein (CRP); (ii) a reduction of monocyteandendothelialadhesionmoleculesincludingvery lateactivationantigen4(VLA-4)(32%),monocytechemoat- tractantprotein(MCP-1)(46%),solublevascularcelladhesion molecule-1 (VCAM-1) (17%) and intercellular adhesion molecule-1(ICAM-1)(-9%)(Estruchetal.,2004).Similarly,4- weeksupplementationofredwinedecreasedplasmafibrino- genlevelsin15healthymalevolunteers,whowereinstructed todrink250mL/dayofthisbeverage(12%alcohol,1.2g/Ltotal polyphenols, 0.64g/L total anthocyanins and 1.0g/L total proanthocyanidins). However, the authors also found an increase of mean platelet volume and serum levels of inflammatory and endothelial cell activation markers, as ICAM-1,E-selectinandIL-6(TozziCiancarellietal.,2011).On theotherhand,150mL/dayofredwine(15g/dayofalcohol)for 3weeksfailedtoreduceserumCRPlevelsandonlyslightly decreasedfibrinogenconcentrationsin87Norwegianhealthy volunteers35–70yearsold(meanage50.0years)(Retterstol etal.,2005).
Inanotherrandomized,crossoverclinicaltrial,20g/dayof ethanolasredorwhitewine(1glassof100mLatlunchand dinner)wereadministeredto35healthywomenaged20–50 years(meanage38.0years)for4weeks.Bothwinesreduced serumbiomarkersofinflammationandendothelialactivation insubjects,evenifanti-inflammatoryeffectsassociatedwith moderate red wine consumption were higher than those produced by white wine, probably because of a different polyphenolcontent(Sacanellaetal.,2007).
Themoderateintakeofredwineoranalcoholicbeverage withaverylowpolyphenolcontentwasinvestigatedinterms of influence on serum antioxidant vitamins, antioxidant status,lipidprofileandoxidabilityoflow-densitylipoprotein Fig.2–Presenceofmainpolyphenols(anthocyanins,
resveratrolandproanthocyanidins),phenolicacids (hydroxycinnamates)andnewphytochemicals (phytosterolsandmelatonin)ingrapeberryandseed tissues.
Fig.3–Recentlydiscoveredbioactivephytochemicalsin wineareindoleamines(melatonin)andphytosterols(b- sitosterol,stigmasterolandcampesterol).
journalofappliedbiomedicine 12 (2014) 193–202
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(LDL)particles.Fortyhealthymenaged30–50years(meanage 38.0years)received30gofethanolperdayasredwine(two 160mLglassesatdinner)orgin(100mLatdinner),for28days.
In particular, compared to gin intervention, wine intake reduced plasma superoxide dismutase (SOD) activity, mal- ondialdehyde(MDA)and oxidizedLDLlevels(Estruchetal., 2011).
Byasimilarstudydesign(arandomized,crossoverclinical trial), the same authors also demonstrated that red wine exertedhigherprotectiveeffectsonglucosemetabolismand lipidprofilethanotheralcoholicbeverages.Sixty-sevenmen aged55–75yearswereinstructedtoconsumegin(100mL/day, containing30gofethanol),redwine(272mL/day,containing 30g of ethanol and 798mg of total polyphenols), or de- alcoholizedredwine(272mL/day,containing1.14gofethanol and733mgoftotalpolyphenols)for4weeks.Participantswere at high cardiovascular risk, reporting family history of prematurecardiovasculardiseaseand/orpresenceofdiabetes, hypertension,dyslipidemia and overweight/obesity.Plasma insulinandinsulinresistance decreasedafter interventions withbothwines;high-density lipoprotein(HDL)-cholesterol, apolipoprotein(Apo)A-1andApoA-2increasedafterredwine and gin administration. On the other hand, only red wine reduced lipoprotein plasma concentrations (Chiva-Blanch et al., 2013a). In another study, the same authors showed thatbothethanolandnon-alcoholiccomponentsofredwine mayregulatesolubleinflammatorymediatorsinhigh-cardio- vascularriskpatients,whereasonlyphenoliccompoundsmay modulateleukocyteadhesionmolecules(Chiva-Blanchetal., 2012a).De-alcoholizedredwinealsodecreasedsystolicand diastolicblood pressures inpatients at highcardiovascular risk,andthesevariationscorrelatedwithincreasedconcen- tration of plasma nitric oxide (NO) (a potent vasodilator) (Chiva-Blanchetal.,2012b).
The relationship between body mass index (BMI) and plasmatriglycerideswasinvestigatedin42Brazilianindivid- uals(64%men,meanage46.0years,meanBMI25.13kg/m2) consuming250mL/dayofredwineatmealsfor2weeks.In general,redwineincreasedplasmalevelsoftriglyceridesand thetriglycerides/HDL-cholesterol ratio. When subjectswere divided into three categories, according to their BMI, the authorsreportedthatindividualswithhigherBMI,although non obese, were at higher risk for elevation in plasma triglyceridesandthetriglycerides/HDL-cholesterolratioafter short-timeredwineconsumption(Cesenaetal.,2011).
Possibleprebioticeffectsassociatedwithredwineintake were recently suggested. Ten healthy male volunteers received red wine (272mL/day), de-alcoholized red wine (272mL/day) or gin (100mL/day) for 20 days. Total fecal DNAanalysisbyreal-timeqPCRrevealedthat,comparedwith baseline,dailyconsumptionofredwinepolyphenolssignifi- cantlyincreasedthenumberofEnterococcus,Prevotella,Bacter- oides,Bifidobacterium,Bacteroidesuniformis,Eggerthellalenta,and Blautiacoccoides–Eubacteriumrectalegroups.Inparallel,systolic anddiastolic bloodpressures,triglyceride, totalcholesterol, HDL-cholesterol and CRP concentrations decreased signifi- cantly.Besidespromotingthegrowthofprobioticbacteria,red winepolyphenolsalso inhibitedpathogenic bacteriainthe human microbiota, such as Clostridiumspp (Queipo-Ortuño etal.,2012).
Aspreviouslymentioned,healthbenefitsofmoderatewine consumptionhave,atleastinpart,beenattributedtogrape polyphenols. Protection against oxidative damage of a Mediterraneandietcomparedwithawestern(US)diet,with orwithouttheconcomitantintakeofredwine,wasassessedin 42youngadults(20–27yearsold).Volunteerswererandomly assignedtoeithertheMediterraneandietgrouporthewestern dietgroupfor3monthsand,onlyduringthesecondmonth, they received 240mL/day of red wine. Mediterranean diet increasedplasmavitaminCandb-carotenelevelsand total antioxidantactivity,whilewesterndietraisedonlyvitaminE content. Wine supplementation, analyzed combining both diet groups,increased: (i)plasmavitaminC, b-caroteneand uric acid concentrations and total antioxidant activity; (ii) plasmaandurinarytotalpolyphenolsand(iii)redbloodcell glutathione levels, while decreasing plasma vitaminE and glutathionecontents.Westerndietgroupalsoshowedhigher concentrations of 8-hydroxy-20-deoxyguanosine (8-OHdG, a markerofoxidativeDNAdamage),inDNAofperipheralblood leukocytes, andplasmanitrotyrosine(amarkerof oxidative protein damage) when compared with Mediterranean diet group.Wineintakesignificantlyreduced8-OHdGandplasma nitrotyrosineinbothdiets,particularlyinthewesterngroup.
Theauthorsconcludedthatmoderateredwineconsumption counteracted theoxidative damage causedbywestern diet (Urquiagaetal.,2010).
Furthermore,everifonfewparticipants,itwasshownthat 300mL/dayofalcohol-freeredwinefor1weekincreasedthe activities of antioxidant enzymes (superoxide dismutase, catalaseandglutathionereductase)in8volunteersaged25– 40(meanage28.0)followingalowphenolicdiet(Nogueretal., 2012). However, despite a general consensus attributing antioxidant benefits to sustained wine consumption in healthy volunteers, Covas and colleagues concluded, in a review paper, that there is no evidence, at present, that supportsaswineconsumptionisassociatedwithantioxidant benefitsotherthantocounteractapossibleprooxidanteffect of the ethanol. On the contrary, data on the antioxidant protectiveeffectsofredwineinconditionsofoxidativestress are promising (Covas et al., 2010). These conclusions are consistent with our recent results showing that red wine drinkingwasnotassociatedtoareducedsalivaryantiradical capacity, which, conversely, was greatly improved by the intakeofacapsuleofredwineextract(Varonietal.,2013).
Finally, perspectives of a moderate red wine intake in secondarypreventionofcardiovasculardiseaseswereevalu- ated.Thirty-ninepostmyocardialinfarctpatients(32menand 7women,meanage65.0)weredividedinto2groups:'redwine drinkers',administeredwith250mL/dayofredwine(3.81g/L total polyphenols) at main meals for 2 weeks, and 'water drinkers'.Duringthisperiod,allsubjectsreceiveda'western prudent'diet,inspiredbytheMediterraneandietprinciples.
ModerateredwineintakereducedtotalcholesterolandLDL- cholesterol, and improved erythrocyte membrane fluidity (Rifleretal.,2012).
Functionalchanges
Hypertensionandbloodpressurevariationscanbeconsidered useful indirect indicators to analyze a potential protective
effectof wineagainst cardiovascular diseases. In terms of alcoholintake,anincreaseoftheriskofhypertensionhasbeen reportedwitharegulardrinkingpattern,inadose-dependent manner (Taylor et al., 2009), or with consumption outside meals, independently from the ethanol amount (Stranges etal.,2004),whileamoderateintakeofalcoholappearednotto affectblood pressure inanormotensive population(Okubo etal.,2001).AsChiva-Blanchetal.pointedout,diverseeffects of different alcoholic beverages on blood pressure can be mainlyrelatedtotheirdifferentpolyphenolcontent(Chiva- Blanchet al., 2013b),as shown onhigh cardiovascular risk subjects,wheremoderatealcoholconsumption,intheformof ginorredwine,didnotaffectbloodpressure,differentlyfrom de-alcoholizedredwinewhichreducedthisparameter(Chiva- Blanchetal.,2012b).
Atrialfibrillationisalesscommon,butrelevantriskfactor exposingpatienttocardiovascularevents.Inameta-analysis focusing on high risk populations already affected by cardiovascular events, a slight/moderate alcoholintake (5– 25g/day)wassignificantlyassociatedwithalowerincidenceof secondary cardiovascular and all-cause mortalities, while long-termmoderatealcoholconsumptionwasrelatedtothe developmentoftheseconditions:theauthorsrecommended to avoid alcohol consumption in these patients (Costanzo etal.,2010).
Geneticvariations
1Bgene(ADH1B)encodesforalcoholdehydrogenase(ADH), theenzymerepresentingthefirststepofethanolmetabolism (Edenberg, 2007); a single nucleotide polymorphism (rs1229984) hasbeen recentlyassociated withlow levelsof alcoholconsumptionandbloodethanolandwithreducedrisk ofalcoholdependenceamongdrinkers(Yokoyamaetal.,2014).
Basedonaverylargesample(260,000participants),arecent studyreportedthatcarriersoftheA-allelehadslightlowerrisk ofischemicstrokewithanoddsratioof0.83(Katoetal.,2011;
Droganetal.,2012;Lawloretal.,2013;Holmesetal.,2014).In particular,Holmesandcoworkersidentifiedrelationbetween carriers of this allele and cardiovascular traits (non-HDL cholesterol,interleukin 6and C reactive protein) including coronaryheartdisease(Holmesetal.,2014).Thesedataare consistentwithAsianstudiesonthers671geneticvariantof thealdehydedehydrogenase2gene(ALDH2),enzymewitha reducedabilitytodetoxifyethanolandrelatednegativeeffects onbloodpressure,bodymassindexandnon-HDLcholesterol levels(Katoetal.,2011;Lawloretal.,2013).
Observational studies
Thebeneficialpropertiesofredwineareknownsincemore than three decades. In 1979, St. Leger and colleagues first described a significant inverse relationship between wine consumptionandriskof deathfromcoronaryheartdisease (St.Legeret al., 1979).Morerecently,evidence of ahealth- promoting effect of red wine on cardiovascular health emergedfrommanyepidemiologicalstudies.Inaprospective study,Djousséandcollaboratorsinvestigatedtheassociation betweenalcoholconsumptionandbothriskandmortalityfor
cardiovasculardiseasesin26,399('non-Mediterranean')parti- cipantsfromtheWomen'sHealthStudy,withameanfollow- upof12.2years.Ascomparedwithabstainers,alcoholintake of5–15g/daywasassociatedwith26%,35%and51%lowerrisk ofcardiovasculardisease,totalmortalityandcardiovascular disease-relatedmortality,respectively.Inmoderatedrinkers, 86%ofreducedcardiovasculardiseaseriskwasexplainedby effectsonlipids,glucosemetabolism,inflammatory/haemo- staticfactorsandbloodpressure.Furthermore,nodifferential association forbeverage type,i.e.beer, wineorspirits,and studiedoutcomeswasobservedbytheauthors(Djousséetal., 2009).Similarly,inacohort(N=31,367)ofUSadultmenfrom theprospectiveAerobicCenterLongitudinalStudy,≤6drinks/
weekreducedtheriskofcardiovasculardiseasemortalityof about29%.Whenalcoholconsumptionwasstratifiedbytype (wine, beerand liquor),no differencewas observed(Howie etal.,2011).
InalargeFrenchpopulation,theurbanParis-Ile-De-France Cohort,composedof149,773subjects(97,406menand52,367 women with a mean age of 47.615 and 47.012 years, respectively),relationshipbetweenalcoholintakeandcardio- vascularriskwasinvestigated.Thesubjectsweredividedinto four groups according to alcohol consumption: never, low (<10g/day),moderate(10–30g/day)andhigh(>30g/day).With theexceptionofthesubgroupofyoungsubjects(<30yearsof age),alcoholicbeveragesmainlyconsistedofwine.Inaddition, wineconsumptionincreasedwithage,whereasthoseofbeer andappetizersdecreased.Moderatealcoholdrinkersshowed morefavorableclinicalandbiologicalprofilesassociatedwith lower cardiovascular riskfactors, including low BMI, waist circumference,heartrate,bloodpressure,fastingtriglycerides, fasting glucose, plasma LDL-cholesterol and high levels of plasmaHDL-cholesterol(Hanseletal.,2010).
TheItalianLongitudinalStudyonAgingisacross-sectional multi-center study on 1896 menaged 65–84 years, mainly moderate wineconsumers (98%)asalifelonghabit. Partici- pants were divided into six alcohol consumption groups:
lifelong abstainers, ≤12g/day, 13–24g/day, 25–47g/day, 48– 96g/dayand>96g/day.Amongdrinkers,meandailyintakesof alcoholfromwine,beerandspiritswere26.7g/day,0.6g/day and 3.8g/day, respectively. Long-lasting moderate drinkers showedlowerlevelsofsystemicinflammatorymarkers,better hematologicalparametersandsafermetabolicandglycemic profiles.Inparticular,moderatealcoholconsumptioninolder agewasassociatedtolowervaluesoffibrinogenandinsulin resistance,andhigherlevelsofHDL-cholesterolandApoA-1 lipoprotein,evenifthispatternofdrinkingwasalsoassociated with higher LDL-cholesterol and systolic blood pressure (Perissinottoetal.,2010).
The relative importance of the main components of Mediterranean diet in producing the inverse association between increased adherence to this dietary style and all- causemortalitywasinvestigatedintheGreeksegmentofthe EuropeanProspectiveInvestigationintoCancerandnutrition (EPIC). The population of this prospective cohort study consisted of 23,349 men and women, without a previous diagnosisofcancer,coronaryheartdiseaseanddiabetes.After a follow-up of 8.5 years, the contributions of individual components ofMediterranean diet tothis associationwere moderate ethanol consumption(23.5%, men>10g/day and journalofappliedbiomedicine 12 (2014) 193–202
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<50g/day,women>5g/dayand<25g/day,mostlyintheform ofwineatmainmeals),lowintakeofmeatandmeatproducts (16.6%),highconsumptionofvegetables(16.2%),fruitandnuts (11.2%),monounsaturatedtosaturatedlipidratio(10.6%)and legumes(9.7%)(Trichopoulouetal.,2009).
Theassociationbetweenalcoholconsumptionandcoro- nary heart disease was investigated in the Spanish EPIC cohort.Participantsincluded15,630menand25,808women andthemedianfollow-upperiodwas10years.Subjectswho reportedanalcoholintakehigherthan5g/dayateither20,30, 40or50yearsofage,butnotduring the12monthspriorto recruitment were categorized as former drinkers. Never- drinkers weredefined as subjects who did not report any consumptionhigherthan5g/dayatanyageand0g/dayinthe 12monthspriortorecruitment.Alcoholintakewasclassified insixcategoriesformen(formerdrinkers,never-drinkers,low ethanolintakeof0–5g/day,moderateethanolintakeof5–30g/
day,highethanolintakeof30–90g/dayandveryhighethanol intakeofmorethan90g/day)andfivecategoriesforwomen (formerdrinkers,never-drinkers,lowethanolintakeof0–5g/
day,moderateethanolintakeof5–30g/dayandhighethanol intakeof 30–90g/day). Inmenaged29–69years, moderate, high and very high ethanol consumptionswereassociated witha reduced cardiovascular risk, with a morethan 30%
lowerincidenceof coronaryheart disease. Thisassociation wasonlystatisticallysignificantinmen,probablyduetothe low number of coronary heart disease cases in women (N=128).Thetypeofalcoholconsumed(wine,beer,fortified wines)didnotaffecthazardratios(Arriolaetal.,2010).
TheTurkishAdultRiskFactorStudyprospectivelyassessed the long-term impact of alcohol consumption on different outcomes, in3443 menand women (mean age 47.6 years) includedatbaselineandfollowed-upforameanof7.4years.
End-pointsincludedoverallmortality,coronaryheartdisease, diabetesand metabolic syndrome.Dailyalcoholintakewas categorizedasfollows:lightdrinking,lessthan1drink(1unit ofalcohol,i.e.30mLspiritsor300mLbeeror120mLwine);
moderatedrinking,1to3unitsofalcohol;heavydrinking,>3 units. Heavy alcohol consumption increased the risk for diabetes, coronary heart disease and, in men, all-cause mortalityandmetabolicsyndrome,evenifwithoutastrong statisticalsignificance.Conversely,moderateintakeofalcohol was not associated with any adverse outcome, but it was associated to a borderline decrease of cardiovascular risk, overallmortalityand,inwomen,toasignificantlylowerrisk for metabolicsyndrome. Interestingly, 62% of ethanol con- sumedinTurkeyisasbeer,morethan30%asspiritsandonly 5%aswine,averydifferentdrinkingpatterncomparedwith populationsofSouthEurope(Italy,FrenchandSpain),where winepredominates(Onatetal.,2009).
Associationof alcohol consumptionandcardiovascular disease outcomes has been investigated in systematic reviews and meta-analysis. Data from 84 eligible studies reportedarelativerisk (RR),formoderatealcohol drinkers comparedwithnon-drinkers,of0.75,0.71and0.75referringto cardiovascular disease mortality, incident coronary heart diseaseandcoronary heartdiseasemortality, respectively (Ronksleyetal.,2011).Inanothermeta-analysis,apreviously reportedJ-shapeddose–responserelationshipbetweenwine and alcohol consumption and the risk of cardiovascular
eventsandall-causemortalitywasconfirmed(Costanzoetal., 2011).InJ-shapedcurve,regularandmoderatewinedrinking,at the nadirof J, is beneficial, whereas abstinence and heavy intake, on the short and long arm, respectively, are both detrimental,thoughtoadifferentextent(DiCastelnuovoetal., 2002).Ameta-analysisof34prospectivecohortstudies,with morethan1millionsubjectsandalmost100,000deathbyany cause, showeda J-shapedassociation betweenself-reported alcoholconsumptionandmortality(DiCastelnuovoetal.,2006).
Anotherstudyreportedthatthemaximumintakeofwineat whichprotectionwasstillapparentdecreasedfrom72to66orto 41g/day wheneither combinedfatal andnon-fatalvascular events, or cardiovascular mortality or total mortality were consideredasendpoints,respectively.Theminimaldosesof wineatwhichitsmaximalprotectioncouldbeobtainedwere21, 24and10g/dayforthethreerespectiveendpoints(Costanzo et al., 2011). The same authors described a J-shaped dose- responsecurveinpatientswithcardiovascularrisk,withlightto moderatealcoholconsumption(5–25g/day)significantlyasso- ciatedwithalowerincidenceofcardiovascularandall-cause mortalities(Costanzoetal.,2010).
Finally,ameta-analysisofinterventionalstudieswasalso carried out. The effects of alcohol consumption on 21 biomarkersassociatedwiththeriskofcoronaryheartdisease were investigated in adults without known cardiovascular disease. Alcohol significantly increased the levels of HDL- cholesterol, ApoA-1 and adiponectin, but a dose–response relationwasobservedonlyforalcoholandHDL-cholesterol.
Alcohol decreased fibrinogen levels, but did not affect triglycerideconcentrations.Analyseswerestratifiedbytype of beverage(wine,beerandspirits),butresultsweresimilar (Brienetal.,2011).
Discussion
Despite the main evidences are related to variations of surrogatefactorsorriskfactors,suchasseruminflammatory mediators or functional studies and thus a conclusive statementisnotcompletelypossible,thepolyphenolcontent ofredwineappearstoovercomethe(detrimental)effectsof ethanol,atleastwhenconsideringaregularlighttomoderate red wine intake at main meals and not in a high risk population. Indeed,the balancebetweenthesetwocompo- nentsseemstobegreatlydependentonthespecifictypeof beverageconsidered,asnoticeablenotonlyinviewofwine overspirits orbeer(Estruchetal., 2004,2011;Chiva-Blanch etal.,2012a,2013b),butalsobycomparingwhiteandredwine, thelatter athighercontentof polyphenols(Sacanellaetal., 2007).Noteworthy,thecomparisonbetweenredwineandde- alcoholizedredwinedecreasedbloodpressureinpatientsat highcardiovascularrisk(Chiva-Blanchetal.,2012b),excluding atrialfibrillation.
Thesefindingscanbe,atleastinpart,explainedbycurrent evidences relatedtowinechemicals,thus wesupposethat beneficial effects of wine on reducing inflammatory and vascular biomarkerscouldbeascribednotonlytophenolic content,butalsotothepresenceofmanyotherphytochem- icals,suchasmelatoninandphytosterols,asrecentlyreported (Ruggieroetal.,2013;Vitalinietal.,2013).Melatoninprotects
against atherosclerosis-related cardiovascular diseases, resultingfromdirectfreeradical-scavengingactivity,indirect antioxidantpropertiesandanti-inflammatoryactivity(Favero et al., 2013). Similarly, phytosterols have been reported to reducethe riskof cardiovasculardiseases byinhibitingthe absorptionofintestinalcholesterolandre-circulatingendog- enousbiliarycholesterol,promotingitsexcretion(Dhankhar, 2013).
Another additional topic is related to the significant increaseofseveralpre-bioticbacteriaafterdailyconsumption ofredwine,associatedwithadecreaseofserumbiomarkersof cardiovasculardisease(Queipo-Ortuñoetal.,2012).Changesof bacterialpopulationappeartobecausedbywinepolyphenols, increasinggutmicrobiotaenergymetabolismwhich,inturn, enhances host lipid metabolism and triglyceride clearance (Queipo-Ortuñoetal.,2012).
A further element which strongly affects ethanol vs.
phytochemicalsequilibriumcanberelatedtogeneticfactors ofindividuals, on whatconcernsgenetic variantsencoding alcoholmetabolizing enzymes (alcoholand aldehydedehy- drogenases,AHDandALDH),resultinginalteredexposureto acetaldehyde,atoxicmetaboliteofethanol.Ifcarriersofthe AHD1Brs1229984A-alleleareassociatedwithamorefavorable cardiovascular profile (Holmes et al., 2014), other studies suggested the association of ALDH2 polymorphism with higher risk of coronary heart disease than other alleles (QuertemontandDidone,2006;Droganetal.,2012).
Onthebasisoftheseresults,aregularlighttomoderate intakeofredwinecanbeconsideringbeneficialforcardiovas- cularhealth.Asthematteroffacts,duringthelastdecades,the definitionof‘‘moderatealcoholconsumption’’changedover countries,correspondingtoagenerallydecreasedamountof ethanolconsidered(Chiva-Blanchetal.,2013b).
However,severallimitationscanbeobservedthroughout studies above reported, contributing to render decisive assertions more difficult. Firstly, a great methodological heterogeneity among different studies can be detected, resultingnot onlyfrom the outcomes considered, but also from the different amounts of ethanol and polyphenols containedindiversewines,usingdifferentgrapesandwine- makingtechniques.Their‘‘equilibrium’’potentiallychanges eachtimeanewtypeofwineistakenintoaccount.Secondly, mostof works didnotinvestigatethe role ofa furtherkey element influencing the effect of wine on cardiovascular system: the drinking patterns (Bagnardi et al., 2013b). As already concluded by Chiva-Blanch and co-workers, heavy and/orbingealcoholintakesareconfirmedtoberelevantrisk factorsforcardiovasculardiseases,whiletheeffectofalight wineintakeremains stillcontroversial (Chiva-Blanch etal., 2013a,b).
To elucidate this debate, a fullcomprehension of wine chemistryaswelltheroleofspecific(classof)compoundswill bepivotal.Biomedicine-related fields could address tothis topic, investigating ethanol and bioactive components, to comprehendwhichconstituentpredominates.Interestingly, environmental medicine which explores, among the other topics,theeffectsofdietonpathophysiologicalstates,willbe greatly enriched by studies on wine drinking and wine bioactivephytochemicals,alsoconsideringthegrowingrole ofthisbeverageallovertheworld(Berger,2011).Moreover,the
recentfindingsconcerningthepresenceofmelatonininwine wouldopenanewfieldofbiomedicalresearch,i.e.chronobi- ology (Berger, 2011), with the potential use of dietary melatonininregulatingcircadianrhythms.
Inordertoclarifywhetherwinerepresentsanindependent factorforcardiovasculardisease,futurestudiesshouldstratify investigations by ‘‘unique’’ intake of wine, as alcoholic beverage. If throughout interventional studies, long-term wineadministration isobviouslysubjectedtomanyethical restrictions, bothinhealthyanddiseasedsubjects,observa- tional studies need to be correctly interpreted, because of manybiasandconfoundingfactors,inordernottomisinter- pret random effect and cause–effect relationship. Indeed, additionalriskorprotectivefactors,suchassmokinghabitora dietrichinfruitandvegetables,respectively,couldinfluence results, as well as publication bias and the possibility of incorrectreportingofalcoholconsumption,mainlyindefining differentdrinkingpatterns.
Conclusions
Thestudiesexaminedinthissurveysuggestasredwinemay conferan'addedvalue'comparedtootheralcoholicbeverages, particularly spirits (Fig. 4). As regards cardioprotection, experiments usingwine,de-alcoholizedwineandspirits,in conditions of moderate intake, point to health benefits deriving from polyphenols and, possibly, other bioactive phytochemicalsthatmaycounteractthedetrimentaleffects ofethanol.Ontheotherhand,becauseofthepositiveeffectsof lowamountsofalcoholonHDL-cholesterolandhaemostatic factors,ethanolandpolyphenolsmayalsoexertadditiveand/
or synergistic protective effects on cardiovascular system (Hanseletal.,2012;LiandFörstermann,2012).
However,evenifresultsfromclinicaltrialsrepresentthe highestlevelofevidenceinmedicine,studiesinhumanshave someintrinsicandenvironmentallimitations.Forinterven- tionalstudies,wineadministrationis,obviously,subjectedto many ethical limitations, both in healthy and diseased subjects.Similarly,observationalstudieshavetobeproperly interpretedbecauseofmanybiasandconfoundingfactors,in order not to misinterpret random effect and cause–effect relationship.Forinstance,Mediterraneanpopulationsseemto bemorephysicallyactivethanthenorthEuropeancounter- part, evenonlyfor climaticconditions.Anotherexample is relatedtowinedrinkers,whichseemtobemorehealthfanatic thanbeerorspiritconsumers.Theseaspectsmay‘‘confound’’
thescenariowheretheclinicalstudiesareconducted.
Toconclude,wewouldliketofurtherclarifytheissueof 'regular, low to moderate red wine consumption at main meals'.Thissentenceindicatesthatbothpatternandamount and wine intake are relevant. Episodic heavy (or binge) drinking is considered more harmful that consumption of lessthanorequalto2drinksperday,butmorethan0,formen, andlessthanorequalto1drinkperday,butmorethan0,for women(Stockley,2012;Chiva-Blanchetal.,2013b).Lastly,red winepolyphenols,independentlyfromethanol,reducedthe pro-oxidant effects of a fat-rich meal, thus reducing the postprandialsusceptibilityofLDLtooxidation(Natellaetal., 2001).
journalofappliedbiomedicine 12 (2014) 193–202
199
Conflict of interests
Theauthorsdeclarenoconflictofinterest.
Acknowledgements
Authorsaregratefultotheirinstitutionsforfinancialsupport.
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