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Nutrition & Metabolism

This Provisional PDF corresponds to the article as it appeared upon acceptance. The fully-formattedPDF version will become available shortly after the date of publication, from the URL listed below.

Chocolate and Prevention of Cardiovascular Disease: A Systematic Review

Nutrition & Metabolism2006, 3:2 doi:10.1186/1743-7075-3-2

Eric L Ding ([email protected])Susan M Hutfless ([email protected])

Xin Ding ([email protected])Saket Girotra ([email protected]

)

ISSN 1743-7075

Article type Review

Submission date 23 Sep 2005

Acceptance date 3 Jan 2006

Publication date 3 Jan 2006

Article URL http://www.nutritionandmetabolism.com/content/3/1/2

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Dingetal. ChocolateCVD

ChocolateandPreventionofCardiovascularDisease:ASystematicReview

EricL.Ding*,SusanM.Hutfless,XinDing,SaketGirotra

DepartmentofEpidemiology(E.L.D,S.M.H.,X.D.),HarvardUniversity,SchoolofPublicHealth,

Boston,MA,USA

DepartmentofNutrition(E.L.D.),HarvardUniversity,SchoolofPublicHealth,Boston,MA,USA

DepartmentofMedicine(S.G.),MedicalCollegeofWisconsin,Milwaukee,WI,USA

*Correspondence:

EricL.Ding

DepartmentsofEpidemiologyandNutrition

HarvardSchoolofPublicHealth

677HuntingtonAve,Kresge9thFloor

Boston,MA,02115UnitedStatesofAmerica

Tel:717-360-2725

Fax:617-566-7805

[email protected]


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Abstract

BACKGROUND:Consumptionofchocolatehasbeenoftenhypothesizedtoreducetheriskof

cardiovasculardisease(CVD)duetochocolateshighlevelsofstearicacidandantioxidant

flavonoids.However,debatestilllingersregardingthetruelongtermbeneficialcardiovascular

effectsofchocolateoverall.

METHODS:WereviewedEnglish-languageMEDLINEpublicationsfrom1966throughJanuary

2005forexperimental,observational,andclinicalstudiesofrelationsbetweencocoa,cacao,

chocolate,stearicacid,flavonoids(includingflavonols,flavanols,catechins,epicatechins,and

procynadins)andtheriskofcardiovasculardisease(coronaryheartdisease(CHD),stroke).Atotal

of136publicationswereselectedbasedonrelevance,andqualityofdesignandmethods.An

updatedmeta-analysisofflavonoidintakeandCHDmortalitywasalsoconducted.

RESULTS:Thebodyofshort-termrandomizedfeedingtrialssuggestscocoaandchocolatemay

exertbeneficialeffectsoncardiovascularriskviaeffectsonloweringbloodpressure,anti-

inflammation,anti-plateletfunction,higherHDL,decreasedLDLoxidation.Additionally,alarge

bodyoftrialsofstearicacidsuggestsitisindeedcholesterol-neutral.However,epidemiologic

studiesofserumanddietarystearicacidareinconclusiveduetomanymethodologiclimitations.

Meanwhile,thelargebodyofprospectivestudiesofflavonoidssuggeststheflavonoidcontentof

chocolatemayreduceriskofcardiovascularmortality.Ourupdatedmeta-analysisindicatesthat

intakeofflavonoidsmaylowerriskofCHDmortality,RR=0.81(95%CI:0.71-0.92)comparing

highestandlowesttertiles.

CONCLUSIONS:Multiplelinesofevidencefromlaboratoryexperimentsandrandomizedtrials

suggeststearicacidmaybeneutral,whileflavonoidsarelikelyprotectiveagainstCHDmortality.

Thehighestprioritynowistoconductlargerrandomizedtrialstodefinitivelyinvestigatetheimpact

f h l t ti l t di l t


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Introduction

Cardiovasculardisease(CVD),asagroup,isaleadingcauseofthedeathintheUnitedStates

[1],andworldwide,causingover16.7milliondeathsgloballyin2002[2].In1990,greaterthan

85,000,000disability-adjustedlife-yearswerelostworldwideduetocoronaryheartdisease(CHD)

andstroke;thisCVDdiseaseburdenisprojectedtoriseto143,000,000disability-adjustedlife-years

by2020[2].Studiessuggestcardiovasculardiseasesmaybepreventablebylifestylemodifications,

suchasexerciseandnutrition[3-7].Additionally,theAmericanHeartAssociation,American

DiabetesAssociation,andtheU.S.PreventiveServicesTaskForcehaveeachindicatedthelikely

importanceofdietforthepreventionofCVD[8-10].

IntheAmericandiet,fruits,vegetables,tea,wineandchocolatearemajorsourcesof

antioxidants,whichhavebeenshowntohaveprotectiveeffectsagainstCVD[11,12].Oneclassof

antioxidants,flavonoids,commonlyfoundinsuchfoods,haveattractedgreatinterestinpotentially

loweringriskofCVD.Sincecocoaproductscontaingreaterantioxidantcapacityandgreater

amountsofflavonoidsperservingthanallteasandredwines[12,13],itisimportanttoexplore

chocolatespotentialeffectsonCVD.

Sinceancienttimes,chocolatehaslongbeenusedasamedicinalremedy[14]andbeen

proposedinmedicinetodayforpreventingvariouschronicdiseases[15,16].Whilechocolatehas

alsosometimesbeencriticizedforitssaturatedfatcontent,mostlyintheformoflong-chainstearic

acid,chocolatehasalsobeenlaudedforitsantioxidantpotential.However,tothisdatethereareno

long-termrandomizedfeedingtrialsofchocolatetoassesseffectsonactualcardiovascularevents.

Nevertheless,therehavebeenmanyshort-termtrialsofcocoaandchocolateexaminingeffectson

cardiovascularintermediates,andnumerousepidemiologystudiesofstearicacidandflavonoids

exploringassociationswithcardiovascularoutcomes.

Thi t ti i t h i l l t th i t l d


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potentialbenefitsofthechocolatecomponentsstearicacidandflavonoids;reviewtheiroverall

effectsonCVDriskfactorintermediatesandCVDendpoints;andconductameta-analysisoftotal

flavonoidintakeandriskofCHDmortality.

Methods

WereviewedEnglish-languageMEDLINEpublicationsfromJanuary1965throughJune

2005forexperimental,observational,andclinicalstudiesofrelationsbetweentheexposuresearch

termsofchocolate,stearicacid,flavonoids(includingflavonols,flavanols,catechins,epicatechins,

andprocynadins)andtheoutcomesearchtermsofcardiovasculardisease(coronaryheartdisease,

ischemicheartdisease,stroke),cholesterol,bloodpressure,platelet,oxidation,andthrombosis.

Approximately400paperswerereviewed.Basedontherelevance,strength,andqualityofthe

designandmethods,136publicationswereselectedforinclusion.

Wemainlyfocusedonstudiesinhumans,particularlyrandomizedtrialsofeitherparallelor

cross-overdesign,andprospectiveobservationalstudies.Sincenorandomizedtrialshaveyet

assessedchocolateinrelationtodefinitiveCVDoutcomes,prospectiveobservationalstudies

evaluatingchocolatesub-componentsandtheriskofCVDoutcomeswereweightedequallyinthe

overallevaluation.Foroverallobjectiveevaluation,thestrengthoftheevidencewasevaluatedby

thedesignandqualityofindividualstudies,theconsistencyoffindingsacrossstudies,andthe

biologicplausibilityofpossiblemechanisms.Finally,consistentwithmethodsoftheoutdatedprior

analysis[17],anupdatedmeta-analysiswasconductedandrelativerisksestimatespooledusinga

random-effectsmodel[18].

Review

St i id i h l t


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Saturatedfathaslongbeenthoughttocontributetoatherosclerosis,andthus,adversefor

CVDrisk.However,stearicacidhasbeensuggestedtobeanon-atherogenictypeofdietary

saturatedfat.Stearicacidisalong-chain18:0saturatedfattyacidfoundcommonlyinmeatsand

dairyproducts.Cocoabutter,afatderivedfromcocoaplantsandpredominantlyfoundindark

chocolate[19],containsanaverageof33%oleicacid(cis-18:1monounsaturated),25%palmiticacid

(16:0saturated),and33%ofstearicacid[20].Thoughtitisgenerallyconsideredthatsaturatedfats

overalladverselyincreasethetotalcholesterolandLDLlevels[21-23],earlystudieshavealso

suggestedstearicacidmaybenon-cholesterolemic[21,22].Thishasbeenconfirmedinaseriesof

studiesandameta-analysisof60controlledfeedingtrialswhichconcludesstearicacidneither

lowersHDL,norincreasesLDLortotalcholesterol[24-28].Themeta-analysisalsoestimates,that

per1%energyisocaloricreplacementofstearicacidforcarbohydrates,stearicacidintakeis

predictedtobeneficiallylowerserumtriglyceridesby-17.0nmol/L(p


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desaturationofstearicacidtomonosaturatedoleicacid[35,42-45],afatconsidered

hypocholesterolemic[27,46-48]andprotectiveagainstcoronaryheartdisease[3,49].

Twootherpathwayssuggestedforpotentialbenefitarestearicacidspotentialanti-platelet

andbloodpressurereductionsactions.Feedingtrialshaveshownthatstearicacidreducesmean

plateletvolume[50,51],anindexofplateletactivation.However,mixedfindingshavebeen

observedregardingtherelationshipbetweenstearicacidsandfactorVIIccoagulationfactor,a

predictoroffatalCHD[52-54].Thoughanearlystudysuggestedthatstearicacidmayincrease

factorVIIc[55],noeffectonlevelsoffactorVIIcbystearicacidwasobservedintwoothertrials

[56,57].Moreover,additionaltrialshaverefutedtheearliersmallstudyand,infact,shownthat

stearicacidloweredthelevelsoffactorVIIccoagulationfactorcomparedtopalmitic[50,58]and

othersaturatedfattyacids[58].Asfortherelationshipbetweenstearicacidandbloodpressure,two

feedingtrialsfoundstearicaciddidnotadverselyaffectsystolicbloodpressure[28,59].

Furthermore,cross-sectionalanalysiswithintheMultipleRiskFactorInterventionTrialevenfound

stearicacidlevelsmaybeinverselyassociatedwithdiastolicbloodpressure[60].

Insummary,giventhevastmajorityofstudiesshowingstearicacidhasbeneficialorneutral

effectsonbloodpressuresandclottingparameters,itappearsunlikelystearicacidintakewould

adverselyaffectCVDriskthroughtheseriskfactors.Dataindicatesstearicaciddoesnotadversely

affectestablishedtraditionallipidriskfactors,withevenfavorableloweringofserumtriglyceridesif

isocaloricallyreplacedforcarbohydrates.

StearicAcidObservationalStudies.However,theobservationalstudiesofstearicacids

associationwithCVDareinconclusive.(Table2)Amongretrospectivestudies,aJapanesecase-

controlstudyofserumlevelsreportednoassociationforstenosis[61],aNorwegianstudyfound

loweroddsofMI[62],whileaCostaRicanstudyofdietaryintakefoundhigherriskofMI[63]with

hi h i t k f t i id H th lt f th C t Ri t d h ld t b i


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susceptibletoreportingbias[64].Nevertheless,higherratesofCHDandCADprogressionwas

foundinseveralprospectivestudies[65-68],whilestrokewasnotincreasedinanotherstudy[69].

Ontheotherhand,severallimitationsexistforobservationalstudiesofstearicacid.First,

researchershavecautionedthatanalysesofdietarystearicacidareverydifficultduetohigh

correlationsofstearicacidintakewithotherfattyacids(oftenr=0.7to0.9),thusimpedingoptimal

studyofassociations[65].Additionally,thelargerprospectivestudythatfoundhigherriskofCHD

alsonotedchocolatewasaverysmallcontributor(5%)oftotalstearicacidintake,withredmeatsas

primarysourcesofstearicacid.Finally,sincethereexistshighinterconversionofstearicacidto

unsaturatedfattyacids[35,42-45],studiesinvolvingserumlevelsofstearicaciddonotanswerthe

relevantcausalquestionofdietaryintakeofstearicacidandriskofdisease.Theassociationsof

long-termserumstearicacidlevelsrepresenttheeffectsofpost-conversionstearicacidlevelsaftera

largeproportionoftheoriginaldietarystearicacidhasalreadybeenconvertedawayto

monounsaturatedfat,whichiswell-establishedtoexertprotectiveeffectsagainstCVD[3,27,46-

49].

Thus,relativelylittleinformationcanbeinferredfromobservationalstudiesofthe

associationofstearicacidandCHD,andnoepidemiologicstudyhas,thusfar,appropriatelyand

optimallyansweredthecausalquestionoftheassociationofdietarystearicacidintakeandriskof

CVD.However,asufficientbodyofstrongevidencefromshorttermrandomizedtrialssuggests

stearicacidcomponentsinchocolatemaybebeneficialforcardiovascularhealth.However,further

researchinthisareaiswarranted.

Flavonoidsinchocolate

A100gbarofmilkchocolatecontains170mgofflavonoidantioxidants,procyanidinsand

flavanols[12].ItisestimatedthatchocolateisaleadingsourceofprocyanidinintakeinWestern


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plants[72].ThebasicstructureofflavonoidsisaC6-C3-C6backbonewithtwoarmomaticringsand

varyingdegreesofhydroxylationdifferentiatingoneflavonoidtypefromanother[73].Flavonoids

canbedividedintovarioussubclasses,importantofwhichareflavones,flavonols,flavanones,

catechins,anthocyanidinsandisoflavones.Cocoa,isparticularlyrichintheflavonoids,epicatechin,

catechin,andprocyanidins(polymersofcatechinsandepicatechins)[74].(Figure1)

Variousstudieshavecomparedthecontentoftheflavanoidsincocoawithotherfoodstuffs

quantitatively.Figure2showsthecomparativecontentofflavonoidsinmilkchocolateanddark

chocolateversusotherhigh-flavonoidfoods.Cocoahasbeenshowntohavethehighestcontentof

polyphenols(611mg/serving)andflavanoids(564mg/servingofepicatechin),greaterthaneventea

andwine[13].Perserving,darkchocolatecontainssubstantiallyhigheramountsofflavonoidsthan

milkchocolate(951mgofcatechinsper40gservingcomparedto394mginwhitechocolate)[75],

andlevelsofepicatechinindarkchocolateiscomparabletoredwineandtea[75].Alsoofnote,dark

chocolatecontainssignificantlygreateramountsoftotalphenolsaswellascatechinsthanmilk

chocolateperserving(126+-7.4mol/gvs.52.2+-20.2mol/g)[75].Inadditiontodarkchocolate

havinghigherflavonoidcontent,thebiologiceffectsofflavonoidsmayalsobegreaterindark

chocolatebecausemilkinmilkchocolatemayinhibittheintestinalabsorptionofflavanoids[76].

Finally,chocolateisalsoabundantinprocyanidinflavonoids,comparablewithlevelsin

procyanidin-richapples[77].Thus,chocolateisarichsourceofflavonoids,particularlycatechins,

epicatechinsandprocyanidins.

Mechanisms.Chocolateflavonoidshaveshowngooddose-responsebioavailabilityin

humans[11,78,79].Thereexistsseveralmechanismsofhowflavonoidsmaybeprotectiveagainst

CVD;theseinclude:antioxidant,anti-platelet,anti-inflammatoryeffects,aswellaspossibly

increasingHDL,loweringbloodpressure,andimprovingendothelialfunction.Thebodyoftrials

i l i h l t fl id i i d i T bl 1


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Centraltothepathogenesisofatherosclerosisistheoxidationoflow-densitylipoprotein

(LDL).Thechemicalstructureofflavonoidsgivesthecompoundfreeradicalscavengingability,

whichmeansflavonoidsmayhaveantioxidanteffects[80].Variousstudieshaveconfirmedtherole

offlavanoidsasantioxidantsinbiologicalsystems.Flavanoidsinchocolatehavebeenshownto

exertpotentantioxidanteffectsinvitroassaysunderartificialoxidativestress[13,81-84]aswell

increaseantioxidantcapacityaspartofvariouschocolatefeedingtrials[79,85-89].Additionally,

becauselipidsolubleflavonoidsmayintercalateintothemembranesoflipoproteinparticles,studies

haveshownflavonoidstodecreaselipidperoxidationofbiologicalmembranes[90].Furthermore,a

randomizedtrialalsodemonstratedthatflavonoid-richfoodscanprotecthumanlymphocytesfrom

oxidativedamageinvivo[91].

Additionally,aggregationofplateletsatthesiteofplaqueruptureandendothelial

dysfunctionhasbeenimplicatedinthepathogenesisofatherosclerosis.Currentresearchhasshown

thatanumberofcomponentsofchocolate,particularlycatechinandepicatechin,havesignificant

antiplateleteffects,quantitativelysimilartothatofaspirin[92].Randomizedtrialsstudyingplatelet

activationmarkers,microparticleformationandprimaryplateletaggregationasendpointshave

foundthatdailyintakeofcocoabeveragesproducesasignificantreductioninalltheseendpoints

amonghealthyvolunteers[93-96].Therewerealsosignificantcorrelationsbetweenthereductionin

theseendpointsandtheplasmaconcentrationsofcatechinandepicatechin[93-96].Anotherstudy

foundasignificantreductioninplateletactivationingroupsconsuming100gofdarkchocolatewhen

comparedtothoseconsumingsimilaramountsofwhitechocolateandmilkchocolate[97].In

addition,randomizedtrialshavealsoshownthatconsumptionofhigh-flavanoiddarkchocolateis

associatedwithasignificantimprovementofendothelialfunction,markedbyincreaseinbrachial

arteryflowmediateddilation[98-100],likelymediatedbychocolateflavonoidsincreasinglocal

d ti f it i id [99 100]


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Chocolatemayalsoinfluencelevelsofleukotrienesandprostacyclins.Leukotrienesare

potentvasocontrictors,proinflammatoryagentsandstimulateplateletaggregation,whereas

prostacyclinisavasodilatorandinhibitsplateletaggregation.Consumptionofchocolatewithhigh

procyanidincontent(147mg)wasshowninafeedingtrialtosignificantlylowerthelevelsof

leukotrienes(29%)andincreasethelevelsofprostacyclin(32%)whencomparedtoagroup

consumingalowprocyanidin(3.3mg)chocolate[101].Invitrostudieshaveindeeddemonstrated

chocolatecomponentstoinhibitlipoxygenasepathways,whichgivesrisetoproinflammatory

leukotrienes[102,103].Inflammationisnowrecognizedasanotherindependentmechanisminthe

pathogenesisofatherosclerosis,withvariousinflammatorymarkershavingbeenshowntopredict

riskoffutureCVDevents[104-108].Inadditiontoanti-inflammatoryeffectsonthelipoxygenase

pathway,cocoapolyphenolshavealsobeenshowntodecreaseinflammationviaseveral

mechanisms,namely:inhibitionofmitogeninducedactivationofTcells,polyclonalactivationofB

cells,reducedexpressionofinterleukin-2(IL-2)messengerRNA,andreducedsecretionofIL-2byT

cells.[109]Otherhavealsofoundchocolateprocyanidinscanmodulateofavarietyofother

cytokines(e.g.IL-5,TNF-,TGF-),reducingtheirinflammatoryeffects[110-114].

Furthermore,multiplecocoafeedingtrialshavealsofoundchocolatetoincreaseHDL

cholesterol[85,86,115],anddecreasebloodpressure[116-119].Finally,therearealsosuggestive

findingsinafewtrialsthatindicatehigh-flavonoidchocolatemayalsolowerLDLcholesterol[119],

andimproveinsulinsensitivity[116].

Thus,thelargebodyofevidencefromlaboratoryfindingsandrandomizedtrialssuggestthat

high-flavonoidchocolatemayprotectagainstLDLoxidation,inhibitplateletaggregation,improve

endothelialfunction,increaseHDL,lowerbloodpressure,andreduceinflammationthereby

protectiveagainstriskofCVD.

Fl id Ob i l S di M h i i di i l i i id d fl id


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assumeeffectsfromshorttermtrialseffectswillnecessarilytranslateintolongtermeffectsonCVD

outcomes.Therefore,oneneedstoexamineobservationalstudiesfollowedtoCVDevents.While

onesmallstudyfoundmoderateconsumptionofcandyandchocolatewasassociatedwithlowerall-

causemortality[120],thisanalysisneitherisolateschocolatenorCVDevents.Thus,inabsenceof

specificstudiesofchocolateflavonoidsandriskofCVD,studiesofallflavonoidsarethebest

availableevidencetoinferrisk.

TheprospectivestudiesofflavonoidsandriskofCVDaresummarizedinTable3.The

earliestinternationalecologicstudysuggestedflavonoidintakemaybeassociatedwithlowerrates

ofCHDmortality[121].WhilesomestudiesreportflavonoidintakeisnotassociatedwithCHD

incidence[122-124],twootherprospectivestudiessuggestedflavonoidsmaylowerriskofMI[125,

126].Forstroke,theevidenceisfairlyconsistent.Otherthanonesmallearlystudywhichfounda

significantlylowerriskofstrokewithhighertotalflavonoidintake[127],moststudiesindicatedno

associationforriskofstroke[124,128-130].However,mostofthesestudieshadinsufficientpower

toadequatelystudystroke,norenoughpowertostratifyonvarioussubtypesofstrokewithdifferent

etiologies.

However,themostextensivelyconsistentfindingistheassociationbetweenflavonoidintake

andCHDmortality.AtotalofeightcohortstudiesfoundriskoflowerCHDmortalitywithtotalor

specificflavonoidintake[71,121,123,125,126,128,130-132],withonestudyfindingmarginally

protectiveassociationamongmenwithpriorCVDconditions[123].Onlyonestudyreported

absolutelynoassociationbetweenflavonoidintakeandCHDmortality[133].However,asnotedby

theauthorsofoneofthestudies,ahighbackgroundconsumptionofmilkwithteaintakemayhave

ledtothenullfinding[133],sincemilkintakehasbeenshowntopreventtheintestinalabsorptionof

flavonoids[76].

A t l i f th 7 ti t di i t S t b 2001 f d th t ll


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includealargesubsequentcohortstudyof38,445women[124],whichfoundanon-significant

inverseassociationbetweenflavonoidintakeandCHDmortality.However,resultsfromourupdated

meta-analysisstillindicateasignificantprotectiveassociationexistsbetweenflavonoidintakeand

riskofCHDmortality,RR=0.81(95%CI:0.71-0.92),comparinghighestvs.lowesttertiles.

However,alimitationofinferenceexistsinthatflavonoidsconsistsofawidevarietyof

polyphenolcompounds,thevarietyofwhichmaydifferbetweenstudiesduetovaryingsourcesof

dietaryflavonoids.Nonetheless,darkchocolatedoescontainsubstantiallymoreflavanolsthantea,

apple,onions,andredwine[12].Additionally,chocolatehasalltheflavonoidsoftea[134],has4

timesthecatechinsoftea[134],hasmanyflavonoidsnotfoundintea[135],andsubstantially

contributestothetotalflavonoidintakeinthedietofmanycountries[136].However,inferencefrom

observationalstudiesontheprotectiveeffectofflavonoidsinchocolateonCVDriskissomewhat

indirectandmayneedtobeexaminedbyfurtherstudies.

Overall,theseepidemiologicfindings,combinedwiththelargebodyofevidencefromshort

termrandomizedchocolatefeedingtrials,suggestsflavonoidintakefromchocolateislikely

protectiveagainstCVD,particularlyCHDmortality.Additionally,giventhatdarkchocolatehas

substantiallyhigherlevelsofflavonoidsthanmilkchocolate,andthatmilkmayinhibitabsorptionof

flavonoidsitwouldbemoreprudenttoconsumehighflavonoiddarkchocolateratherthanmilk

chocolate.

Conclusion

AccordingtotheInternationalCocoaOrganization,productionhasrisenfrom1.2million

tonsperyearin1960to3.2milliontonsperyearin2004[137].Giventherapidlyincreasingworld

consumptionofchocolateandrisingglobalratesofCVD,itisimportanttoestablishchocolates

i ti ith CVD i k Th j t d i i l b l ti ld h f d


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Baseduponoursystematicreview,multiplelinesofevidencefromlaboratoryexperiments

andrandomizedtrialssuggeststearicacidmaybeneutral,whileflavonoidsarelikelyprotective

againstCVD,thelatterofwhichiswellsupportedbyprospectiveobservationalstudiesthatsuggest

flavonoidsmaylowertheriskofCHDmortality.Thoughithasbeenapproximatedthateating50gof

darkchocolateperdaymayreduceonesriskofCVDby10.5%(95%CI:7.0%-13.5%)[16],such

crudeestimateswerebasedonresultsfromstudiesofshortduration,extrapolatedtolongtermCVD

outcomes.Therefore,thehighestprioritynowistoconductlong-termrandomizedfeedingtrials,

beyondshorttermstudiesofCVDriskfactorintermediates,inordertodefinitivelyinvestigatethe

impactofchocolateconsumptiononcardiovascularoutcomes.


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23

Table1.SummaryofChocolateandCocoaFeedingTrials

Author Year

No.

Participants

Trial

Design Duration Intervention Outcome(s)

Kondo[83] 1996 12 Crossover

1meal,pre/post-

mealmeasurement Cocoa(35gdelipidated),vs.none DecreasedLDLoxidation

Rein[138] 2000 30 Parallel 1meal,2&6hrs

Cocoabeverage(300ml,19gprocyanidin),

caffeinatedbeverage(17mgcaffeine),orwater

Decreasedplateletactivation,decreasedplatelet

function

Wang[79] 2000 20 Crossover

1meal,1

week/phase

Procyanidin-richchocolate(27,53,80g),vs.

none

Increasedantioxidantcapacity,decreasedoxidative

stress

Osakabe[88] 2001 15 Parallel daily,2weeks Cocoapowder(36g/day),vs.sugar DecreasedLDLoxidation(increasedlagtime)

Wan[85] 2001 23 Crossover

daily,4

weeks/phase

Cocoapowder(22g/day)+darkchocolate(12

g/day),vs.averageAmericandiet

DecreasedLDLoxidation(increasedlagtime),

IncreasedHDLconcentration

Schramm[101] 2001 10 Crossover

1meal,2&6hrs,1

week/phase

Chocolate(35g,high4mg/gvs.low0.09mg/g

procyanidin)

Increasedprostacyclin,decreasedleukotriene(likely

decreasedplateletactivation,anti-inflammatory)

Holt[95] 2002 18 Crossover 1meal,2hrs Chocolatechips(25gsemi-sweet),vs.none Decreaseplateletfunction

Mathur[86] 2002 25 Crossover

daily,6

weeks/phase

Darkchocolate(37g/day),cocoapowder(31

g/day),vs.none DecreasedLDLoxidizability,marginalHDLincrease

Pearson[92] 2002 16 Crossover

1meal,1

day/phase

Cocoabeverage(300ml,19gflavanolcocoa

powder),cocoabeverage+aspirin,oraspirin

Decreasedplateletactivation,decreasedplatelet

function,alladditiveofaspirineffects.

Heiss[99] 2003 20 Crossover

1meal,1

day/phase

Cocoabeverages(100ml,highorlowflavan-3-

ol) IncreasedNObioactivity,improvedendothelialfunction


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24

Innes[97] 2003 30 Parallel 1meal,4hrs

Dark(75%cocoa,highestflavonoidcontent),

milk(20%cocoa),orwhitechocolate(no

flavonoids)

Darkchocolateinhibitedcollagen-inducedplatelet

aggregation

Murphy[94] 2003 32 Parallel daily,28days Cocoaflavonoidtablets(234mg),vs.placebo

Decreasedplateletfunction,nodifferenceoxidation

status

Serrafini[76] 2003 12 Crossover

1meal,1

day/phase

Darkchocolate(100g),darkchocolate(100g)+

milk(200ml),or200gmilkchocolate Increaseantioxidantcapacity,inabsenceofmilk

Taubert[118] 2003 13 Crossover

daily,14

days/phase

Darkchocolate(100g,500mgpolyphenols),vs.

whitechocolate(90g,0mgpolyphenols)

Lowersystolicanddiastolicbloodpressurewithdark

chocolate

Wiswedel[90] 2004 20 Crossover

1meal,1week

washout

Highflavanol(1.87mg/ml)vs.lowflavanol

(0.14mg/ml)cocoabeverage

Lowerlevelsoflipidperoxidationindicatorswithhigh

flavanolcocoabeverage

Engler[98] 2004 21 Parallel daily,2weeks Chocolate(highvs.lowflavonoid)

Improvedendothelialfunction,nodifferenceoxidative

stress,lipidswithhighflavonoidchoc.

Mursu[115] 2004 45 Parallel daily,3weeks

Darkchocolate,darkchocolateenrichedwith

cocoapolyphenols,orwhitechocolate

IncreasedHDLconcentration,nochangeLDL

oxidizability

Grassi[116] 2005 15 Crossover

daily,15

days/phase

Darkchocolate(100g,500mgpolyphenols),vs.

whitechocolate(90g,0mgpolyphenols)

Lowersystolicbloodpressure,improvedinsulin

sensitivity,lowerinsulinresistance

Zhu[139] 2005 8 Parallel 1meal,1-2-4-8hrs

Cocoabeverage(highflavonoid);0.25,0.38,

0.50g/kgbodyweightdose

Reducedsusceptibilitytofree-radicalinduced

hemolysis

Vlachopoulos[140] 2005 17 Crossover

1meal,1

day/phase

Darkchocolate(100g,2.62gprocyanidin),vs.

none

Improvedendothelialfunction,vasodilationofbrachial

artery,nochangeinbloodpressure

Fraga[119] 2005 28 Parallel daily,14days

Highflavanolmilkchocolate(105g,168mg

flavanols)vs.lowflavonoidchocolate(


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Table2.ObservationalStudiesofStearicAcidandCardiovascularOutcomes

Author Year Studydesign N,PopulationStearicacidassessmentmethod

CHD/MIOutcomes Other

Kromhout[141] 1995 Ecologic12,763men,16cohortsof7CS Dietaryintake CHDmortality

Simon[68,69] 1995 Prospective96cases,96controls,USA-MRFIT Serumlevels CHDincidence

Null-strokeincidence

Watts[67] 1996 Prospective 50men,Australia Dietaryintake CADprogression

Hojo[61] 1998 Case-control71cases,60controls,Japan Serumlevels Null-stenosis

Hu[65] 1999 Prospective80,082women,USA-nurses Dietaryintake CHDincidence

Yli-Jama[62] 2002 Case-control103cases,104controls,Norway Serumlevels MIincidence

Kabagambe[63] 2003 Case-control485cases,508controls,CostaRica Dietaryintake MIincidence

Wang[66] 2003 Prospective3591whites,USA Serumlevels CHDmortality

Abbreviations:7CS,7CountriesStudy;MRFIT,MultipleRiskFactorInterventionTrial;*HighstearicacidlevelamongmenfromgeographicareasofhighIHDmortality


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Figure1.Structuralskeletonofflavonoidsandclassificationhierarchyofcommonflavonoids

[INSERTFIGURE1][Captionbelow]*Flavanolisthepredominateclassofflavonoidfoundincocoaandchocolate


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Figure2.Flavonoidcontentandantioxidantcapacity(ORAC)ofmilkchocolateanddarkchocolateversusotherhighflavonoidfoods

[INSERTFIGURE2][Captionbelow]*Brewed,per2gbag/200mlwater Antioxidantactivityisreportedasoxygenradicalabsorbancecapacity(ORAC)Adaptedfrom:Steinbergetal.JAmDietAssoc103:215-23.

Ding et al Chocolate CVD


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28

Table3.ProspectiveStudiesofFlavonoidsandCardiovascularOutcomes

Author Year Studytype N,PopulationFollow-upYears

FlavonoidType

CHD/MIIncidence

CHD/MIMortality

StrokeMortality Comments:

Hertog[125,142]*,Keli[127]

1993,1996 Prospective

552to806Men,Dutch

5,then10*

TotalFlavonoids

*Update1997analysisfindsevenstrongerCHDassociation[142]

Knekt[131] 1996 Prospective5133M+W,Finland 26

TotalFlavonoids

Rimm[123] 1996 Prospective 34789Men,USA 6TotalFlavonoids Null *

*marginalsignificance,ifpasthistoryofCVD

Hertog[133] 1997 Prospective 1900Men,UK 14TotalFlavonoids Null *

*marginalsignificance,*milkconsumedw/tea

Yochum[130] 1999 Prospective34492PostMwomen,Iowa 10

TotalFlavonoids Null

Hirvonen[126,129]2000,2001 Prospective

23596Men,Finland 6.1

TotalFlavonoids MI * Null

*suggestive,butnon-significant

Arts[143] 2001 Prospective 806men,Dutch 10Catechins(Flavonoid) Null

Arts[128] 2001 Prospective34492PostMwomen,Iowa 13

Catechins(Flavonoid)

Geleinjse[122] 2002 Prospective4807M+W,Dutch 5.6

TotalTeaFlavonoids Null

Knekt[132] 2002 Prospective10054M+WFinland 28

Specificflavonoids

alsotype2diabetes

Sesso[124] 2003 Prospective38445women,USA 6.9

TotalFlavonoids Null Null Null

META-ANALYSIS(updated)** TotalFlavonoidsCHDMortality RR=0.81(95%CI:0.71-0.92)* (extremetertiles)

**Updatedmeta-analysisincludes:allstudiesoftotalflavonoidsandCHDmortality;comparisonoftopvs.bottomtertile.


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Figure 1


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Figure 2

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