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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
This peer-reviewed article was published immediately upon acceptance. It can be downloaded, printed anddistributed freely for any purposes (see copyright notice below).
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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
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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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
Figure1.Structuralskeletonofflavonoidsandclassificationhierarchyofcommonflavonoids
[INSERTFIGURE1][Captionbelow]*Flavanolisthepredominateclassofflavonoidfoundincocoaandchocolate
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Dingetal. ChocolateCVD
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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Dingetal. ChocolateCVD
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