NontraditionalRiskFactorsforCardiovascularDiseaseinDiabetesEndocrineReviews2004;25(1):153-75.內(nèi)分泌新陳代謝科楊純宜醫(yī)師IntroductionType2DMdisproportionatelyaffectedbyCVD.Increasedprevalenceofestablishedriskfactors,suchasobesity,dyslipidemia,andHTN,inpersonswithDMTraditionalriskfactorsdonotfullyexplaintheexcessriskforCHDassociatedwithDMOthernon-traditionalriskfactorsmaybeimportantinDMSeveraltherapeuticstrategiescurrentlyusedcanimprovenontraditionalriskfactors,e.g.statinsreducemarkersofinflammationinplasma,insulinsensitizershavevarietyeffectonmanytheseriskfactors.NontraditionalriskfactorsFrequentlyclusterinindividualptsandpossiblyinteractwitheachother,othersappeartobeindependentofeachotherCVDisacomplexmultifactorialdiseaseandthatmanyoftheseprocessesarefunctioningsimultaneously.TheseriskfactorsprovideinsightsintothepathogenesisofCHDinDMManyriskfactorsreflectunderlyinginflammations,eithersecondarytoatherosclerosisitselformaypresentnonspecificinflammatoryresponsetoinfections(morecommoninuncontrolledDM)Thesefactorshavepotentialtoenhancecoagulationandthromboticprocess,perpetuatingthevasculardiseaseortriggeringvasculareventsNon-traditionalRiskFactorsManyoftheseriskfactorsmaybecommonantecedentsforbothDMandCHD,supportingthehypothesisthatbothdisordersariseseparatelyfrom“commonsoil“Possiblecommonantecedentsincludeinsulinresistance(IR)andinflammation,whichshowntobeindependentriskfactorsforCHDandtype2DM.Inflammation,endothelialdysfunction,andabnormalitiesofcoagulationareallassociatedwithIRandmaytherebybecomecommonantecedentsofbothCHDandDMTable1RiskfactorsforCVDindiabetesTraditional NontraditionalHypertension IRDyslipidemia EndothelialdysfunctionFamilyhistoryof Vascularreactivity,NOPrematureCVDCigarettesmoking ADMA Impairedfibrinolysis

PAI-1 Inflammation

hs-CRP,WBC Adhesionmolecules,MMP-9

Microalbuminuria

Hyperhomocysteinemia Postprandialabnormalities Vascularwallabnormalities IMT,calcification,ComplianceNaturalhistoryofvascularabnormalitiesinthepathogenesisofCVDinDMEarliesteventinatherosclerosisisendothelialcelldysfunctionmanifestingasdeficienciesofnitricoxide(NO)andprostacyclin.Canbeinducedbyvariousnoxiousinsultsincludingdyslipidemia,diabetes,hypertension,smokingetc.PrediabeticstatemaybeassociatedwithendothelialdysfunctionpossiblyduetoIRNexteventisthebindingmononuclearcells,suchasmonocytesandT-lymphocytestotheendothelium,mediatingbyadhesionmoleculesontheendothelialsurface,suchasVCAM,ICAM,andE-selectin.Oncethemonocytemigratesintosubendothelialspace,itmatureintoresidentmacrophage,takenuplipidlargelythroughscavengerreceptors(SR-AandCD-36),andbecomefoamcellLaterstage,smoothmusclecellsmigratetothesurfaceandformthefibrouscapofthelesionFinally,lipid-ladenmacrophagesreleasematrixmetalloproteinases(MMP-9)causingplaqueruptureandacutecoronarysyndromes-suchasMIandunstableanginaOxidativestressPlaysacrucialroleinatherosclerosis,especiallyindiabetesOX-LDLexistence--aproatherogenicroleOx-LDLrecognizedbyscavengerreceptorpathwayonmacrophages-unregulatedcholesterolaccumulation-foamcellformationFactorspromoteincreasedoxidativestressinDMincludeantioxidantdeficiencies,increasereactiveoxygenspecies(ROS),andprocessofglycationandglycooxidationClinicalmarkersinclude

F2-isoprostanes(prostaglandin-likecompoundsfromfreeradical-catalyzedperoxidationofarachidonicacid)emergedasnovelanddirectmeasuresofoxidativestress,increasedinbothurineandplasmaofT2DM

Nitrotyrosine,anothermarkerofproteinoxidation,alsoelevatedinplasmaofT2DM,aswellasevidenceofoxidativedamagetoDNAHyperinsulinemia/IRInsulinresistancesyndrome(IRS)ormetabolicsyndrome-clusterofCVriskfactorsfrequently,butnotalways,associatedwithobesity(Figure1).Reaven(1988)-associationofIRandobesity,T2DM,highTG,andlowHDLMcFarlane(2001)-IRSandCVDOtherCVriskfactorsbeenincluded-inflammation,abnormalfibrinolysis&endothelialdysfunction(Fig1)Duetoincreaseprevalenceofobesityandotherabnormalities,IRShasbecomeamajorclinicalandpublichealthproblemFigure1InteractionofnontraditionalriskfactorsindiabetesDefineInsulinResistance(IR)HyperinsulinemiaFastingplasmainsulinaloneHOMA(homeostasismodelassessment)-fastingplasmainsulinxfastingglucose(mmol/l)/22.5.GlucoseinfusionclampstudyWHO(1999)andNECP-ATPIII(2001)definethesyndrome-shownatincreasedriskofCVD(Table1).QuebecHeartStudy

(DespresJPetc.NEJM1996;334:952-957)Prospectivestudiessuggest

hyperinsulinemiamaybeanimportantriskfactorforischemicheartdisease1898Men45-76yrofage,whodidnothaveischemicheartdisease,Afirstischemiceventoccurin114men,fastinginsulinconc.18%higherthancontrolHighfastinginsulinconc.wereanindependentpredictorofIHDHelsinkiPolicemenStudy

(PyoralaMetc.DiabetesCare2000;23:1097-1102)

(PyoralaMetc.Arterioscler

Thromb

Vasc

Biol2000;20:538-44)Hyperinsulinemiawasassociatedwithincreasedall-causeandCVmortalityIRSpredictstheriskofCADandstrokeinhealthmiddle-agedmen(22yrsfollowup)OtherpopulationstudiesInsulinandriskofCVdisease:ametaanalysis(Circulation1998;97:996-1001)TheAtherosclerosisRiskinCommunitiesStudy(ARIC)study(DiabetesCare1997;20:935-42)HaffnerSMetc.JAMA1990;263:2893-8.ThesestudiesconfirmthatcomponentsofthesyndromearepresentforseveralyrsbeforetheonsetofT2DMandthatthe“clockforCHDstartstickingbeforetheonsetofclinicaldiabetes”(Haffner)ProposedmechanismslinkingIRwithCVDindiabetesIRassociatedwithseveralotherCVriskfactors:1.Obesity(centraldistribution,varietyhormoneandcytokines)2.Dyslipidemia

(highTg,lowHDL,“Bpattern”LDL)3.Hypertension(higherfastinginsulin,reduceinsulin-mediatedglucosedisposal)4.Abnormalinsulinsignaling,hyperinsulinemia,andthevasculature

(insulin-vasodilatory,antiinflamamtory

properties,growthfactor,NOproduction)=>IRisakeyabnormality,itisassociatedcloselywithtraditionalCVriskfactorsEndothelialDysfunction(ED)Endotheliumisacriticaldeterminantofvasculartone,reactivity,inflammation,vascularremodeling,maintenanceofvascularpatency,andbloodfluidity.ImportanceofEDinpathogenesisofCVDinDMhasbeenrecentlyrecognized.EDmaybeaprognostic/riskmarker.Functionsofendotheliumaremaintainedthroughparacrine

andendocrineregulatorysubstancesecretedfromendothelialcells.Vasodilators,NO,mostpotentvasodilator,prostacyclin.Vasoconstrictors,suchasendothelin1Allinvolvedinmaintainingthebalancebetweensmoothmusclecellgrowth,promotionandinhibition,thrombosisand

fibrinolysis,inflammation,andcelladhesionEndothelium-dependentvasodilatorandvasoconstrictormechanismsAssessmentofendothelialfunctionBiochemicalparameters-riskfactorsforCVD,includevWF,thrombomodulin,VCAM,ICAM,E-Selectin,andP-SelectinFunctionalassessment-dependentontheabilityofbloodvesselstodilateinresponsetovariedstimuli,suchasshearstressandacetylcholineinfusion-releaseNO-measureendothelium-dependentvasodilationTheabilityofbloodvesselstodilateinresponsetostimuli,includingischemia-calledvascularreactivityorflow-mediateddilation(FMD)-brachialarteryreactivity-noninvasivemethodtoassessarterialendothelialfunction.Endothelialinjuryisanearlyeventinatherosclerosis,abnormalFMDmayprecededevelopmentofstructuralchangeinvesselwall-shownininsulin-resistantstateandtype2DMEDmaybeaprecursorofIRS(Table2)Table2AlterationsinthevascularendotheliumassociatedwithDMandiRAbnormalitiesSignificanceReleaseofandresponsivenesstoNO ImpairedendothelialfunctionandreactivityExpression,synthesis,andplasmalevels Vasoconstrictionandhypertensionofendothelin-IProstacyclinrelease ImpairedvasodilationAdhesionmoleculeexpression IncreasedmonocyteadhesiontovesselwallAdhesionofplateletsandmonocytes Foamcellformation,thrombosis,and inflammationProcoagulantactivity ThrombosisAdvancedglycosylatedendproducts IncreasedstiffnessofarterialwallImpairedfibrinolyticactivity DecreasedclotbreakdownProposedmechanismslinkingEDwithCVDinDMInsulinitselfhasvasodilatoryactionsviaaNO-dependentmechanismInsulinregulatesNOS,thatsynthesizesNOfrom

arginine,whichimpairedininsulin-resistantsubjects.NOplaysacriticalroleinmaintenanceofvascularhealth,abnormalitymayexplainincreasedCVDinIRS.ObesityandT2DMareassociatedwithresistancetothevasculareffectsofinsulinAbnormalitiesininsulinsignalingleadnotonlytoIRbutalsoabnormalitiesinvasculatureInsulinsignalingthroughthephosphatidylinositol-3-kinae(PI-3K)pathwayisimportantinNOproductioninhumanvascularendothelialcellsEDistheearliestabnormalityassociatedwithCVDandoccursveryfrequentlyinDM,oftenprecedingtheonsetofhyperglycemiaInsulinAsymmetricdimethylarginine(ADMA)IncreasedADMAareassociatedwithEDandincreasedriskofCVD.ADMA-anendogenousandcompetitiveinhibitorofROS.SerumlevelelevatedinatherosclerosisandthosewhowithriskfactorsforatherosclerosisADMAplasmalevelsarecorrelatedwiththeseverityofEDandatherosclerosis.ADMAinhibitNOproduction,impairbloodflow,accelerateatherogenesis,andinterferewithangiogenesisStuhlinger-demonstratedplasmaADMApositivelycorrelatedwithimpairmentofinsulin-mediatedglucosedisposalinMS.Avandiaenhanceinsulinsensitivity(SI)&reducedADMAlevelTetrahydrobiopterin(BH4)EssentialcofactorforthecatalyticactivityofeNOS,depletedduringoxidativestressDepletedBH4causeseNOStouncouple,resultsindecreasedNOproductionIRdiminishtheactivityofenzymethatproduceBH4incoronaryarteries—BH4depletion&EDTreatmentofBH4showntoimproveEDinDMImpairedFibrinolysisandProthromboticstateEndogenousfibrinolyticsystemrepresentsequilibriumbetweenactivatorsofplasminogen(primarilytPA)andinhibitorsoftheseactivators(PAI-1)Lowgradecoagulationiscontinuous,thusfibrinolyticactivityisnecessarytomaintainthefluidityofblood.Excessiveinhibitionoffibrinolysis—coagulationandthrombosis—CVevent.ImpairedfibrinolyticfunctioninDMcorrelateswithseverityofvasculardiseaseinDMandisariskfactorforMIinbothDMandnondiabeticsubjects.ImpairedfibrinolysisnowrecognizedasimportantcomponentofIRSandcontributetoincreaseriskofCVevents(HaffnerSM.DiabetesCare1999;22:562-8)PAI-1elevatedininsulin-resistant,obesity,PCOSwomen.Fastinginsulinelevationassociatedwithimpairedfibrinolysisandhypercoagulabilityinnormalglucosetolerance.HyperinsulinemiaassociatedwithimpairedfibrinolysisinIGT.ExcessiveriskforCVDassociatedwithhyperinsulinemiaandIGTmaybemediatedbyenhancedpotentialforacutethrombosis.AbdominalfatproducesPAI-1andcontributetoincreasedplasmaPAI-1conc.inhumanobesityassociatedwithIRImpairedFibrinolysisandProthromboticstateCoagulationdisordersCoagulationdisordersalsoplayroleinincreasingriskofCHDinT2DMHyperreactivityofplateletsinT2DMduetoincreasedNo.ofglycoproteinrecpetorsandlowactivityofguanylate

cyclase.Otherfactors:alterationsinserumfibrinogen,factorV,II,VII,increasedD-dimer,vWBFantigen,A-IIantiplasmin,anddecreasedantithrombinIIIcoagulationabnormalitiesplayaroleinincreasingfrequencyandseverityofthromboticeventsinDMTable3ImpactofIRanddiabetesonthrombosisamd

fibrinolysisFactorspredisposingtothrombosisPlatelethyperaggregability

PlateletcAMPandcGMPThromboxanesynthesisElevatedconcentrationsofprocoagulants

Fibrinogen

vWFandprocoagulantactivityThrombinactivityDecreasedconcentrationandactivityofantithromboticfactorsAntithrombinIIIactivityFactorsattenuatingfibrinolysis

DecreasedtPAactivityIncreasedPAI-IsynthesisandactivityIncreasedbloodviscosityProposedmechanismslinkingimpairedfibrinolysisandthrombosiswithCVDindiabetesAbnormalfibrinolysisduetochangesindynamicequilibriumbetweenendogenoustPAandPAI-1Insulin,proinsulin,VLDL,variouscytokinesregulatePAI-1synthesisandrelease.GreatestelevationsofPAI-1occurwhencombinationwithhyperinsulinemia,hyperglycemia,andincreasedFFAinobeseinsulin-resistantsubjects.Impairedfibrinolysisiscloselyrelatedtothemetabolicsyndrome.InT2DMBasalfibrinolyticactivityisdecreased-acceleratedatherosclerosisbyexposingvascularluminalwallsurfacestopersistentandrecurrentthrombi.PAI-1contentisincreasedinatheroscleroticlesions-interventiontoreduceIRandimproveglycemiccontrolmayimprovefibrinolyticresponseIncreasedPAI-1inarterialwall-decreaselocalfibrinolysisandelevatethrombusformationandunfavorableevolutionofatheroscleroticplaquesInsulinalsoinhibitsplateletfunction,PAI-1,andtranscriptionfactorsassociatedwithcoagulation

increasedPAI-1andincreasedcoagulationareverycloselylinkedtoIRandcouldcontributetoCVDinDMInflammationandCVDindiabetesInflamamtionhasrecentlybeenassociatedwithCVeventsinseveralstudiesInflammatorymarkersalsopredictthedevelopmentofincidentdiabeteshasledtoformulationthatinflammationmaybetheunderlyinglinkbetweenDMandCVDhs-CRP-acute-phaseproteinproducedbyliverinresponsetocytokineproduction(IL-6,IL-1,TNF-a)-predictfutureCVeventsOtherinflammationriskfactors,includingoxidizedlipids,infectiousagents,andcytokinefromadipocytesorotherinflammationcells,stimulateIL-6production(asmessengercytokine)-stimulateliverproducedCRP.ADIPOSETISSUEINFLAMMATIONLIVERCRPINSULINRESISTANCEATHEROSCLEROSISCHEMOKINESIL-6TNF-aPhysician’sHealthStudy

(RidkerPM.AnnInternMed1999;130:933-7)CRPpredicttheriskoffutureMIandstroke.AspirinreductiontheriskinfirstMIappearsdirectlyrelatedtolevelofCRP.RaisingthepossibilitythatantiinflammatoryagentsmayhaveclinicalbenefitsinpreventingCVD.Women’sHealthStudy

(RidkerPM.Circulation1998;98:731-33)122apparentlyhealthyparticipantswhosubsequentlysuffered1stMI&244matchedcontrol3yrfollowupperiodmeasureCRPWomenwhodevelopCVeventshadhigherbaselineCRPThosehadhighestCRPhad5foldincreaseinriskofanyvasculareventand7foldincreaseriskofMIorstroke.RidkeralsodemonstratedthathighestquartileCRP(>2.1mg/l)had>2.5xincreasedriskofCVDcomparedwithlowestquartileofCRP(<0.55mg/l)Ridkerdemonstratedthaths-CRPisadditivetototalcholesterolindeterminingtheriskof1stMI,subjectshavehs-CRP>75%andtotalChol<75%hadsignificantincreasedriskofeventsMetabolicsyndromeandCRP

(NHANESIII.Atherosclerosis2003;168:351-8)14719healthywomenfollowup8yrs24%hadMSatentryCVevent-freesurvivalrates:CRP>3mg/lweresimilartosurvivalratesashaving3ormorecharacteristicsofmetabolicsyndromeApplicationofCRPforCVdiseasedetectionandprevention

(RidkerPMM.Circulation2003;107:363-7.)CRP<1,1-3,>3mg/lcorrespondtolow,moderate,high-riskgroupsforfutureCVevents.IndividualswithLDL<130mg/dlwhohadCRP>3mg/lrepresentahigh-riskgroupadditionCRPtostandardcholesterolevaluationmayprovideasimpleandinexpensivemethodtoimproveglobalriskpredictionandcompliancewithpreventiveapproaches.ProposedmechanismslinkinginflammationwithCVDindiabetesNotclearBurkereportedthatCRPispresentinlipidcoreofatherothromboticlesionsinsubjectswhodiesuddenly,CRPispresentadjacenttocholesterolandclotsRecentinvivostudydemonstratedthatCRPdirectlyquenchestheproductionofNO,throughposttranscriptionaleffectsoneNOSmRNAstability.CRPpromotemonocyte

chemotaxis,cytokinerelease,andtissuefactorsecretion.Inendothelialcells,CRPinhibitseNOSandstimulatesadhesionmolecules(VCAM,ICAM)andadhesionofmonocytestoendothelialcells.CRPandDM

hs-CRPclusterswithotherriskfactorsassociatedwithDM,metabolicsyndrome.ElevatedCRPiscommoninobesityTNFaareelevatedinobesityandfallwithBWlossHighglycemicloaddietmayincreaseROSElevatedhs-CRPinhigh-risksubjectmaypredictthesubsequentdevelopmentofT2DM(CardiovascularHealthStudy,InsulinResistanceAtherosclerosisStudy)

WestofScotlandCoronaryPreventionStudy(WOSCOPS)

(SattarN.Circulation2003;108:414-9)MeasureCRPin5245men,127havingtransitionfromNGTtoDMduringstudyBaselineCRPwasanimportantpredictorofthedevelopmentofdiabetesinunvariateanalysisHighestquintileCRP(>4.18mg/l)associatedwith>3xriskofdevelopingDMat5yrsindependentofotherestablishedriskfactors.

InfectionandatherosclerosisNodefinitiveproofInfection-CRP-cellular&molecularchangesChlamydiapneumoniae

andCMVexacerbatedlesiondevelopmentonanimalmodelsofatherosclerosisandrestenosisMicroalbuminuriaDefinedaspresenceofurinaryalbuminabovenormalbutbelowdetectablerangewithconventionalurinedipstickmethodology.ComplicationofDM-kidneychange2ndtohyperglycemiaUAE20-200ug/min(30-300ug/minofCronspoturineor30-300mg/24hr)PredictprogressionofdiabeticnephropathySeveralstudiesdemonstratedmicroalbuminuriaisariskfactorforCVeventsRecentdatasuggestitmayoccureveninnondiabeticsandaprecursorofCVDandmayberelatedtoIR.MicroalbuminuriamayprecedeandpredictthedevelopmentofT2DMProgressionofmicroalbuminuriaisassociatedwithworseningprognosisforCVDriskSeveralstudiesdemonstratedmicroalbuminuriaisariskfactorforCVevents

DeckertT.DiabetesCare1992;15:1181-91Microalbuminuria.Implicationformicro-andmacrovasculardisease.WinocourPH.Atherosclerosis1992;93:71-81.MicroalbuminuriaandassociatedCVriskfactorsinthecommunity.GersteinHC.JAMA2001;286:421-6.

AlbuminuriaandriskofCVevents,death,andheartfailureindiabeticandnondiabeticindividuals.TuttleKR.AmJKidneyDis1999;34:918-25.UrinaryalbuminandinsulinaspredictorsofCAD:anangiographicstudyBorch-JohnsonK.Arterioscler

Thromb

Vasc

Biol1999;19:1992-7.Urinaryalbuminexcretion.AnindependentpredictorodischemicheartdiseaseSpoelstra-deM.DiabetesCare2001;24:2097-2101RapidprogressionofalbuminexcretionisanindependentpredictorofCVmortalityinptswithT2DMandmicroalbuminuria.ProposedmechanismslinkingmicroalbuminuriawithCVDindiabetesPopulation-basedstudies-increasedUAEratehasbeenshowntoclusterwithotherCVDriskfactorsandincludedinthecriteriausedbyWHOtodefineIRSMicroalbuminuriahasbeencorrelatedwithinsulinlevels,saltsensitivity,resistancetoinsulin-stimulatedglucoseuptake,centralobesity,dyslipidemia,LVH,andtheabsenceofnocturnaldropsinbothSBPandDBP.ElevatedSBPisasignificantdeterminingfactorinthedevelopmentofmicroalbuminuriaandtheprogressionofalbuminuriainT2DMInIRindividual,microalbuminuriamaybeamanifestationofEDindicatingendothelialpermeabilityandisalsorelatedtoincreasedcarotidintima-mediathickness(IMT)Microalbuminuriareflectsincreasedleakageofalbuminacrossendothelialbarrierandaclinicallyeasilymeasurableindicatorofendothelialintegrity.HyperhomocysteinemiaRecentdatasuggestedelevatedplasmatotalhomocysteine(tHcy)maybeariskfactorforCVDingeneral,includingDMItisaindependentfactors,multipleriskfactorshaveadditiveeffectswithtHcy.Multipleriskfactorinterventionapproachneededinptathigh-riskforCVDaswithDMElevatedplasmatHcy,bothfastingandpostmethionineload,areassociatedwithhigherprevalenceofCVDinDMEachmicromole/LincrementoffastingtHcyconc.Associatedtooddratio1.45forthepresenceofCHDAnotherstudy,odd-ratioper5mmol/LincrementsintHcyconc.foranyCVDwas1.38inNGT,1.55inIGT,2.33inNIDDM.thisfindingsmayrelatetoaninteractionofage,IR,anddiabetesonbothhomocysteinemetabolismandCVDProposedmechanismslinkinghomocysteinewithCVDinDMPutativemechanismsincludeendothelialcellinjury,ED,increasedvascularsmoothmusclecellgrowth,increasedplateletadhesiveness,enhancedLDLoxidationanddepositioninthearterialwall,anddirectactivationofthecoagulationcascadeThevascularchangesinhyperhomocysteinemiaaremultifactorialEvidenceexiststhatdirectlyrelateshyperhomocysteinemiatoED.Vascularreactivity,endothelium-dependentandindependentvasodilationissignificantlyimpairedinelderlyptwithhyperhomocysteinemiaHyperhomocysteinemiaalsoassociatedwithalbuminuria

andrenalfailure.UAEratescorrelatewithfastingandpostmethionineloadplasmatHcyconc.PtwithDMandmicroalbuminuriahavehigherfastingtHcy.Insulinregulatehomocysteinemetabolismthroughtregulatecystathionine

b-synthaseVascularwallabnormalities-carotidIMTAnkle-brachialpressureindex(ABI)isausefulnoninvasivemeasurefordetectsubclinicalPADLowABIprovideinformationbeyondthatprovidebyCVriskfactormeasurementsIMTrepresentsastructuralabnormalityinthearterialwallandisaparticularlygoodpredictorofsubsequentCVriskIMTisasafenoninvasiveandvalidatedmethodpermitsquantitativemeasurementsofvesselwallIMTvaluescorrelatewellwithCVoutcomes,otherCVriskfactors,andchangeinriskduringdiseasemanagement-becomeanimportantcomponentofepidemiologicalstudiesofCVriskManystudiessuggestedalinkbetweenincreasedcarotidIMTandIRCompatiblewiththepossibleeffectofhyperinsulinemiaongrowthofvascularsmoothmusclecellsandextracellularmatrixCarotidIMTisincreasedinnewlydiagnosedT2DMptswithoutovertCVD.Thus,carotidIMTrepresentsastructuralabnormalityinarterialwallandagoodpredictorofsubsequentCVriskIncreasedarterialstiffnessisanotherindicatorofearlyatherosclerosisbeenfoundwithincreasedfrequencyinDMSimplemeasureofpulsepressuremaybeanindicatorofarterialstiffness,morerobustmethodismeasurementofaorticpulsewavevelocityMeasurementofarterialstiffnessbeenshowninseveralstudiestobepredictiveofCVeventsinDMandnondiabeticsArterialstiffnessisassociatedwithIR,andalsocorrelateswithcarotidIMTandED.Vascularwallabnormalities-arterialstiffnessCalcificationofarterialwallAnothervascularabnormalityinclinicalpracticeiscalcificationofarterialwallAppliedusingelectronbeam-computedtomography(EBCT)asasimplenoninvasivemarkerofestablishedCVDAbnormalcalciumscoresonEBCTareremarkablycommoninDMCarotidIMTandEBCTprovidevalidmeasuresofsubclinicalatherosclerosisProposedmechanismslinkingvascularwallabnormalitieswithCVDinDMAsignificantnegativeassociationbetweenSIandtheIMTofthecarotidarterybothinHispanicsandnon-HispanicwhitesTherewasnoassociationinblacksIncreasedarterialstiffnessinDMmayberelatedtoglycationofarterialcollagenandelastinandaccumulationofAGEsNondiabeticyoungrelativesofptwithDMalsohavearterialstiffness,suggestinggeneticinfluenceorearlymetabolicabnormalitysuchasIRptwithDMhaveseveralabnormalitiesinthevesselwallthatarerelatedtobothIRandhyperglycemiaandmaypredictfutureeventsPostprandialhyperglycemiaIncreasingevidencethatpostprandialstateisanimportantcontributingfactortothedevelopmentofCVD(HaffnerSM.EndocrRev1998;19:583-92)InDM,postprandialphaseischaracterizedbyarapidandlargeincreaseinbloodglucoselevels,mayberelevanttothepathophysiologyoflatecomplicationAfterameal,postprandiallipemiaandhyperhomocysteinemiamayalsocontributetovascularabnormalitiesOGTT,usedasthemodelofthepostprandialstateEpidemiologicalstudiesshownIGTisassociatedwithincreasedriskofCVDStudiesdemonstartedthatsubjectswithmildtomoderatehyperglycemia,afteranOGTT,haveanincreasedCVrisk.Postchallenge,aswellaspostprandialglucoseconc.inT2DMwerefoundtobedirectlyassociatedwithincidentCVD,independentnotonlyafastingglucose,butalsootherriskfactors.DECODEstudy

(Diabetalogia1999;42:647-54.)

AssessedmortalityassociatedwithADAfasting-glucosecriteriacomparedwithWHO2hrpostchallengeglucosecriteriaFrom13prospectiveEuropeancohortstudies18048menand7316women,aged30yrorolderMeanfollow-up7.3yrComparedwithsubjectshadnormalfastingglucose,ptwithnewlydiagnosedDMbyADAfastingcriteriahadasignificantincreasedhazardratiofordeath.Incontrast,forimpairedfastingglucose,thehazardratiowereincreasedformenbutnotforwomen.FortheWHOcriteria,ratiosweresignificantltincreasedinbothmenandwomenfornewlydiagnosedDMaswellasIGT.Mortalityincreasedwithincreasing2hrglucoseProposedmechanismslinkingpostprandialhyperglycemiawithCVDinDMMoststudiesindicatethathighpostprandialTgandparticularlypostprandialrichTgremnants,constituteanincreasedriskforCVDMechanisms:increasedpostprandialglucoselevelandlipidconc.mayd