OfficialreprintfromUpToDate

www.uptodate.com2017UpToDate

Pathogenesisofatherosclerosis

Author: XueQiaoZhao,MD,FACC
SectionEditors: JuanCarlosKaski,DSc,MD,DM(Hons),FRCP,FESC,FACC,FAHA,PeterLibby,MD
DeputyEditor: GordonMSaperia,MD,FACC

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2017.|Thistopiclastupdated:May17,2016.

INTRODUCTIONAtherosclerosisisapathologicprocessthatcausesdiseaseofthecoronary,cerebral,and
peripheralarteries[1,2].Thebasicaspectsofthepathogenesisofatherosclerosiswillbereviewedhere.Formsof
acceleratedarteriopathies,suchasrestenosisfollowingpercutaneouscoronaryinterventionwithstentingand
coronarytransplantvasculopathydifferinpathogenesisandarediscussedseparately.(See"Intracoronarystent
restenosis"and"Pathogenesisofandriskfactorsforcardiacallograftvasculopathy".)

EPIDEMIOLOGYAtherosclerosisbeginsinchildhoodwiththedevelopmentoffattystreaks(table1).The
advancedlesionsofatherosclerosisoccurwithincreasingfrequencywithaging[35].Thefollowingpoints
demonstratethefrequencyofatherosclerosisinWesternpopulationsanditsprogressionwithage:

Inanautopsystudyof2876menandwomenaged15to34yearswhodiedofnoncardiaccauses,all
individualshadaorticfattystreaks[6].

Inanotherautopsystudyof760young(age15to34years)victimsofaccidents,suicides,orhomicides,
advancedcoronaryatheromatawereseenin2and0percentofmenandwomenaged15to19,and20and
8percentofmenandwomenaged30to34[5].

Inastudyof260perirenalaorticpatchescollectedduringorgantransplantation,thefirstthreedecadesof
lifewerecharacterizedbyintimalthickeningandxanthomas.Thefourth,fifth,andsixthdecadeswere
characterizedbymorecomplicatedplaquesofpathologicalintimalthickening,earlyandlatefibroatheromas
withthinfibrouscaps,rupturedplaques,healedrupture,andfibroticcalcifiedplaques[7].

Usingintracoronaryultrasound,oneinsixUnitedStatesteenagershaveabnormalintimalthickening[4].

HISTOLOGY

FattystreaksThefirstphaseinatherosclerosishistologicallyoccursasfocalthickeningoftheintimawith
accumulationoflipidladenmacrophages(foamcells)andextracellularmatrix(table1andfigure1)[8].Smooth
musclecellscanalsopopulatetheintima,someofwhichmayarisefromhematopoieticstemcells[9],migrate,
andproliferate.Lipidsaccumulateearlyinfattystreakformationyieldingbothintracellularlipidandextracellular
deposits,whichproducethefattystreak.Biglycan,asmalldermatansulfateproteoglycandetectedintheintima
ofatheroscleroticcoronaryarterysegments,canbindandtraplipoproteins,includingverylowdensity
lipoproteinsandlowdensitylipoprotein[10].ThefattystreakcanalsocontainTlymphocytes.(See'Inflammation'
below.)Foamcellsconstitutethehallmarkoftheearlyatheroma.

Astheselesionsexpand,moresmoothmusclecellsaccumulateintheintima.Thesmoothmusclecellswithinthe
deeplayerofthefattystreakaresusceptibletoapoptosis,whichisassociatedwithfurthermacrophage
accumulationandmicrovesiclesthatcancalcify,perhapscontributingtothetransitionoffattystreaksinto
atheroscleroticplaques(table1)[11].
FibrouscapFibrouscapatheromasaredefinedasplaqueswithawelldefinedlipidcorecoveredbyafibrous
cap,whichmayberelativelyacellular(madeofdensecollagen)ormayberichinsmoothcells.(See"Pathology
andpathogenesisofthevulnerableplaque".)

VasavasorumThevasavasorumformanetworkofmicrovesselsthatoriginatesprimarilyfromthe
adventitiallayeroflargearteries.Thesevesselssupplyoxygenandnutrientstotheouterlayersofthearterial
wall[12].Asatheroscleroticplaquesdevelopandexpand,theyacquiretheirownmicrovascularnetwork(vasa
vasorum),extendingfromtheadventitiathroughthemediaandintothethickenedintima[13].Thesethinwalled
vesselsarepronetodisruption,leadingtohemorrhagewithinthesubstanceoftheplaqueandcontributingtothe
progressionofcoronaryatherosclerosis[14,15].

FibrousplaqueThefibrousplaqueevolvesfromthefattystreakviaaccumulationofconnectivetissuewithan
increasednumberofsmoothmusclecellsfilledwithlipidsandoftenadeeperextracellularlipidpool.

AdvancedlesionsMoreadvancedlesionsdevelopamicrovasculaturefromboththeluminalandmedial
aspects,andoftencontainanecroticlipidrichcore,andeventuallycalcifiedregions(table1)[3].

Atheromaformationassociateswithcoronaryarteryremodeling(figure2)[16].Positiveremodelingisdefinedas
expansionoftheplaqueandexternalelasticmembraneareaduetoacompensatoryincreaseinlocalvessel
size,whilenegativeremodelingreferstoasmallerexternalelasticmembraneareaatthelesionsiteduetothe
localshrinkageofvesselsize(image1AB).

Positiveremodelinghasbeenfelttobeacompensatorymechanisminearlycoronaryarterydisease,preventing
luminallossdespiteplaqueaccumulation.However,arterialremodelingconsequenttoplaqueformationand
expansionisassociatedwithabnormalarterialphysiologyaswellasthedevelopmentofclinicalsymptoms[16].
Positiveremodelingisseenwithcomplex,unstableplaquesinpatientspresentingwithunstableanginain
contrast,negativeremodelingisassociatedwithobstructiveplaquesinpatientswithstableangina[17].(See
"Theroleofthevulnerableplaqueinacutecoronarysyndromes".)

PATHOGENESISMultiplefactorscontributetothepathogenesisofatherosclerosis,includingendothelial
dysfunction,dyslipidemia,inflammatory,andimmunologicfactors,plaquerupture,andsmoking.(See"Overview
ofestablishedriskfactorsforcardiovasculardisease"and"Cardiovascularriskofsmokingandbenefitsof
smokingcessation".)

EndothelialdysfunctionTheendotheliumformsanactivebiologicinterfacebetweenthebloodandallother
tissues.Thesinglelayerofcontinuousendotheliumliningarteriesformsauniquethromboresistantlayerbetween
bloodandpotentiallythrombogenicsubendothelialtissues.Theendotheliumalsomodulatestone,growth,
hemostasis,andinflammationthroughoutthecirculatorysystem.Endothelialvasodilatordysfunctionisaninitial
stepinatherosclerosisandisfelttobecausedprincipallybylossofendotheliumderivednitricoxide[18].This
issueisdiscussedindetailseparatelyandwillonlybrieflybereviewedhere.(See"Coronaryarteryendothelial
dysfunction:Clinicalaspects".)

Endothelialdysfunctionisassociatedwithmanyofthetraditionalriskfactorsforatherosclerosis,including
hypercholesterolemia,diabetes,hypertension,cigarettesmoking.Inparticular,endothelialdysfunctionisinduced
byoxidizedlowdensitylipoprotein(LDL)andinsomerespectscanbeconsideredasafinalcommonpathway
(table2)[19].Itcanbeimprovedwithcorrectionofhyperlipidemiabydietorbytherapywithastatin(HMG
coenzymeAreductaseinhibitor),whichincreasesthebioavailabilityofnitricoxide[20,21],withangiotensin
convertingenzymeinhibitors[22],orwithhighdosesofantioxidantssuchasvitaminCorflavonoidscontainedin
redwineandpurplegrapejuice[23,24].However,clinicalbenefitsofthesetherapieshaveonlybeen
demonstratedconvincinglyforstatins.(See"Coronaryarteryendothelialdysfunction:Clinicalaspects"and
"Mechanismsofbenefitoflipidloweringdrugsinpatientswithcoronaryheartdisease"and"Nutritional
antioxidantsincoronaryheartdisease".)

InflammationEvidenceofinflammationinatheroscleroticlesionshasbeennotedfromtheearliesthistologic
observationsandinflammationiscentraltounderstandingthepathogenesisofatherosclerosis[2528].
MacrophagesthathavetakenupoxidizedLDLreleaseavarietyofinflammatorysubstances,cytokines,and
growthfactors[29,30].Amongthemanymoleculesthathavebeenimplicatedare:monocytechemotacticprotein
(MCP)1[31,32]intercellularadhesionmolecule(ICAM)1[31]macrophageandgranulocytemacrophage
colonystimulatingfactors[33,34]CD40ligandinterleukin(IL)1,IL3,IL6,IL8,andIL18[3537]andtumor
necrosisfactoralpha[3840].TheroleofIL6isdiscussedseparately.(See"Overviewofestablishedriskfactors
forcardiovasculardisease",sectionon'Interleukin6'.)

Evidencesupportingtheimportanceofinflammationinthepathogenesisofatherosclerosiscomesfromthe
observationthatmarkersofincreasedordecreasedsystemicinflammationassociatedwiththeriskof
atherosclerosis.Someofthesemarkersarediscussedinthenextsections.

SerumCRPThebeststudiedofthesemarkersistheacutephasereactantCreactiveprotein(CRP).
AlthoughCRPisconsistentlyassociatedwithatheroscleroticcardiovasculardisease,geneticdatadonotsupport
itsfunctionasacausalriskfactor.TheroleofCRPincardiovasculardiseaseisdiscussedindetailseparately.
(See"Creactiveproteinincardiovasculardisease".)

LpPLA2LipoproteinassociatedphospholipaseA2(LpPLA2)isamacrophagesecretedenzymethatmay
perpetuateplaqueinflammationandwhoseelevatedlevelspredicta40to400percent(averagingabout100
percent)increasedriskofmyocardialinfarction(MI)andstrokeinpopulationstudiesfullyadjustedforother
cardiovasculardiseaseriskfactors.ClinicaltrialswithaninhibitorofLpPLA2[41]didnotshowimproved
outcomes.(See"Preventionofcardiovasculardiseaseeventsinthosewithestablisheddiseaseorathighrisk",
sectionon'Therapieswithoutwellestablishedbenefit'.)

CytokinesCytokinesmayparticipateinthepathogenesisofatherosclerosis[42].Mediatorssuchas
interleukin1ortumornecrosisfactoralphahaveamultitudeofatherogeniceffects.Theyenhancetheexpression
ofcellsurfacemoleculessuchasICAM1,VCAM1,CD40,CD40L,andselectinsonendothelialcells,smooth
musclecells,andmacrophages.Proinflammatorycytokinescanalsoinducecellproliferation,contributetothe
productionofreactiveoxygenspecies,stimulatematrixmetalloproteinases,andinducetissuefactorexpression.
Othercytokines,suchasinterleukin4andinterleukin10,areantiatherogenic.Stillothers,suchasinterferon
gamma,canpromoteexperimentalatherogenesis.(See"Theroleofthevulnerableplaqueinacutecoronary
syndromes".)

LeukocyteactivationLeukocyte(circulatingmonocytes,andtoalesserextentTlymphocytes)recruitment
isseenearlyintheatheroscleroticlesion,providingsomeevidenceoftheroleofsystemicinflammation[43].

FurtherevidenceinsupportofsystemicinflammationcomesfromastudyinwhichtheinflammatorymRNA
profileofcirculatingleukocyteswastestedin524menwithapriorMIand628controls[44].Thepatients,
comparedtocontrols,hadmRNAprofilesshowingincreasedlevelsofmanyinflammatorymRNAs.

Tolllikereceptor4Furtherevidencefortheroleofinflammationcomesfromstudyofpolymorphismsin
thetolllikereceptor4genethatconferdifferencesintheinflammatoryresponsetoGramnegativepathogens
andperhapsotherligands[45].Aparticularpolymorphismofthisgene,Asp299Gly,presentsin7percentofan
Italianpopulation,diminishesreceptorcycling,andisassociatedwithdiminishedinflammatoryresponsetoGram
negativepathogens.

CarriersoftheAsp299Glypolymorphism,comparedtopatientswithonlywildtypealleles,havereduced
circulatinglevelsofavarietyofinflammatorymarkers,includingCRP,adhesionmolecules,andIL6,anda
reducedincidenceofcarotidatherosclerosis(oddsratio0.54)asdetectedbyultrasonography.Theyhavean
increasedrateofseriousbacterialinfections.

PregnancyassociatedplasmaproteinA(PAPPA)PAPPAisahighmolecularweight,zincbinding
metalloproteinasethatisthoughttodegradetheproteinsthatmaintaintheintegrityoftheprotectivefibrouscap
ofatheroscleroticplaques[46].PAPPA,originallyfoundinpregnantwomen,isproducedbysyncytiotrophoblast
cells,butalsobyosteoblasts,fibroblasts,endothelial,vascularsmoothmusclecells,and
monocytes/macrophages[4751].Furthermore,PAPPAhasbeenidentifiedinvulnerablecoronaryplaquesbut
notinstableones[52].SeveralstudieshavedemonstratedthatPAPPAisapotentiallyimportantbiomarkerof
plaqueinstabilityandinflammationinpatientswithacutecoronarysyndrome[53,54].

DyslipidemiaLipidabnormalitiesplayacriticalroleinthedevelopmentofatherosclerosis[30,5561].Early
experimentsinanimalsdemonstratedacceleratedatherosclerosiswithahighcholesteroldiet.Thiswasfollowed
byepidemiologicstudiesconductedincountriesaroundtheworldthatshowedanincreasingincidenceof
atherosclerosiswhenserumcholesterolconcentrationswereabove150mg/dL(3.9mmol/L)(figure3).

Theroleofthedifferentlipidparticlesinthedevelopmentofatherosclerosisisdiscussedelsewhere.(See
"Lipoproteinclassification,metabolism,androleinatherosclerosis".)

Itisuseful,however,tosummarizethemajorobservations.

HighlevelsofLDLcholesterol[55,61]areparticularlyimportantriskfactorsforatherosclerosis(algorithm1)
[56].

LDLaccumulatesinthecholesterolesterenrichedmacrophages(foamcells),butnotthelipidcore,of
atheroscleroticplaque[62].OxidativemodificationofLDLfacilitatesmacrophageuptakeviaunregulated
macrophagescavengerreceptors(amongthem,CD36,alsocalledscavengerreceptorB)andfor
acceleratedaccumulationofcholesterol[63,64].MacrophageuptakeofLDLcholesterolmayinitiallybean
adaptiveresponse,whichpreventsLDLinducedendothelialinjury[65].However,cholesterolaccumulationin
foamcellsleadstomitochondrialdysfunction,apoptosis,andnecrosis,withresultantreleaseofcellular
proteases,inflammatorycytokines,andprothromboticmolecules[65].

OxidizedLDLcancausedisruptionoftheendothelialcellsurface[66],promoteinflammatoryandimmune
changesviacytokinereleasefrommacrophagesandantibodyproduction(see'AntioxidizedLDLantibodies'
below),andincreaseplateletaggregation.Itmayalsoplayaroleinplaqueinstability.LevelsofoxidizedLDL
areincreasedinpatientswithanacutecoronarysyndromeandarepositivelycorrelatedwiththeseverityof
thesyndrome[67,68].MeasurementofoxidizedLDLhasnotbeenstandardizedorvalidatedasaclinically
usefulbiomarker,however,andantioxidantstrategieshaveconsistentlyfailedtoimprovecardiovascular
outcomesinclinicaltrials.

HDL,incontrasttoLDL,hasputativeantiatherogenicpropertiesthatincludereversecholesteroltransport,
maintenanceofendothelialfunction,andprotectionagainstthrombosis.Thereisaninverserelationship
betweenplasmaHDLcholesterollevelsandcardiovascularrisk(table3).Valuesabove75mg/dL(1.9
mmol/L)areassociatedwithalongevitysyndrome.Valuesabove60mg/dL(1.5mmol/L)countasanegative
riskfactorintheFraminghamRiskAssessment[69].However,cardiovasculardiseaseeventreductionfrom
increasingHDLcholesterolhasnotbeenestablished,particularlyinpatientswithwellcontrolledLDL
cholesterollevels[7072].AmendelianrandomizationstudyshowedthatraisedplasmaHDLcholesterol
levelsthroughsomegeneticmechanismsarenotassociatedwithlowerriskofMI[73].Studiesshowedthat
HDLcholesteroleffluxhadacloserelationshipwithclinicalatherosclerosis[74]andCVevents[75].These
datachallengetheconceptthatraisingHDLcholesterollevelswilluniformlytranslateintoareductioninthe
riskofCVevents.OneexplanationforthelackofbenefitfromtherapiesthatraiseHDLcholesterollevels
 testedsofaristhattheymaynotimprovethereversecholesteroltransportroleofHDL.(See"HDL
cholesterol:Clinicalaspectsofabnormalvalues".)Geneticstudieshavecastdoubtonthecausal
relationshipbetweenlowHDLlevelsandreducedriskofatheroscleroticevents.Thus,HDLmayserveasa
biomarkerofrisk,butnoevidenceyetshowsthatHDLcholesterolisamodifiableriskfactor.

Currentepidemiologicandgeneticevidencesupportacausalrolefortriglyceriderichlipoproteins,
particularlythosethatcontainapolipoproteinC3.

Ananalysisin60,608individualsfoundthatnonfastingremnantcholesterol,whichisnonfastingtotal
cholesterolminusHDLcholesterolandminusLDLcholesterol,iscausallyassociatedwithischemicheart
diseaseandwithlowgradeinflammation[76,77].(See"Hypertriglyceridemia".)

Observationalandgeneticstudiessupportacausalroleforlipoprotein(a),whichisLDLcovalently
associatedwithapolipoprotein(a).Unfortunately,nocurrentlyestablishedtherapycanreduceLp(a)and
cardiovascularevents.(See"Lipoprotein(a)andcardiovasculardisease".)

Theroleoflipoprotein(a)israthermultidimensionalduetoitsstructure,wheretheLDLlikemoietyofLp(a)
servestopromoteatherosclerosis,whereastheplasminogenlikeapo(a)moleculepromotesthrombosisby
interferingwithfibrinolysis[78,79].AdditionalfunctionsofLp(a)includeinitiationofsignalingpathwaysin
macrophages[80]andvascularendothelialcells[81,82],resultinginproatherogenicchangesincell
phenotypeandgeneexpression.Lp(a)bindingtomacrophagescouldleadtofoamcellformationand
localizationofLp(a)atatheroscleroticplaques[83].Clinically,Lp(a)hasbeenconsideredasanemerging
riskforatheroscleroticvasculardiseasemoreimportantly,Lp(a)isassociatedwithincreasedresidual
cardiovasculareventriskinJUPITER[82]andAIMHIGH[84],whichsuggestthatLp(a)remainsariskfactor
insubjectswithaggressiveLDLcholesterollowering.(See"Lipoprotein(a)andcardiovasculardisease".)

HypertensionHypertensionisamajorriskfactorforthedevelopmentofatherosclerosis,particularlyinthe
coronaryandcerebralcirculations[8587].Itcanincreasearterialwalltension,potentiallyleadingtodisturbed
repairprocessesandaneurysmformation[2].

SmokingCigarettesmokingisanothermajorriskfactor[8587]anditimpactsallphasesofatherosclerosis
fromendothelialdysfunctiontoacuteclinicalevents,thelatterbeinglargelythrombotic[88].Thefollowing
observationshavebeenmade:

Inhumans,cigarettesmokeexposureimpairsendotheliumdependentvasodilation,perhapsthrough
decreasednitricoxide(NO)availability[8991].

Cigarettesmokingisassociatedwithanincreasedlevelofmultipleinflammatorymarkers,includingC
reactiveprotein,interleukin6,andtumornecrosisfactoralphainbothmaleandfemalesmokers[9295].

CigarettesmokingmaydecreaseavailabilityofplateletderivedNO,decreaseplateletsensitivityto
exogenousNO(bothofwhichmayleadtoincreasedactivationandadhesion)[96,97],increasefibrinogen
levels[98,99],anddecreasefibrinolysis[100].

CigarettesmokingincreasesoxidativemodificationofLDL[101]anddecreasestheplasmaactivityof
paraoxonase,anenzymethatprotectsagainstLDLoxidation[102].Thetriglyceride/HDLabnormalitiesseen
amongsmokershavebeensuggestedtoberelatedtoinsulinresistance[103].

DiabetesInadditiontoatherogeniceffectsfromthediabetesrelateddyslipidemia(elevatedtriglycerides,low
levelofHDLcholesterol,andsmall/denseLDLparticles),asmentionedabove,therehavebeenmanyclinicaland
experimentalstudiesrevealingthathighlevelsofinsulinprecededevelopmentofarterialdiseases[104110].
MacrophagesexpressmostinsulinsignalingmoleculesexceptIRsubstrate1(IRS1)andglucosetransporter
type4[111,112].EventhoughinsulinactivatestheIR/IRS2/PI3K/Aktpathwayinmacrophagesasinothertypes
ofinsulinresponsivecells,therehavebeenfewstudiesinvestigatingthebiologicalfunctionsofinsulinsignaling
inmacrophages.Apublishedstudy[113]evaluatedifinsulinaffectsmacrophagefoamcellformationandfound
thatinsulinincreasedtheexpressionofCD36anddecreasedABCA1expression,whichmaypromote
cholesterolaccumulationinhumanmonocytederivedmacrophages.Thestudyalsoshowedthatlow
concentrationofadiponectinincreasedthephosphorylationofAkt(Ser436)bythesamedegreeasinsulinand
hadthesamemodulatingeffectonCD36andABCA1asinsulin.Atherosclerosisandtype2diabetesshare
similarpathologicalmechanisms,includingelevationincytokineslikeMCP1andinterleukin6(IL6),which
contributetounderlyinginflammationofboth[114].OxidizedLDLisabundantinbothoftheseconditionsandmay
inducesecretionoftheseproinflammatorycytokinesinmacrophages[115].Clinically,theoverallriskincrease
conferredbytype2diabetesisdrivenbyacceleratedprogressionofpreexistingatherosclerosistoclinical
cardiovasculareventsvascularriskismuchlowerindiabeticpatientswithoutpreexistingsignificantcoronary
arterydisease[116].

TissuefactorTissuefactoristheprimaryinitiatorofcoagulationand,inadvancedatherosclerosis,isfoundin
theplaque.(See"Overviewofhemostasis".)Tissuefactor,aswellasotherfactorssuchasenhancedplatelet
activity,maycontributetothedevelopmentofthrombosisfollowingplaquerupture.(See"Theroleofthe
vulnerableplaqueinacutecoronarysyndromes".)Tissuefactoralsoplaysaroleintheprogressionof
atherosclerosisviacoagulationdependentandcoagulationindependentmechanisms.Inonestudy,tissuefactor
overexpressionincreasedneointimalareaandplaquesizebyincreasingmuralthrombusandsmoothmusclecell
migrationandacceleratingendothelialregrowthovertheplaqueafterrupture[117].

AngiotensinIIIncreasedplasmaconcentrationsofangiotensinIIpromotethedevelopmentandseverityof
atherosclerosis,particularlywhencombinedwithhyperlipidemia[118].AngiotensinIImayplayaroleinthe
modulationofvascularsmoothmusclecellproliferationandtheproductionofextracellularmatrix[119,120].(See
"ActionsofangiotensinIIontheheart".)

Endothelin1Endothelin1maycontributetothepathogenesisofatherosclerosisatallstages,evenwhenthe
plaqueisclinicallyimperceptible[121,122].Endothelin1isapotentvasoconstrictoraswellasamitogenfor
vascularsmoothmusclecells,stimulatingtheirmigrationandgrowth.OxidizedLDLcanstimulateitsproduction
andenhanceitsvasoconstrictoreffects[123].(See"Roleofendothelininheartfailurewithreducedejection
fraction".)

Endothelin1immunoreactivityisubiquitouswithintheintracellularandextracellularcompartmentsofhuman
coronaryatherosclerotictissueandisreleasedfromthesesitesinresponsetomechanicalstress[124].In
addition,endothelinconvertingenzyme1,thefinalenzymeforendothelin1production,isexpressedinsmooth
musclecellsandmacrophagesofhumancoronaryatheroscleroticlesionsatallstagesofdevelopment[122,125].

AdhesionmoleculesIntercellularadhesionmolecule1(ICAM1)andvascularcelladhesionmolecule1
(VCAM1)arecellsurfaceglycoproteinsinducedatendothelialsitesofinflammationthatmediatetheadherence
ofleukocytestoendothelium.(See"Leukocyteendothelialadhesioninthepathogenesisofinflammation".)Alow
levelofICAM1isexpressedonnormalendothelialcellsandisseeninnormalarterialsegments,whileVCAM1
expressionoccursonlywithinflammationandispresentinthemicrovesselsofhumanatheroscleroticlesions
[126].

TheexpressionofbothICAM1andVCAM1areupregulatedinatheroscleroticlesions,butVCAM1appearsto
bemoreimportantintheinitiationofatherosclerosis[127].Pselectin,aplateletandendothelialcellreceptorthat
mediatesadhesionbetweenvascularcells,alsomaypromotemigrationofinflammatorycellsintoearlyand
advancedatheroscleroticlesions[128,129].
MonocyteadhesiontoendothelialcellsisreducedbyLarginine,theprecursorofnitricoxide[130]andalpha
tocopherol(vitaminE),andincreasedbyandrogensdueinparttoenhancedendothelialcellsurfaceexpression
ofVCAM1[131].Antibodiesthatblockadhesionmoleculesmayameliorateelementsoftheinflammatory
responseinatheroscleroticplaques[132].

FlowcharacteristicsThefrequentoccurrenceofatheromaatsitesofbends,branches,andbifurcationsof
coronaryarteriessuggeststhatalteredbloodflowandlowshearstresscanplayaroleinthedevelopmentof
atherosclerosis.Disturbedflowcanalterendothelialcellfunction[133]inamannerthatimpairsatheroprotective
functions[29].Thesechangesmaybemediatedbystimulationofthereleaseofnitricoxidefromtheendothelial
cells[134,135].

Atherosclerosispreferentiallyaffectsregionsofcoronaryarteriesthatexperiencelowshearstressordisturbed
flow[136].Inaddition,lowshearstressisassociatedwithanincreaseinintimamedialthicknessofthecommon
carotidarteryinhealthymen[137].

AntioxidizedLDLantibodiesOxidationofLDLinvolvestheoxidationoffattyacidsthatproduce
hydroperoxidesandgenerateactivealdehydessuchasmalondialdehyde[138].Malondialdehydecanmodifythe
lysineresiduesonapolipoproteinB,whichrendersthemoleculemoreattractivetothescavengerreceptoronthe
macrophage.TheoxidizedLDL,modifiedbyoxidationorbyderivatizationofthelysylresidues,canbecome
antigenic.

AntibodiestooxidizedLDLlocalizeinhumanatheroscleroticplaquesandintheplasmaofpatientswith
atherosclerosis[139,140].ThetiterofantibodiestooxidizedLDLriseduringthemonthafterpresentationwithan
acutecoronarysyndromeandarehigherthaninpatientswithchroniccoronarydiseaseornormalcoronary
arteries[68].Thisissueisdiscussedindetailelsewhere.(See"Functionandclinicalapplicationsof
immunoglobulins",sectionon'Antibodyspecificityandcrossreactivity'.)

MitochondrialDNAdamageThehypothesisthatmitochondrialDNA(mtDNA)injurymightleadtoplaque
developmentandvulnerabilityhasbeenproposedandtestedinexperimentalanimalmodels[141,142].Inthe
hyperlipidemicApoEknockoutmousemodel,mtDNAlesionsfoundintheaortasprecededthedevelopmentof
aorticplaques[143].MoremtDNAlesionsandlargerplaquesizeweredetectedintheaortasofmiceexpressing
mitochondrialmutation[143].Inpatients,associationofleukocytemtDNAwithatheroscleroticplaquevulnerability
wasexaminedintheVirtualHistologyinVulnerableAtherosclerosis(VIVA)trial[144].Inthisstudy,mtDNA
lesionswerefoundtobeuniquelyassociatedwiththincapfibroatheroma,whichareassociatedwithahighriskof
cardiovascularevents[144,145].Takentogether,thesefindingssuggestapossibleroleofmtDNAinjuryinplaque
progressionanddisruption.

GeneticassociationsThegeneticinfluencesonatherosclerosisformation,progression,andatherosclerotic
vasculareventshasattractedmuchattention.Twomajorgeneticstudyapproacheshavebeenundertakenfora
betterunderstandingofthemolecularmechanismofatherosclerosis.Thefirstisthecandidategeneapproach,in
whichgenesinknownatherogenesispathwaysaretestedfortheirroleinatherosclerosisinvitro,invivo,andin
associationstudies[146148].Thesecondapproachisconductinggenomewidelinkagestudiestofind
atherogenesisregulatingquantitativetraitloci.Thismethodhasthepotentialtofindnewatherosclerosisgenes.
Theavailabilityofwholegenomesequencesinhumansandmice,especiallytheabundantsinglenucleotide
polymorphismandhaplotypeinformation,hasmadeitpossibletoperformgenomewideassociationstudies,
anotherunbiasedapproach,toidentifydiseasegenesrelativelyquicklyascomparedwithtraditionalgenetic
methods[149].

Itislikelythatthecomplexpathophysiologicalprocessesthatoccurinatherosclerosisarenotdeterminedbya
singleorsmallnumberofgenes.Inaddition,environmentalfactors,andtheirinteractionswithgenes,likely
participate.Inthegeneralpopulation,geneticpolymorphismsofmanygenesinthepathwaysoflipidmetabolism,
inflammation,andthrombogenesis.

Geneticandgenomicstudieshavehelpedtoidentifynewertherapeutictargetsinatherosclerosis.Forexample,
discoveryofgeneticvariantsofPCSK9[150156]inregulatingLDLClevelshasledtoarapiddevelopmentof
PCSK9inhibitorasapotentialtherapyforLDLCloweringandreducingcardiovascularevents.Furthermore,
geneticmanipulationsinanimalmodelswillacceleratethepaceofatherosclerosisresearch[157].(See"PCSK9
inhibitors:Pharmacology,adverseeffects,anduse".)

InfectionChronicinfectionmaycontributetothepathogenesisofatherosclerosis.Themajororganismsthat
havebeenstudiedareChlamydiapneumoniae,cytomegalovirus(CMV),andHelicobacterpylorihowever,
enterovirus(primarilycoxsackieBvirus),hepatitisAvirus(HAV),andherpessimplexvirus(HSV)type1andtype
2havealsobeenimplicated.(See"Overviewofpossibleriskfactorsforcardiovasculardisease",sectionon
'Infection'.)

Chronicinfectioncouldactbyanumberofmechanisms,includingdirectvascularinjuryandinductionofa
systemicinflammatorystate.(See'Inflammation'above.)

Despitetheattractivenessofinfectionasapotentialimportantcontributingfactor,clinicalevidencetosupportits
roleislacking,andantibiotictherapydoesnotreducetheriskofrecurrentmyocardialinfarction.

C.pneumoniaeinfectionMultipleobservationsraisethepossibilityofacausalroleforChlamydophila
(alsoreferredtoasChlamydia)pneumoniaeinthepathogenesisofatheroscleroticcardiovasculardisease.
However,theclinicalbenefitsofantiChlamydiadrugtherapyhavenotbeensubstantiated[158].

CytomegalovirusinfectionInfectionwithCMVandotherherpesviruses,suchasHSV,hasbeen
implicatedinsomebutnotallstudiesinthedevelopmentofatherosclerosis,restenosis,andtransplant
vasculopathy[159164].

SerumantiCMVantibodylevelsaresignificantlyelevatedinpatientswithcoronarydiseasewhencomparedto
controlsubjects[160,165]andinthosewithcarotidintimalthickening(ameasureofsubclinicalatherosclerosis)
[166].Inaddition,CMVantigens,nucleicacidsequences,andDNAhavebeendetectedinsmoothmusclecells
ofcarotidarteryplaquesobtainedfrompatientsundergoingendarterectomy[167].

CMVinfectionmightpromotethedevelopmentofatherosclerosisbyincreasingtheuptakeofoxidizedLDLin
vascularsmoothmusclecells[168]andbyincreasingtheneointimalresponsetovascularinjury[169].

CoxsackieBvirusinfectionArolehasbeenpostulatedfortheenteroviruscoxsackieBvirusinthe
pathogenesisofcoronaryheartdisease[170].However,norigorousevidenceexiststosupportitsrolein
atherosclerosis.

H.pyloriThereisalsosomeevidencelinkingH.pyloriinfectionwithatherosclerosisandprematureMI
[171,172].However,itisuncertainifthisrelationshipisbaseduponthebacteriumitselforitsassociationwith
otherconfoundingfactorsrelatedtoatherosclerosis,primarilylowersocioeconomicclass,olderage,andsmoking
[173].

PathogenburdenInadditiontoindividualinfections,thetotalpathogenburden,ie,thenumberof
pathogenstowhichanindividualhasbeenexposed,maybeanimportantriskfactorforatherosclerosis[174
177].Thiswasillustratedinareportof375patientsundergoingcoronaryangiographyantibodytiterstoa
numberofpathogensweremeasuredandassessmentofcoronaryendothelialfunctionwasperformedin218
[175].Thepathogenburden,morethananysinglepathogen,correlatedwiththepresenceandseverityof
coronarydiseaseandwasanindependentpredictorofendothelialdysfunction.Thelikelihoodofatherosclerosis
wasmarkedlyincreasedinpatientswithfourorfivepositivetitersandelevatedserumCRP.

PathogenburdenwithatheroscleroticlesionshasbeendirectlyassessedbytestingforbacterialrDNAsignatures
bypolymerasechainreactioninspecimensobtainedduringcatheterbasedatherectomy[178].BacterialDNA
wasfoundinallpatientswithameanof12speciesperlesionbacterialDNAwasnotseenincontrolmaterialor
anyunaffectedcoronaryarteries.Itispossiblethatsecondarycolonizationmayacceleratediseaseprogression.

EffectofvaccinationVaccinationagainstinfluenzahasbeenevaluatedforapotentialbenefitin
preventingcardiovasculardisease[179181].Severalstudieshavefoundabeneficialeffectofinfluenza
vaccinationoncardiovascularevents[179,180].Whilethesestudiesareofinterestanddodocumentabeneficial
effectofinfluenzavaccinationinolderadults,theydonotestablishacausativerelationshipbetweeninfluenza
infectionandthepathogenesisofatherosclerosis.(See"Seasonalinfluenzavaccinationinadults",sectionon
'Olderadults'and"Geriatrichealthmaintenance",sectionon'Influenzavaccine'.)

ROLEOFPLAQUERUPTUREAtherosclerosisisgenerallyasymptomaticuntiltheplaquestenosisexceeds
70or80percentoftheluminaldiameter,whichcanproduceareductioninflow,aswithcoronarybloodflowto
myocardium.Thesestenoticlesionscanproducetypicalsymptomsofanginapectoris.

Acutecoronaryandcerebrovascularsyndromes(unstableangina,myocardialinfarction,suddendeath,and
stroke)aretypicallyduetoruptureofplaqueswithlessthan50percentstenosis[182184].Plaquerupturemay
alsobesilentrepeatedsilentrupturesandthrombosis,followedbywoundhealing,maycauseprogressionof
atherosclerosis,withanincreaseinplaqueburdenandpercentstenosisandnegativearterialremodeling[185].
Instudiesofpatientswithacutecoronarysyndromeswhounderwentimagingwithintravascularultrasound(and
weretreatedwithpercutaneouscoronaryinterventionoftheculpritlesion),recurrentmajoradverse
cardiovasculareventswerepredictedbythefindingofculpritandnonculpritlesionswiththincapfibroatheromas
[144,145].

Thepathologyandpathogenesisofthevulnerableplaqueanditsroleinacutecoronarysyndromesare
discussedelsewhere.(See"Pathologyandpathogenesisofthevulnerableplaque"and"Theroleofthe
vulnerableplaqueinacutecoronarysyndromes".)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsand
BeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandare
comfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)

Basicstopic(See"Patienteducation:Atherosclerosis(TheBasics)".)

SUMMARY

Althoughatherosclerosisisoneofthemoststudiedhumandiseases,anagreeduponunifyinghypothesis
thatfullyexplainsitspathogenesisremainselusive.
 Multiplefactorscontributetothepathogenesisofatherosclerosis,includingendothelialdysfunction,
inflammatoryandimmunologicfactors,plaquerupture,andthetraditionalriskfactorsofhypertension,
diabetes,dyslipidemia,andsmoking.Despitetheattractivenessofinfectionasapotentialcontributingfactor,
clinicalevidencetosupportitsroleislacking.(See'Pathogenesis'above.)

Atherosclerosisbeginsinchildhoodwiththedevelopmentoffattystreaks.Theadvancedlesionsof
atherosclerosisoccurwithincreasingfrequencywithaging.(See'Epidemiology'above.)

Thehistologicstagesofatherosclerosisincludefattystreak,fibrouscap,fibrousplaques,andadvances
lesions.Withtheavailabilityofadvancedvascularimagingtechniques,theplaquehistologicalcharacteristics
canbeidentifiedinvivo.(See'Histology'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

REFERENCES

1.FaxonDP,FusterV,LibbyP,etal.AtheroscleroticVascularDiseaseConference:WritingGroupIII:
pathophysiology.Circulation2004109:2617.
2.LibbyP,RidkerPM,HanssonGK.Progressandchallengesintranslatingthebiologyofatherosclerosis.
Nature2011473:317.
3.StaryHC,ChandlerAB,DinsmoreRE,etal.Adefinitionofadvancedtypesofatheroscleroticlesionsanda
histologicalclassificationofatherosclerosis.AreportfromtheCommitteeonVascularLesionsofthe
CouncilonArteriosclerosis,AmericanHeartAssociation.Circulation199592:1355.
4.TuzcuEM,KapadiaSR,TutarE,etal.Highprevalenceofcoronaryatherosclerosisinasymptomatic
teenagersandyoungadults:evidencefromintravascularultrasound.Circulation2001103:2705.
5.McGillHCJr,McMahanCA,ZieskeAW,etal.AssociationofCoronaryHeartDiseaseRiskFactorswith
microscopicqualitiesofcoronaryatherosclerosisinyouth.Circulation2000102:374.
6.StrongJP,MalcomGT,McMahanCA,etal.Prevalenceandextentofatherosclerosisinadolescentsand
youngadults:implicationsforpreventionfromthePathobiologicalDeterminantsofAtherosclerosisinYouth
Study.JAMA1999281:727.
7.vanDijkRA,VirmaniR,vonderThsenJH,etal.Thenaturalhistoryofaorticatherosclerosis:asystematic
histopathologicalevaluationoftheperirenalregion.Atherosclerosis2010210:100.
8.DaviesMJ,WoolfN,RowlesPM,PepperJ.Morphologyoftheendotheliumoveratheroscleroticplaquesin
humancoronaryarteries.BrHeartJ198860:459.
9.SataM,SaiuraA,KunisatoA,etal.Hematopoieticstemcellsdifferentiateintovascularcellsthatparticipate
inthepathogenesisofatherosclerosis.NatMed20028:403.
10.O'BrienKD,OlinKL,AlpersCE,etal.Comparisonofapolipoproteinandproteoglycandepositsinhuman
coronaryatheroscleroticplaques:colocalizationofbiglycanwithapolipoproteins.Circulation199898:519.
11.KockxMM,DeMeyerGR,MuhringJ,etal.Apoptosisandrelatedproteinsindifferentstagesofhuman
atheroscleroticplaques.Circulation199897:2307.
12.HeistadDD,MarcusML,LarsenGE,ArmstrongML.Roleofvasavasoruminnourishmentoftheaorticwall.
AmJPhysiol1981240:H781.
13.BargerAC,BeeuwkesR3rd,LaineyLL,SilvermanKJ.Hypothesis:vasavasorumandneovascularization
ofhumancoronaryarteries.Apossibleroleinthepathophysiologyofatherosclerosis.NEnglJMed1984
310:175.
14.KolodgieFD,GoldHK,BurkeAP,etal.Intraplaquehemorrhageandprogressionofcoronaryatheroma.N
EnglJMed2003349:2316.
15.VirmaniR,NarulaJ,FarbA.Whenneoangiogenesisricochets.AmHeartJ1998136:937.
16.SchoenhagenP,ZiadaKM,VinceDG,etal.Arterialremodelingandcoronaryarterydisease:theconceptof
"dilated"versus"obstructive"coronaryatherosclerosis.JAmCollCardiol200138:297.
17.SchoenhagenP,ZiadaKM,KapadiaSR,etal.Extentanddirectionofarterialremodelinginstableversus
unstablecoronarysyndromes:anintravascularultrasoundstudy.Circulation2000101:598.
18.KittaY,ObataJE,NakamuraT,etal.Persistentimpairmentofendothelialvasomotorfunctionhasa
negativeimpactonoutcomeinpatientswithcoronaryarterydisease.JAmCollCardiol200953:323.
19.AndersonTJ,MeredithIT,CharbonneauF,etal.Endotheliumdependentcoronaryvasomotionrelatesto
thesusceptibilityofLDLtooxidationinhumans.Circulation199693:1647.
20.HarrisonDG,ArmstrongML,FreimanPC,HeistadDD.Restorationofendotheliumdependentrelaxationby
dietarytreatmentofatherosclerosis.JClinInvest198780:1808.
21.JohnS,SchlaichM,LangenfeldM,etal.Increasedbioavailabilityofnitricoxideafterlipidloweringtherapy
inhypercholesterolemicpatients:arandomized,placebocontrolled,doubleblindstudy.Circulation1998
98:211.
22.ManciniGB,HenryGC,MacayaC,etal.Angiotensinconvertingenzymeinhibitionwithquinaprilimproves
endothelialvasomotordysfunctioninpatientswithcoronaryarterydisease.TheTREND(TrialonReversing
ENdothelialDysfunction)Study.Circulation199694:258.
23.LevineGN,FreiB,KoulourisSN,etal.Ascorbicacidreversesendothelialvasomotordysfunctioninpatients
withcoronaryarterydisease.Circulation199693:1107.
24.SteinJH,KeevilJG,WiebeDA,etal.Purplegrapejuiceimprovesendothelialfunctionandreducesthe
susceptibilityofLDLcholesteroltooxidationinpatientswithcoronaryarterydisease.Circulation1999
100:1050.
25.PaolettiR,GottoAMJr,HajjarDP.Inflammationinatherosclerosisandimplicationsfortherapy.Circulation
2004109:III20.
26.HanssonGK.Inflammation,atherosclerosis,andcoronaryarterydisease.NEnglJMed2005352:1685.
27.LibbyP,RidkerPM,HanssonGK,LeducqTransatlanticNetworkonAtherothrombosis.Inflammationin
atherosclerosis:frompathophysiologytopractice.JAmCollCardiol200954:2129.
28.WeberC,NoelsH.Atherosclerosis:currentpathogenesisandtherapeuticoptions.NatMed201117:1410.
29.BerlinerJA,NavabM,FogelmanAM,etal.Atherosclerosis:basicmechanisms.Oxidation,inflammation,
andgenetics.Circulation199591:2488.
30.SteinbergD,WitztumJL.Oxidizedlowdensitylipoproteinandatherosclerosis.ArteriosclerThrombVasc
Biol201030:2311.
31.GawazM,NeumannFJ,DickfeldT,etal.Activatedplateletsinducemonocytechemotacticprotein1
secretionandsurfaceexpressionofintercellularadhesionmolecule1onendothelialcells.Circulation1998
98:1164.
32.TsaoPS,WangB,BuitragoR,etal.Nitricoxideregulatesmonocytechemotacticprotein1.Circulation
199796:934.
33.TakahashiM,KitagawaS,MasuyamaJI,etal.Humanmonocyteendothelialcellinteractioninduces
synthesisofgranulocytemacrophagecolonystimulatingfactor.Circulation199693:1185.
34.RajavashisthT,QiaoJH,TripathiS,etal.Heterozygousosteopetrotic(op)mutationreducesatherosclerosis
inLDLreceptordeficientmice.JClinInvest1998101:2702.
35.RectenwaldJE,MoldawerLL,HuberTS,etal.Directevidenceforcytokineinvolvementinneointimal
hyperplasia.Circulation2000102:1697.
36.BrizziMF,FormatoL,DentelliP,etal.Interleukin3stimulatesmigrationandproliferationofvascularsmooth
musclecells:apotentialroleinatherogenesis.Circulation2001103:549.
37.SimoniniA,MoscucciM,MullerDW,etal.IL8isanangiogenicfactorinhumancoronaryatherectomy
tissue.Circulation2000101:1519.
38.LiH,FreemanMW,LibbyP.Regulationofsmoothmusclecellscavengerreceptorexpressioninvivoby
atherogenicdietsandinvitrobycytokines.JClinInvest199595:122.
39.TintutY,PatelJ,ParhamiF,DemerLL.Tumornecrosisfactoralphapromotesinvitrocalcificationof
vascularcellsviathecAMPpathway.Circulation2000102:2636.
40.KaartinenM,PenttilA,KovanenPT.Mastcellsinruptureproneareasofhumancoronaryatheromas
produceandstoreTNFalpha.Circulation199694:2787.
41.DavidsonMH,CorsonMA,AlbertsMJ,etal.Consensuspanelrecommendationforincorporating
lipoproteinassociatedphospholipaseA2testingintocardiovasculardiseaseriskassessmentguidelines.
AmJCardiol2008101:51F.
42.YoungJL,LibbyP,SchnbeckU.Cytokinesinthepathogenesisofatherosclerosis.ThrombHaemost2002
88:554.
43.FalkE.Pathogenesisofatherosclerosis.JAmCollCardiol200647:C7.
44.WettingerSB,DoggenCJ,SpekCA,etal.HighthroughputmRNAprofilinghighlightsassociationsbetween
myocardialinfarctionandaberrantexpressionofinflammatorymoleculesinbloodcells.Blood2005
105:2000.
45.KiechlS,LorenzE,ReindlM,etal.Tolllikereceptor4polymorphismsandatherogenesis.NEnglJMed
2002347:185.
46.LaursenLS,OvergaardMT,NielsenCG,etal.Substratespecificityofthemetalloproteinasepregnancy
associatedplasmaproteinA(PAPPA)assessedbymutagenesisandanalysisofsyntheticpeptides:
substrateresiduesdistantfromthescissilebondarecriticalforproteolysis.BiochemJ2002367:31.
47.LawrenceJB,OxvigC,OvergaardMT,etal.Theinsulinlikegrowthfactor(IGF)dependentIGFbinding
protein4proteasesecretedbyhumanfibroblastsispregnancyassociatedplasmaproteinA.ProcNatl
AcadSciUSA199996:3149.
48.OrtizCO,ChenBK,BaleLK,etal.Transforminggrowthfactorbetaregulationoftheinsulinlikegrowth
factorbindingprotein4proteasesysteminculturedhumanosteoblasts.JBoneMinerRes200318:1066.
49.ConoverCA,HarringtonSC,BaleLK.DifferentialregulationofpregnancyassociatedplasmaproteinAin
humancoronaryarteryendothelialcellsandsmoothmusclecells.GrowthHormIGFRes200818:213.
50.LiW,LiH,GuF.CRPandTNFinducePAPPAexpressioninhumanperipheralbloodmononuclearcells.
MediatorsInflamm20122012:697832.
51.SangiorgiG,MaurielloA,BonannoE,etal.Pregnancyassociatedplasmaproteinaismarkedlyexpressed
bymonocytemacrophagecellsinvulnerableandrupturedcarotidatheroscleroticplaques:alinkbetween
inflammationandcerebrovascularevents.JAmCollCardiol200647:2201.
52.BayesGenisA,ConoverCA,OvergaardMT,etal.PregnancyassociatedplasmaproteinAasamarkerof
acutecoronarysyndromes.NEnglJMed2001345:1022.
53.IversenKK,DalsgaardM,TeisnerAS,etal.PregnancyassociatedplasmaproteinA,amarkerforoutcome
inpatientssuspectedforacutecoronarysyndrome.ClinBiochem201043:851.
54.IversenKK,DalsgaardM,TeisnerAS,etal.UsefulnessofpregnancyassociatedplasmaproteinAin
patientswithacutecoronarysyndrome.AmJCardiol2009104:1465.
55.ReportoftheNationalCholesterolEducationProgramExpertPanelonDetection,Evaluation,and
TreatmentofHighBloodCholesterolinAdults.TheExpertPanel.ArchInternMed1988148:36.
56.GordonT,CastelliWP,HjortlandMC,etal.Highdensitylipoproteinasaprotectivefactoragainstcoronary
heartdisease.TheFraminghamStudy.AmJMed197762:707.
57.RommPA,GreenCE,ReaganK,RackleyCE.Relationofserumlipoproteincholesterollevelstopresence
andseverityofangiographiccoronaryarterydisease.AmJCardiol199167:479.
58.ManninenV,TenkanenL,KoskinenP,etal.JointeffectsofserumtriglycerideandLDLcholesterolandHDL
cholesterolconcentrationsoncoronaryheartdiseaseriskintheHelsinkiHeartStudy.Implicationsfor
treatment.Circulation199285:37.
59.CriquiMH,HeissG,CohnR,etal.Plasmatriglyceridelevelandmortalityfromcoronaryheartdisease.N
EnglJMed1993328:1220.
60.AssmannG,SchulteH.Relationofhighdensitylipoproteincholesterolandtriglyceridestoincidenceof
atheroscleroticcoronaryarterydisease(thePROCAMexperience).ProspectiveCardiovascularMnster
study.AmJCardiol199270:733.
61.SummaryofthesecondreportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelon
Detection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelII).JAMA
1993269:3015.
62.IulianoL,MaurielloA,SbarigiaE,etal.Radiolabelednativelowdensitylipoproteininjectedintopatients
withcarotidstenosisaccumulatesinmacrophagesofatheroscleroticplaque:effectofvitaminE
supplementation.Circulation2000101:1249.
63.PodrezEA,FebbraioM,SheibaniN,etal.MacrophagescavengerreceptorCD36isthemajorreceptorfor
LDLmodifiedbymonocytegeneratedreactivenitrogenspecies.JClinInvest2000105:1095.
64.FebbraioM,HajjarDP,SilversteinRL.CD36:aclassBscavengerreceptorinvolvedinangiogenesis,
atherosclerosis,inflammation,andlipidmetabolism.JClinInvest2001108:785.
65.TabasI.Consequencesofcellularcholesterolaccumulation:basicconceptsandphysiologicalimplications.
JClinInvest2002110:905.
66.VinkH,ConstantinescuAA,SpaanJA.Oxidizedlipoproteinsdegradetheendothelialsurfacelayer:
implicationsforplateletendothelialcelladhesion.Circulation2000101:1500.
67.EharaS,UedaM,NarukoT,etal.Elevatedlevelsofoxidizedlowdensitylipoproteinshowapositive
relationshipwiththeseverityofacutecoronarysyndromes.Circulation2001103:1955.
68.TsimikasS,BergmarkC,BeyerRW,etal.Temporalincreasesinplasmamarkersofoxidizedlowdensity
lipoproteinstronglyreflectthepresenceofacutecoronarysyndromes.JAmCollCardiol200341:360.
69.NationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation,andTreatmentof
HighBloodCholesterolinAdults(AdultTreatmentPanelIII).ThirdReportoftheNationalCholesterol
EducationProgram(NCEP)ExpertPanelonDetection,Evaluation,andTreatmentofHighBlood
CholesterolinAdults(AdultTreatmentPanelIII)finalreport.Circulation2002106:3143.
70.AIMHIGHInvestigators,BodenWE,ProbstfieldJL,etal.NiacininpatientswithlowHDLcholesterollevels
receivingintensivestatintherapy.NEnglJMed2011365:2255.
71.SchwartzGG,OlssonAG,AbtM,etal.Effectsofdalcetrapibinpatientswitharecentacutecoronary
syndrome.NEnglJMed2012367:2089.
72.HPS2THRIVECollaborativeGroup.HPS2THRIVErandomizedplacebocontrolledtrialin25673highrisk
patientsofERniacin/laropiprant:trialdesign,prespecifiedmuscleandliveroutcomes,andreasonsfor
stoppingstudytreatment.EurHeartJ201334:1279.
73.VoightBF,PelosoGM,OrhoMelanderM,etal.PlasmaHDLcholesterolandriskofmyocardialinfarction:a
mendelianrandomisationstudy.Lancet2012380:572.
74.KheraAV,CuchelM,delaLleraMoyaM,etal.Cholesteroleffluxcapacity,highdensitylipoproteinfunction,
andatherosclerosis.NEnglJMed2011364:127.
75.RohatgiA,KheraA,BerryJD,etal.HDLcholesteroleffluxcapacityandincidentcardiovascularevents.N
EnglJMed2014371:2383.
76.VarboA,BennM,TybjrgHansenA,etal.Remnantcholesterolasacausalriskfactorforischemicheart
disease.JAmCollCardiol201361:427.
77.VarboA,BennM,TybjrgHansenA,NordestgaardBG.Elevatedremnantcholesterolcausesbothlow
gradeinflammationandischemicheartdisease,whereaselevatedlowdensitylipoproteincholesterol
causesischemicheartdiseasewithoutinflammation.Circulation2013128:1298.
78.BoffaMB,KoschinskyML.Updateonlipoprotein(a)asacardiovascularriskfactorandmediator.Curr
AtherosclerRep201315:360.
79.AnglsCanoE,delaPeaDazA,LoyauS.Inhibitionoffibrinolysisbylipoprotein(a).AnnNYAcadSci
2001936:261.
80.SeimonTA,NadolskiMJ,LiaoX,etal.AtherogeniclipidsandlipoproteinstriggerCD36TLR2dependent
apoptosisinmacrophagesundergoingendoplasmicreticulumstress.CellMetab201012:467.
81.ChoT,JungY,KoschinskyML.Apolipoprotein(a),throughitsstronglysinebindingsiteinKIV(10'),mediates
increasedendothelialcellcontractionandpermeabilityviaaRho/Rhokinase/MYPT1dependentpathway.J
BiolChem2008283:30503.
82.ChoT,RomagnuoloR,ScipioneC,etal.Apolipoprotein(a)stimulatesnucleartranslocationofcatenin:a
novelpathogenicmechanismforlipoprotein(a).MolBiolCell201324:210.
83.ZioncheckTF,PowellLM,RiceGC,etal.Interactionofrecombinantapolipoprotein(a)andlipoprotein(a)
withmacrophages.JClinInvest199187:767.
84.AlbersJJ,SleeA,O'BrienKD,etal.RelationshipofapolipoproteinsA1andB,andlipoprotein(a)to
cardiovascularoutcomes:theAIMHIGHtrial(AtherothrombosisInterventioninMetabolicSyndromewith
LowHDL/HighTriglycerideandImpactonGlobalHealthOutcomes).JAmCollCardiol201362:1575.
85.DAWBERTR,MEADORSGF,MOOREFEJr.Epidemiologicalapproachestoheartdisease:the
FraminghamStudy.AmJPublicHealthNationsHealth195141:279.
86.YusufS,HawkenS,OunpuuS,etal.Effectofpotentiallymodifiableriskfactorsassociatedwithmyocardial
infarctionin52countries(theINTERHEARTstudy):casecontrolstudy.Lancet2004364:937.
87.FrohlichJ,AlSarrafA.Cardiovascularriskandatherosclerosisprevention.CardiovascPathol201322:16.
88.AmbroseJA,BaruaRS.Thepathophysiologyofcigarettesmokingandcardiovasculardisease:anupdate.
JAmCollCardiol200443:1731.
89.MayhanWG,SharpeGM.Effectofcigarettesmokeextractonarteriolardilatationinvivo.JApplPhysiol
(1985)199681:1996.
90.MayhanWG,PatelKP.Effectofnicotineonendotheliumdependentarteriolardilatationinvivo.AmJ
Physiol1997272:H2337.
 91.OtaY,KugiyamaK,SugiyamaS,etal.Impairmentofendotheliumdependentrelaxationofrabbitaortasby
cigarettesmokeextractroleoffreeradicalsandattenuationbycaptopril.Atherosclerosis1997131:195.
92.TracyRP,PsatyBM,MacyE,etal.LifetimesmokingexposureaffectstheassociationofCreactiveprotein
withcardiovasculardiseaseriskfactorsandsubclinicaldiseaseinhealthyelderlysubjects.Arterioscler
ThrombVascBiol199717:2167.
93.BermudezEA,RifaiN,BuringJE,etal.Relationbetweenmarkersofsystemicvascularinflammationand
smokinginwomen.AmJCardiol200289:1117.
94.MendallMA,PatelP,AsanteM,etal.Relationofserumcytokineconcentrationstocardiovascularrisk
factorsandcoronaryheartdisease.Heart199778:273.
95.TappiaPS,TroughtonKL,LangleyEvansSC,GrimbleRF.Cigarettesmokinginfluencescytokine
productionandantioxidantdefences.ClinSci(Lond)199588:485.
96.IchikiK,IkedaH,HaramakiN,etal.Longtermsmokingimpairsplateletderivednitricoxiderelease.
Circulation199694:3109.
97.SawadaM,KishiY,NumanoF,IsobeM.Smokerslackmorningincreaseinplateletsensitivitytonitricoxide.
JCardiovascPharmacol200240:571.
98.KannelWB,D'AgostinoRB,BelangerAJ.Fibrinogen,cigarettesmoking,andriskofcardiovasculardisease:
insightsfromtheFraminghamStudy.AmHeartJ1987113:1006.
99.SmithFB,LeeAJ,FowkesFG,etal.Hemostaticfactorsaspredictorsofischemicheartdiseaseandstroke
intheEdinburghArteryStudy.ArteriosclerThrombVascBiol199717:3321.
100.BaruaRS,AmbroseJA,SahaDC,EalesReynoldsLJ.Smokingisassociatedwithalteredendothelial
derivedfibrinolyticandantithromboticfactors:aninvitrodemonstration.Circulation2002106:905.
101.HeitzerT,YlHerttualaS,LuomaJ,etal.Cigarettesmokingpotentiatesendothelialdysfunctionofforearm
resistancevesselsinpatientswithhypercholesterolemia.RoleofoxidizedLDL.Circulation199693:1346.
102.NishioE,WatanabeY.Cigarettesmokeextractinhibitsplasmaparaoxonaseactivitybymodificationofthe
enzyme'sfreethiols.BiochemBiophysResCommun1997236:289.
103.ReavenG,TsaoPS.Insulinresistanceandcompensatoryhyperinsulinemia:thekeyplayerbetween
cigarettesmokingandcardiovasculardisease?JAmCollCardiol200341:1044.
104.PyrlaK.Relationshipofglucosetoleranceandplasmainsulintotheincidenceofcoronaryheartdisease:
resultsfromtwopopulationstudiesinFinland.DiabetesCare19792:131.
105.WelbornTA,WearneK.CoronaryheartdiseaseincidenceandcardiovascularmortalityinBusseltonwith
referencetoglucoseandinsulinconcentrations.DiabetesCare19792:154.
106.DucimetiereP,EschwegeE,PapozL,etal.Relationshipofplasmainsulinlevelstotheincidenceof
myocardialinfarctionandcoronaryheartdiseasemortalityinamiddleagedpopulation.Diabetologia1980
19:205.
107.PyrlK,SavolainenE,KaukolaS,HaapakoskiJ.Plasmainsulinascoronaryheartdiseaseriskfactor:
relationshiptootherriskfactorsandpredictivevalueduring91/2yearfollowupoftheHelsinkiPolicemen
Studypopulation.ActaMedScandSuppl1985701:38.
108.EschwegeE,RichardJL,ThibultN,etal.Coronaryheartdiseasemortalityinrelationwithdiabetes,blood
glucoseandplasmainsulinlevels.TheParisProspectiveStudy,tenyearslater.HormMetabResSuppl
198515:41.
109.HaffnerSM,SternMP,HazudaHP,etal.Hyperinsulinemiainapopulationathighriskfornoninsulin
dependentdiabetesmellitus.NEnglJMed1986315:220.
110.RnnemaaT,LaaksoM,PyrlK,etal.Highfastingplasmainsulinisanindicatorofcoronaryheart
diseaseinnoninsulindependentdiabeticpatientsandnondiabeticsubjects.ArteriosclerThromb1991
11:80.
111.WelhamMJ,BoneH,LevingsM,etal.Insulinreceptorsubstrate2isthemajor170kDaprotein
phosphorylatedontyrosineinresponsetocytokinesinmurinelymphohemopoieticcells.JBiolChem1997
272:1377.
112.MalideD,DaviesHillTM,LevineM,SimpsonIA.DistinctlocalizationofGLUT1,3,and5inhuman
monocytederivedmacrophages:effectsofcellactivation.AmJPhysiol1998274:E516.
113.ParkYM,RKashyapS,AMajorJ,SilversteinRL.Insulinpromotesmacrophagefoamcellformation:
potentialimplicationsindiabetesrelatedatherosclerosis.LabInvest201292:1171.
114.FernndezRealJM,RicartW.Insulinresistanceandchroniccardiovascularinflammatorysyndrome.
EndocrRev200324:278.
115.MillerYI,ViriyakosolS,WorrallDS,etal.Tolllikereceptor4dependentandindependentcytokine
secretioninducedbyminimallyoxidizedlowdensitylipoproteininmacrophages.ArteriosclerThrombVasc
Biol200525:1213.
116.SaelyCH,ReinP,VonbankA,etal.Type2diabetesandtheprogressionofvisualizedatherosclerosisto
clinicalcardiovascularevents.IntJCardiol2013167:776.
117.HasenstabD,LeaH,HartCE,etal.Tissuefactoroverexpressioninratarterialneointimamodels
thrombosisandprogressionofadvancedatherosclerosis.Circulation2000101:2651.
118.DaughertyA,ManningMW,CassisLA.AngiotensinIIpromotesatheroscleroticlesionsandaneurysmsin
apolipoproteinEdeficientmice.JClinInvest2000105:1605.
119.PotterDD,SobeyCG,TompkinsPK,etal.Evidencethatmacrophagesinatheroscleroticlesionscontain
angiotensinII.Circulation199898:800.
120.StrawnWB,ChappellMC,DeanRH,etal.Inhibitionofearlyatherogenesisbylosartaninmonkeyswith
dietinducedhypercholesterolemia.Circulation2000101:1586.
121.LermanA,EdwardsBS,HallettJW,etal.Circulatingandtissueendothelinimmunoreactivityinadvanced
atherosclerosis.NEnglJMed1991325:997.
122.IhlingC,SzombathyT,BohrmannB,etal.Coexpressionofendothelinconvertingenzyme1and
endothelin1indifferentstagesofhumanatherosclerosis.Circulation2001104:864.
123.MathewV,CannanCR,MillerVM,etal.Enhancedendothelinmediatedcoronaryvasoconstrictionand
attenuatedbasalnitricoxideactivityinexperimentalhypercholesterolemia.Circulation199796:1930.
124.HasdaiD,HolmesDRJr,GarrattKN,etal.Mechanicalpressureandstretchreleaseendothelin1from
humanatheroscleroticcoronaryarteriesinvivo.Circulation199795:357.
125.MinaminoT,KuriharaH,TakahashiM,etal.Endothelinconvertingenzymeexpressionintheratvascular
injurymodelandhumancoronaryatherosclerosis.Circulation199795:221.
126.IiyamaK,HajraL,IiyamaM,etal.Patternsofvascularcelladhesionmolecule1andintercellularadhesion
molecule1expressioninrabbitandmouseatheroscleroticlesionsandatsitespredisposedtolesion
formation.CircRes199985:199.
127.CybulskyMI,IiyamaK,LiH,etal.AmajorroleforVCAM1,butnotICAM1,inearlyatherosclerosis.JClin
Invest2001107:1255.
128.JohnsonRC,ChapmanSM,DongZM,etal.AbsenceofPselectindelaysfattystreakformationinmice.J
ClinInvest199799:1037.
129.DongZM,BrownAA,WagnerDD.ProminentroleofPselectininthedevelopmentofadvanced
atherosclerosisinApoEdeficientmice.Circulation2000101:2290.
130.AdamsMR,JessupW,HailstonesD,CelermajerDS.Largininereduceshumanmonocyteadhesionto
vascularendotheliumandendothelialexpressionofcelladhesionmolecules.Circulation199795:662.
131.McCrohonJA,JessupW,HandelsmanDJ,CelermajerDS.Androgenexposureincreaseshumanmonocyte
adhesiontovascularendotheliumandendothelialcellexpressionofvascularcelladhesionmolecule1.
Circulation199999:2317.
132.PatelSS,ThiagarajanR,WillersonJT,YehET.Inhibitionofalpha4integrinandICAM1markedlyattenuate
macrophagehomingtoatheroscleroticplaquesinApoEdeficientmice.Circulation199897:75.
133.HagiwaraH,MitsumataM,YamaneT,etal.LaminarshearstressinducedGROmRNAandprotein
expressioninendothelialcells.Circulation199898:2584.
134.TsaoPS,BuitragoR,ChanJR,CookeJP.Fluidflowinhibitsendothelialadhesiveness.Nitricoxideand
transcriptionalregulationofVCAM1.Circulation199694:1682.
135.GimbroneMAJr,GarcaCardeaG.Vascularendothelium,hemodynamics,andthepathobiologyof
atherosclerosis.CardiovascPathol201322:9.
136.NwasokwaON,WeissM,GladstoneC,BodenheimerMM.Effectofcoronaryarterysizeontheprevalence
ofatherosclerosis.AmJCardiol199678:741.
137.GnassoA,CaralloC,IraceC,etal.Associationbetweenintimamediathicknessandwallshearstressin
commoncarotidarteriesinhealthymalesubjects.Circulation199694:3257.
138.HolvoetP,PerezG,ZhaoZ,etal.Malondialdehydemodifiedlowdensitylipoproteinsinpatientswith
atheroscleroticdisease.JClinInvest199595:2611.
139.InoueT,UchidaT,KamishiradoH,etal.Clinicalsignificanceofantibodyagainstoxidizedlowdensity
lipoproteininpatientswithatheroscleroticcoronaryarterydisease.JAmCollCardiol200137:775.
140.BuiMN,SackMN,MoutsatsosG,etal.Autoantibodytiterstooxidizedlowdensitylipoproteininpatients
withcoronaryatherosclerosis.AmHeartJ1996131:663.
141.YuE,MercerJ,BennettM.Mitochondriainvasculardisease.CardiovascRes201295:173.
142.DavidsonSM,YellonDM.MitochondrialDNAdamage,oxidativestress,andatherosclerosis:wherethereis
smokethereisnotalwaysfire.Circulation2013128:681.
143.YuE,CalvertPA,MercerJR,etal.MitochondrialDNAdamagecanpromoteatherosclerosisindependently
ofreactiveoxygenspeciesthrougheffectsonsmoothmusclecellsandmonocytesandcorrelateswith
higherriskplaquesinhumans.Circulation2013128:702.
144.CalvertPA,ObaidDR,O'SullivanM,etal.AssociationbetweenIVUSfindingsandadverseoutcomesin
patientswithcoronaryarterydisease:theVIVA(VHIVUSinVulnerableAtherosclerosis)Study.JACC
CardiovascImaging20114:894.
145.StoneGW,MaeharaA,LanskyAJ,etal.Aprospectivenaturalhistorystudyofcoronaryatherosclerosis.N
EnglJMed2011364:226.
146.LusisAJ,MarR,PajukantaP.Geneticsofatherosclerosis.AnnuRevGenomicsHumGenet20045:189.
147.HanssonGK,LibbyP.Theimmuneresponseinatherosclerosis:adoubleedgedsword.NatRevImmunol
20066:508.
148.ArnettDK,BairdAE,BarkleyRA,etal.Relevanceofgeneticsandgenomicsforpreventionandtreatmentof
cardiovasculardisease:ascientificstatementfromtheAmericanHeartAssociationCouncilon
EpidemiologyandPrevention,theStrokeCouncil,andtheFunctionalGenomicsandTranslationalBiology
InterdisciplinaryWorkingGroup.Circulation2007115:2878.
149.ChenY,RollinsJ,PaigenB,WangX.Geneticandgenomicinsightsintothemolecularbasisof
atherosclerosis.CellMetab20076:164.
150.CameronJ,HollaL,RanheimT,etal.EffectofmutationsinthePCSK9geneonthecellsurfaceLDL
receptors.HumMolGenet200615:1551.
151.AbifadelM,RabsJP,DevillersM,etal.Mutationsandpolymorphismsintheproproteinconvertase
subtilisinkexin9(PCSK9)geneincholesterolmetabolismanddisease.HumMutat200930:520.
152.HortonJD,CohenJC,HobbsHH.PCSK9:aconvertasethatcoordinatesLDLcatabolism.JLipidRes2009
50Suppl:S172.
153.CohenJ,PertsemlidisA,KotowskiIK,etal.LowLDLcholesterolinindividualsofAfricandescentresulting
fromfrequentnonsensemutationsinPCSK9.NatGenet200537:161.
154.ZhaoZ,TuakliWosornuY,LagaceTA,etal.Molecularcharacterizationoflossoffunctionmutationsin
PCSK9andidentificationofacompoundheterozygote.AmJHumGenet200679:514.
155.CohenJC,BoerwinkleE,MosleyTHJr,HobbsHH.SequencevariationsinPCSK9,lowLDL,andprotection
againstcoronaryheartdisease.NEnglJMed2006354:1264.
156.BennM,NordestgaardBG,GrandeP,etal.PCSK9R46L,lowdensitylipoproteincholesterollevels,and
riskofischemicheartdisease:3independentstudiesandmetaanalyses.JAmCollCardiol201055:2833.
157.DaughertyA,TabasI,RaderDJ.Acceleratingthepaceofatherosclerosisresearch.ArteriosclerThromb
VascBiol201535:11.
158.JoshiR,KhandelwalB,JoshiD,GuptaOP.Chlamydophilapneumoniaeinfectionandcardiovascular
disease.NAmJMedSci20135:169.
159.AdlerSP,HurJK,WangJB,VetrovecGW.Priorinfectionwithcytomegalovirusisnotamajorriskfactorfor
angiographicallydemonstratedcoronaryarteryatherosclerosis.JInfectDis1998177:209.
160.BlumA,GiladiM,WeinbergM,etal.Highanticytomegalovirus(CMV)IgGantibodytiterisassociatedwith
coronaryarterydiseaseandmaypredictpostcoronaryballoonangioplastyrestenosis.AmJCardiol1998
81:866.
161.RidkerPM,HennekensCH,StampferMJ,WangF.Prospectivestudyofherpessimplexvirus,
cytomegalovirus,andtheriskoffuturemyocardialinfarctionandstroke.Circulation199898:2796.
162.SorliePD,NietoFJ,AdamE,etal.Aprospectivestudyofcytomegalovirus,herpessimplexvirus1,and
coronaryheartdisease:theatherosclerosisriskincommunities(ARIC)study.ArchInternMed2000
160:2027.
163.ZhuJ,NietoFJ,HorneBD,etal.Prospectivestudyofpathogenburdenandriskofmyocardialinfarctionor
death.Circulation2001103:45.
164.RupprechtHJ,BlankenbergS,BickelC,etal.Impactofviralandbacterialinfectiousburdenonlongterm
prognosisinpatientswithcoronaryarterydisease.Circulation2001104:25.
165.AdamE,MelnickJL,ProbtsfieldJL,etal.Highlevelsofcytomegalovirusantibodyinpatientsrequiring
vascularsurgeryforatherosclerosis.Lancet19872:291.
166.NietoFJ,AdamE,SorlieP,etal.Cohortstudyofcytomegalovirusinfectionasariskfactorforcarotid
intimalmedialthickening,ameasureofsubclinicalatherosclerosis.Circulation199694:922.
167.MelnickJL,HuC,BurekJ,etal.CytomegalovirusDNAinarterialwallsofpatientswithatherosclerosis.J
MedVirol199442:170.
168.ZhouYF,GuettaE,YuZX,etal.Humancytomegalovirusincreasesmodifiedlowdensitylipoproteinuptake
andscavengerreceptormRNAexpressioninvascularsmoothmusclecells.JClinInvest199698:2129.
169.ZhouYF,ShouM,GuettaE,etal.Cytomegalovirusinfectionofratsincreasestheneointimalresponseto
vascularinjurywithoutconsistentevidenceofdirectinfectionofthevascularwall.Circulation1999
100:1569.
170.EpsteinSE,ZhouYF,ZhuJ.Infectionandatherosclerosis:emergingmechanisticparadigms.Circulation
1999100:e20.
171.PatelP,MendallMA,CarringtonD,etal.AssociationofHelicobacterpyloriandChlamydiapneumoniae
infectionswithcoronaryheartdiseaseandcardiovascularriskfactors.BMJ1995311:711.
172.GunnM,StephensJC,ThompsonJR,etal.SignificantassociationofcagApositiveHelicobacterpylori
strainswithriskofprematuremyocardialinfarction.Heart200084:267.
173.DaneshJ,PetoR.RiskfactorsforcoronaryheartdiseaseandinfectionwithHelicobacterpylori:meta
analysisof18studies.BMJ1998316:1130.
174.EspinolaKleinC,RupprechtHJ,BlankenbergS,etal.Impactofinfectiousburdenonextentandlongterm
prognosisofatherosclerosis.Circulation2002105:15.
175.PrasadA,ZhuJ,HalcoxJP,etal.Predispositiontoatherosclerosisbyinfections:roleofendothelial
dysfunction.Circulation2002106:184.
176.AndersonJL,CarlquistJF,MuhlesteinJB,etal.EvaluationofCreactiveprotein,aninflammatorymarker,
andinfectiousserologyasriskfactorsforcoronaryarterydiseaseandmyocardialinfarction.JAmColl
Cardiol199832:35.
177.MayrM,KiechlS,WilleitJ,etal.Infections,immunity,andatherosclerosis:associationsofantibodiesto
Chlamydiapneumoniae,Helicobacterpylori,andcytomegaloviruswithimmunereactionstoheatshock
protein60andcarotidorfemoralatherosclerosis.Circulation2000102:833.
178.OttSJ,ElMokhtariNE,MusfeldtM,etal.Detectionofdiversebacterialsignaturesinatheroscleroticlesions
ofpatientswithcoronaryheartdisease.Circulation2006113:929.
179.GurfinkelEP,delaFuenteRL,MendizO,MautnerB.Influenzavaccinepilotstudyinacutecoronary
syndromesandplannedpercutaneouscoronaryinterventions:theFLUVaccinationAcuteCoronary
Syndromes(FLUVACS)Study.Circulation2002105:2143.
180.NicholKL,NordinJ,MulloolyJ,etal.Influenzavaccinationandreductioninhospitalizationsforcardiac
diseaseandstrokeamongtheelderly.NEnglJMed2003348:1322.
181.NaghaviM,BarlasZ,SiadatyS,etal.Associationofinfluenzavaccinationandreducedriskofrecurrent
myocardialinfarction.Circulation2000102:3039.
182.FalkE,ShahPK,FusterV.Coronaryplaquedisruption.Circulation199592:657.
183.LittleWC,ConstantinescuM,ApplegateRJ,etal.Cancoronaryangiographypredictthesiteofa
subsequentmyocardialinfarctioninpatientswithmildtomoderatecoronaryarterydisease?Circulation
198878:1157.
184.AmbroseJA,TannenbaumMA,AlexopoulosD,etal.Angiographicprogressionofcoronaryarterydisease
andthedevelopmentofmyocardialinfarction.JAmCollCardiol198812:56.
185.BurkeAP,KolodgieFD,FarbA,etal.Healedplaquerupturesandsuddencoronarydeath:evidencethat
subclinicalrupturehasaroleinplaqueprogression.Circulation2001103:934.

Topic13603Version12.0
GRAPHICS

CriteriaforAmericanHeartAssociationlesionclassificationsystemand
correspondencewithclassificationofgrossarterialspecimens

Commentsand
AHA
Criteria correspondinggross
grade
classification

0 Normalarterywithorwithoutadaptiveintimalthickeningnohold Normaltissue

1 IsolatedMFCscontaininglipidnoextracellularlipidvariableadaptive Initialatheroscleroticlesion,
intimalthickeninggrosslywithlipidstaining sometimesvisiblegrosslywithlipid
staining

2 NumerousMFCs,ofteninlayers,withfineparticlesofextracellularlipid Fattystreak,visiblegrosslywithIII
nodistinctpoolsofextracellularlipid:variableadaptiveintimal staining
thickening

3 NumerousMFCswithpoolsofextracellularlipidnowelldefinedcore Fattyplaque,raisedfattystreak,
ofextracellularlipid intermediatelesion,ortransitional
lesion

4 NumerousMFGspluswelldefinedcoreofextracellularlipid,butwith Atheroma,fibrousplaque,orraised
luminalsurfacecoveredbyrelativelynormalintima lesion

5 NumerousMFCs,welldefinedcoreormultiplecoresofextracellular Fibroartherema,fibrousplaque,or
lipid,plusreactivefibroticcap,vascularization,orcalcium raisedlesion

6 Alloftheaboveplussurfacedefect,hematoma,hemorrhage,or Complicatedlesion
thrombosis

MFC:macrophagefoamcellAHA:AmericanHeartAssociation.

Graphic56922Version2.0
Fattystreak

Crosssectionofahumancoronaryarterydemonstratestheearly
atheroscleroticchangesofafattystreakwiththickeningoftheintima(short
arrow)andasoftlipidcore(longarrow).

CourtesyofCharlesERackley,MD.

Graphic76466Version1.0
Positiveandnegativearterialremodelingextremesofthe
remodelingresponse

Longitudinalsectionsthroughvesselsegmentsshowpositivelyandnegativelyremodeled
lesions.Thelumendiameterismaintainedwithpositiveremodeling,whilethereis
significantluminalnarrowingwithnegativeremodeling.

EEM:externalelasticmembraneRR:remodelingratio(EEMarealesion/EEMareaproximal
reference).

ReprintedwithpermissionfromSchoenhagenP,ZiadaKM,VinceDC,etal.JAmCollCardiol
200138:297.Copyright2001AmericanCollegeofCardiology.

Graphic68786Version2.0
Exampleofnegativeremodeling

Intravascularultrasoundimagesoftheproximalreferenceandlesionsiteare
shown.Theremodelingratio(EEMarealesion/EEMareaproximalreference)is
0.71.

EEM:externalelasticmembrane.

Reprintedwithpermissionfrom:SchoenhagenP,ZiadaKM,VinceDG,etal.JAmColl
Cardiol200138:297.Copyright2001AmericanCollegeofCardiology.

http://www.elsevier.com/locate/jacc
http://www.sciencedirect.com
Graphic72935Version6.0
Exampleofpositiveremodeling

Intravascularultrasoundimagesoftheproximalreferenceandlesionsiteare
shown.Theremodelingratio(EEMarealesion/EEMareaproximalreference)is
1.32.

EEM:externalelasticmembrane.

Reprintedwithpermissionfrom:SchoenhagenP,ZiadaKM,VinceDC,etal.JAmColl
Cardiol200138:297.Copyright2001AmericanCollegeofCardiology.

http://www.elsevier.com/locate/jacc
http://www.sciencedirect.com
Graphic59588Version5.0
Factorsthatcauseandinterventionsthatimproveendothelialdysfunction

Factorsassociatedwithendothelial Interventionsthatimproveendothelial
dysfunction function
Increasedage Larginine

Malesex Antioxidants

FamilyhistoryofCHD Smokingcessation

Smoking Cholesterollowering

Increasedserumcholesterol ACEinhibitors

LowserumHDLcholesterol Exercise

Hypertension MediterraneanDiet

Increasedserumhomocysteine

Diabetesmellitus

Obesity

Highfatmeal

Graphic56643Version2.0
Associationofincreasingplasmacholesteroland
coronaryrisk

Relationbetweenplasmacholesterolconcentrationandsixyearcoronaryheart
diseaseriskin361,662men(ages35to57)screenedduringtheMRFITstudy.
Thereisacontinuous,positive,gradedcorrelationbetweentheplasma
cholesterolconcentrationandcoronaryrisk.Toconvertplasmacholesterolto
mmol/L,divideby38.5.

Datafrom:StamlerJ,WentworthD,NeatonJD.Isrelationshipbetweenserum
cholesterolandriskofprematuredeathfromcoronaryheartdiseasecontinuousand
graded?Findingsin356,222primaryscreeneesoftheMultipleRiskFactor
InterventionTrial(MRFIT).JAMA1986256:2823.

Graphic60146Version7.0
RoleofLDLinatherosclerosis

SchematicrepresentationoftheeffectsofLDLandoxidizedLDLinthe
pathogenesisofatherosclerosis.Othercoronaryriskfactors,lowHDLlevels,
smoking,hypertension,diabetesmellitus,andestrogendeficiencyalsoenhance
theoxidationofLDL.

Graphic70984Version4.0
HDLCandcardiovascularrisk

Multiplierforcardiovascularrisk
HDL,mg/dL
Men Women

30 1.82

35 1.49

40 1.22 1.94

45 1.00 1.55

50 0.82 1.25

55 0.67 1.00

60 0.55 0.80

65 0.45 0.64

70 0.52

75 Longevitysyndrome Longevitysyndrome

InverserelationbetweenplasmaHDLcholesterollevelsandcardiovascularriskinmenandwomen.Multiplyvaluesby38.5to
converttommol/L.

DatafromCastelliWP.AmHeartJ1983106:1191.

Graphic57480Version3.0
Contributor Disclosures
Xue-Qiao Zhao, MD, FACC Grant/Research/Clinical Trial Support: AstraZeneca [PAD]; Amgen [Vascular
Inammation in HIV]; Bayer [Lower extremity artery permeability by MRI], KOWA [HDL function assessments in
HIV]. Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA Speakers Bureau: Menarini
[Angina pectoris (Ranolazine)]; Servier UK; Sano [Angina pectoris (Ivabradine)]. Consultant/Advisory Boards:
Sano UK. Peter Libby, MD Grant/Research/Clinical Trial Support: Novartis [Cardiology (multiple agents)].
Consultant/Advisory Boards: Amgen; AstraZeneca; Boehringer Ingleheim; Bristol-Myers Squibb; Eli Lilly and
Company; Esperion Therapeutics; Genzyme; GlaxoSmithKline; Ionis Pharmaceuticals; Kowa Pharmaceuticals;
Medimmune; Merck; Olatec Therapeutics; Novartis; Pzer; Sano-Regeneron; Takeda Pharmaceuticals; Athera
Biotechnologies; Interleukin Genetics [Cardiology (Multiple agents)]. Gordon M Saperia, MD, FACC Nothing to
disclose

Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

Conict of interest policy