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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.

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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.

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