Handbook of Experimental Pharmacology Volume 170 Editor-in-Chief K.Starke,Freiburgi.Br. EditorialBoard G.V.R.Born,London M.Eichelbaum,Stuttgart D.Ganten,Berlin F.Hofmann,München W.Rosenthal,Berlin G.Rubanyi,Richmond,CA Atherosclerosis: Diet and Drugs Contributors J.Ahrens,M.Anthony,T.Asahara,M.Aviram,S.Bellosta, F.Bernini,C.Bode,C.Bolego,C.Bouchard,G.Chinetti, A.Cignarella,R.St.Clair,P.Cullen,A.Dendorfer,P.Dominiak, C.Fontaine,J.-C.Fruchart,B.Fuhrmann,G.Gabbiani, J.Greeve,A.K.Groen,S.Grundy,H.Hendriks,M.Hersberger, O.M.Hess,M.Kaplan,A.Kosters,K.M.Kostner,G.M.Kostner, P.Kovanen,M.Kratz,F.Kuipers,T.Lakka,T.Lüscher,F.Mach, R.Mensink,D.Müller-Wieland,R.Paoletti,K.Peters, T.Plösch,R.Robillard,M.Rosenblatt,W.Schmitz, H.Schunkert,B.Staels,R.Stocker,P.Suter,M.A.M.A.Thijssen, M.Tikkanen,A.vanTol,E.Vähäkangas,A.vonEckardstein, Q.Xu,S.Ylä-Herttuala Editor Arnold von Eckardstein 123 Professor Dr.med.ArnoldvonEckardstein InstituteofClinicalChemistry UniversityHospitalofZurich Rämistrasse100 8091Zürich Switzerland e-mail:[email protected] With78Figuresand36Tables ISSN0171-2004 ISBN-103-540-22569-2SpringerBerlinHeidelbergNewYork ISBN-13978-3-540-22569-0SpringerBerlinHeidelbergNewYork LibraryofCongressControlNumber:2004113650 Thisworkissubjecttocopyright.Allrightsreserved,whetherthewholeorpartofthematerialis concerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broad- casting,reproductiononmicrofilmorinanyotherway,andstorageindatabanks.Duplicationof thispublicationorpartsthereofispermittedonlyundertheprovisionsoftheGermanCopyrightLaw ofSeptember9,1965,initscurrentversion,andpermissionforusemustalwaysbeobtainedfrom Springer.ViolationsareliableforprosecutionundertheGermanCopyrightLaw. SpringerisapartofSpringerScience+BusinessMedia springeronline.com ©Springer-VerlagBerlinHeidelberg2005 PrintedinGermany Theuseofgeneraldescriptivenames,registerednames,trademarks,etc.inthispublicationdoesnot imply, even in theabsence of a specific statement, thatsuchnames are exempt from the relevant protectivelawsandregulationsandthereforefreeforgeneraluse. Productliability:Thepublisherscannotguaranteetheaccuracyofanyinformationaboutdosageand applicationcontainedinthisbook.Ineveryindividualcasetheusermustchecksuchinformationby consultingtherelevantliterature. Editor:Dr.P.Roos DeskEditor:S.Dathe Coverdesign:design&productionGmbH,Heidelberg,Germany Typesettingandproduction:LE-TEXJelonek,Schmidt&VöcklerGbR,Leipzig,Germany Printedonacid-freepaper 27/3150-YL-543210 Preface Cardiovasculardiseasescontinuetobetheleadingcauseofdeathinthema- jority of industrialized countries. The most frequent underlying pathology, namely atherosclerosis, and its clinicalsequelae, namely coronary heart dis- ease,cerebrovasculardiseaseandperipheralarterydisease,remaincommon although for a long time we have been made aware of avoidable or modi- fiable etiological factors such as smoking, fat-rich diet or lack of exercise, and although these adverse lifestyle factors have been extensively addressed bypopulation-wideprimarypreventionprograms.Cardiovascularmorbidity andmortalityalsoremainhighdespitesuccessfulanti-hypertensiveandlipid lowering drug therapies which help to reduce cardiovascular morbidity and mortality by about 30% in both secondary and tertiary prevention settings. Thiscanpartlybeexplainedbytheincreasinglifeexpectancyandgrowingpro- portionofelderlypeople,especiallyinEuropeandNorthAmerica.Inaddition, theWorldHealthOrganizationmakesthealarmingpredictionthatprobably inresponsetothespreadingofwesterndietarybehaviorandlackofexercise resultinginanincreasingprevalenceofdiabetes,dyslipidemiaandhyperten- sion, cardiovasculardiseasesrather thaninfectiousdiseaseswill becomethe mostfrequentcauseofdeathworldwide. This volume of the Handbook of Experimental Pharmacology entitled “Atherosclerosis” is divided into four parts and intends to give an overview onthepathogenesisofatherosclerosis,establishedtreatmentandprevention regimen,andofperspectivesforthedevelopmentofnewtreatmentmodalities. The three chapters of part I review the state-of-the-art knowledge on the pathogenesis of atherosclerosis and its underlying risk factors. Because of its increasing prevalence and corresponding public health relevance, special attentionisgiventothemetabolicsyndrome,i.e.totheclusteringofriskfactors withinagivenindividual.Althoughtheexpressionofsingleriskfactorsinthis situationmaybemoderate,affectedindividualsareathighriskforcoronary heartdiseaseevents.Inaddition,duetotheimportantetiologicalcontribution of obesity and overweight, the metabolic syndrome is an important reason whyatherosclerosiscontinuestobeasignificantpublichealthburden. TheninechaptersofpartIIaredevotedtotheroleofthevariousmajorand minor components of diet in the pathogenesis of cardiovascular risk factors andatherosclerosis.Thisfieldiscurrentlyexperiencingarenaissancefortwo VI Preface reasons:First,afterfatandnotablycholesterolhadbeenaccusedofbeing“the badguys”foralongtime,novelresearchfindingsandtheepidemicofobesity anddiabetesproducedamoredifferentiatedviewofthepathogeneticrelevance ofthevariousdietarycompounds.Second,bothdrugandfoodindustryhave discovereddietasatherapeutictargetandarecurrentlydevelopingdrugsfor thetreatmentandpreventionofoverweightandfunctionalfoodsenrichedby putativelycardioprotectivenutrients. ThefourchaptersofpartIIIgiveanoverviewofgroupsofdrugswhichin controlledinterventiontrialseffectivelypreventedatheroscleroticcardiovas- cular disease, i.e. statins, fibrates, inhibitors of the renin-angiotensin system andantiplateletagents.Unfortunately,beta-blockersarenotcovered,because theauthorinchargeofthissubjectfinallywithdrewhiscommitment. The14chaptersofpartIVpresentseveraltargetsandperspectivesfornovel pharmacologicalinterventions.Someofthesestrategiesledtothere-evaluation andoptimizationofdrugsalreadyonthemarket,forexamplenicotinicacidor agonistsofperoxisomeproliferatingagentreceptors.Otherstrategieshelpedto developdrugswhichareinphaseIIItrialsandwillprobablybeintroducedinto themarketsoon,forexampleinhibitorsofcholesterylestertransferprotein. Finally, some developments are still in the initial stage and must overcome methodological limitations, such as gene therapy. Especially for this part IV it is important to recall that atherosclerosis is a multifactorial disease which consequentlyoffersmanytargetsfortreatment.Therefore,Ihopethatwedid notleaveoutimportantdevelopments.Someauthorsunfortunatelywithdrew theiroriginalcommitmenttowriteachapterforthisbooksothat,forexample, importantcontroversiallydiscussedstrategies,likehormonereplacementand antibiotictherapies,aremissing. Lastbutnotleast,IwishtothankSpringerVerlagandtheEditorialBoard for giving me the honour and chance to edit a “Handbook of Experimental Pharmacology”onatherosclerosis.Iamverygratefultoallauthorsfor their excellentcontributions.IalsothankMrs.BernadetteHand(Zurich)forcareful language editing and Mrs. Susanne Dathe (Springer Verlag) for her patience andhelpwhileaccompanyingmethroughthisproject. Zurich,February2005 ArnoldvonEckardstein ListofContents PartI. Background ThePathogenesisofAtherosclerosis . . . . . . . . . . . . . . . . . . . . 3 P.Cullen,J.Rauterberg,S.Lorkowski RiskFactorsforAtheroscleroticVascularDisease . . . . . . . . . . . . 71 A.vonEckardstein MetabolicSyndrome:TherapeuticConsiderations . . . . . . . . . . . . 107 S.M.Grundy PartII. TheImpactofDiet PhysicalActivity,ObesityandCardiovascularDiseases . . . . . . . . . 137 T.A.Lakka,C.Bouchard FattyAcidsandAtheroscleroticRisk . . . . . . . . . . . . . . . . . . . 165 M.A.Thijssen,R.P.Mensink DietaryCholesterol,AtherosclerosisandCoronaryHeartDisease. . . . 195 M.Kratz PlantSterolsandStanols . . . . . . . . . . . . . . . . . . . . . . . . . . 215 M.J.Tikkanen CarbohydratesandDietaryFiber . . . . . . . . . . . . . . . . . . . . . 231 P.M.Suter DietaryAntioxidantsandParaoxonasesAgainstLDLOxidation andAtherosclerosisDevelopment . . . . . . . . . . . . . . . . . . . . . 263 M.Aviram,M.Kaplan,M.Rosenblat,B.Fuhrman Soy,IsoflavonesandAtherosclerosis. . . . . . . . . . . . . . . . . . . . 301 R.St.Clair,M.Anthony VIII ListofContents HomocysteineandBVitamins . . . . . . . . . . . . . . . . . . . . . . . 325 S.Cook,O.M.Hess Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 H.F.J.Hendriks,A.vanTol PartIII.Evidence-BasedAnti-AtheroscleroticDrugTherapy LipidandNon-lipidEffectsofStatins . . . . . . . . . . . . . . . . . . . 365 R.Paoletti,C.Bolego,A.Cignarella Fibrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 R.Robillard,C.Fontaine,G.Chinetti,J.-C.Fruchart,B.Staels ACEInhibitorsandAngiotensinIIReceptorAntagonists . . . . . . . . 407 A.Dendorfer,P.Dominiak,H.Schunkert InhibitionofPlateletActivationandAggregation . . . . . . . . . . . . 443 I.Ahrens,C.Bode,K.Peter PartIV.TargetsofFutureAnti-AtheroscleroticDrugTherapy TheABCofHepaticandIntestinalCholesterolTransport . . . . . . . . 465 T.Plösch,A.Kosters,A.K.Groen,F.Kuipers InhibitionoftheSynthesisofApolipoproteinB-Containing Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 J.Greeve TherapyofHyper-Lp(a) . . . . . . . . . . . . . . . . . . . . . . . . . . 519 K.M.Kostner,G.M.Kostner ModulationofHigh-DensityLipoproteinCholesterolMetabolism andReverseCholesterolTransport . . . . . . . . . . . . . . . . . . . . 537 M.Hersberger,A.vonEckardstein InhibitionofLipoproteinLipidOxidation. . . . . . . . . . . . . . . . . 563 O.Cynshi,R.Stocker CorrectionofInsulinResistanceandtheMetabolicSyndrome . . . . . 591 D.Müller-Wieland,J.Kotzka ProtectionofEndothelialFunction . . . . . . . . . . . . . . . . . . . . 619 L.E.Spieker,T.F.Lüscher ListofContents IX ModulationofSmoothMuscleCellProliferationandMigration: RoleofSmoothMuscleCellHeterogeneity . . . . . . . . . . . . . . . . 645 M.-L.Bochaton-Piallat,G.Gabbiani ModulationofMacrophageFunctionandMetabolism . . . . . . . . . . 665 S.Bellosta,F.Bernini InflammationIsaCrucialFeatureofAtherosclerosis andaPotentialTargettoReduceCardiovascularEvents . . . . . . . . . 697 F.Mach AutoimmuneMechanismsofAtherosclerosis . . . . . . . . . . . . . . . 723 K.Mandal,M.Jahangiri,Q.Xu DrugTherapiestoPreventCoronaryPlaqueRuptureandErosion: PresentandFuture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745 P.T.Kovanen,M.Mäyränpää,K.A.Lindstedt ReciprocalRoleofVasculogenicFactorsandProgenitorCells inAtherogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777 T.Murayama,O.M.Tepper,T.Asahara GeneTherapyofAtherosclerosis . . . . . . . . . . . . . . . . . . . . . 785 E.Vähäkangas,S.Ylä-Herttuala SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809 ListofContributors (Addressesstatedatthebeginningofrespectivechapters) Ahrens,I. 443 Jahangiri,M. 723 Anthony,M. 301 Asahara,T. 777 Kaplan,M. 263 Aviram,M. 263 Kosters,A. 465 Kostner,G.M. 519 Bellosta,S. 665 Kostner,K.M. 519 Bernini,F. 665 Kotzka,J. 591 Bochaton-Piallat,M.-L. 645 Kovanen,P.T. 745 Bode,C. 443 Kratz,M. 195 Bolego,C. 365 Kuipers,F. 465 Bouchard,C. 137 Lakka,T.A. 137 Lindstedt,K.A. 745 Chinetti,G. 389 Lorkowski,S. 3 Cignarella,A. 365 Lüscher,T.F. 619 Clair,R.St. 301 Cook,S. 325 Mäyränpää,M. 745 Cullen,P. 3 Müller-Wieland,D. 591 Cynshi,O. 563 Mach,F. 697 Mandal,K. 723 Dendorfer,A. 407 Mensink,R.P. 165 Dominiak,P. 407 Murayama,T. 777 Fontaine,C. 389 Paoletti,R. 365 Fruchart,J.-C. 389 Peter,K. 443 Fuhrman,B. 263 Plösch,T. 465 Gabbiani,G. 645 Rauterberg,J. 3 Greeve,J. 483 Robillard,R. 389 Groen,A.K. 465 Rosenblat,M. 263 Grundy,S.M. 107 Schunkert,H. 407 Hendriks,H.F.J. 339 Spieker,L.E. 619 Hersberger,M. 537 Staels,B. 389 Hess,O.M. 325 Stocker,R. 563