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4:Prevention

Overview
Thischapterreviewsriskfactorsforcardiovasculardiseaseandatheroscleroticriskassessment.Thepathophysiology, contributiontocardiovasculardisease,andtreatmentofriskfactorsincludinglipids,nutrition,obesity,smoking,diabetesandthe metabolicsyndrome,arediscussed.Genderdifferencesincardiovasculardiseasepreventionandtheroleofexercisein diseasepreventionarealsocovered.

Authors
PatrickT.O'Gara,MD,FACC EditorinChief ThomasM.Bashore,MD,FACC AssociateEditor JamesC.Fang,MD,FACC AssociateEditor GlennA.Hirsch,MD,MHS,FACC AssociateEditor JuliaH.Indik,MD,PhD,FACC AssociateEditor DonnaM.Polk,MD,MPH,FACC AssociateEditor SunilV.Rao,MD,FACC AssociateEditor

4.1:AtheroscleroticRiskAssessment
Author(s): EmilM.deGoma,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Calculatethe10yearcoronaryheartdisease(CHD)andgeneralcardiovasculardisease(CVD)Framinghamriskscores (FRS)forprimarypreventionpatientstoestimatecardiovascularrisk. 2. Recognizethelimitationsofbothclinicalriskscoresandnovelriskpredictiontoolstooptimizestrategiesfor cardiovascularriskassessment. 3. Identifyintermediateriskpatientsforwhomadditionaltestssuchascoronaryarterycalcium(CAC)scanning,carotid intimamediathickness(CIMT)assessment,anklebrachialindex(ABI),orhighsensitivityCreactiveprotein(hsCRP) measurementmaybeappropriatetorefinecardiovascularrisk.

RationaleforRiskAssessment
Matchingtheintensityofmanagementtothedegreeofcardiovascularriskhaslong servedasacentraltenetofpreventivecardiovascularmedicine.1,2Thefundamental roleofglobalriskassessmentasagatekeeperinpreventivecardiology acknowledgesthecostsassociatedwithescalatingtherapy.Onapatientlevel,the demonstratedbenefitsofstatinadministration,forexample,mustbeweighed againstthefinancialcostofthemedicationsitself,aswellastheburdenoflong termmonitoringandtheriskofsideeffectsincludingmusclerelatedsymptoms. Fromapopulationperspective,useofriskassessmentmethodspromotesefficient allocationoflimitedhealthcareresources. Analysisofthenumberneededtotreat(NNT),thatis,thenumberofpatients requiringtreatmentinordertoavoidasingleadversecardiovasculareventovera specifiedtimeframe,capturesthelogicofriskassessmentintherapeuticdecision making.Foragivenintervention,lowerNNTsorgreaterreductionsinabsoluterisk havebeenconsistentlyobservedamonghigherriskpopulationscomparedtolower riskgroups(Tables1,2).35Thesedatasupporttheintuitivelyappealingapproachof buildingpreventivemanagementstrategiesstartingfromsoundcardiovascularrisk assessment. Thismodulereviewsclinicalapproachestocardiovascularriskstratificationand summarizesthecurrentstateofcardiovascularriskrefinementmeasuresincluding CRP,ABI,CACscanning,andCIMTevaluation.

Table1

Table2

NNTtoPreventOneCardiovascularEventOver5Years Table1 Estimatesofthenumberneededtotreat(NNT)topreventonehardcardiovasculareventover5yearsbyreducinglowdensitylipoprotein cholesterol(LDLC)from160mg/dlto130mg/dl,130mg/dlto100mg/dl,or100mg/dlto70mg/dlinthepresenceorabsenceofdiabetes, cardiovasculardisease(CVD),coronaryarterydisease(CHD),diabetes,orimpairedfastingglucose(IFG). Reference: 1. RobinsonJGStoneNJ.Identifyingpatientsforaggressivecholesterollowering:theriskcurveconcept.AmJCardiol200698:14058.

5YearNumberNeededtoTreattoPreventOneMyocardialInfarction(MI)orStroke(CVA)StratifiedbyBaselineRisk Table2 References: 1. CooneyMT,DudinaAL,GrahamIM.Valueandlimitationsofexistingscoresfortheassessmentofcardiovascularrisk:areviewfor clinicians.JAmCollCardiol200954:120927. 2. JacksonR,LawesCM,BennettDA,MilneRJ,RodgersA.Treatmentwithdrugstolowerbloodpressureandbloodcholesterolbasedon anindividual'sabsolutecardiovascularrisk.Lancet2005365:43441.

ClinicalRiskScoresforPrimaryPrevention (1of2)
10YearCoronaryHeartDiseaseFraminghamRiskScore Avarietyofclinicalriskequationshavebeendevelopedforuseintheprimary preventionsetting,eachderivedfrommultivariableregressionanalysesoflarge prospectivelyfollowedcohorts(Table3).Becauseclinicalriskscoresachieve moderatediscriminationinpredictingcardiovascularevents,arecosteffective,and utilizewidelyavailabledata,theyprovidethefoundationforcardiovascularrisk assessmentandareprovidedaClassIrecommendationbytheAmericanCollege ofCardiologyFoundation/AmericanHeartAssociation(ACCF/AHA)2010Guideline forAssessmentofCardiovascularRiskinAsymptomaticAdults.3,6 Publishedin1998,the10yearFRSforhardCHDevents(fatalCHDandmyocardial infarction[MI])representsthefirstclinicalcardiovascularriskequationdeveloped.7 Inputvariablesincludeage,sex,totalcholesterol,highdensitylipoprotein cholesterol(HDLC),currentsmoking,systolicbloodpressure,andtheuseof antihypertensivemedications.Onlinetoolsaswellastablesareavailableto facilitatecalculationofthe10yearCHDFRS (http://www.framinghamheartstudy.org/risk/hrdcoronary.html). Oneoftheprimaryreasonsthe10yearhardCHDFRSremainsthedominant methodofriskassessmentintheUnitedStatesisduetoitsincorporationintothe NationalCholesterolEducationProgram(NCEP)AdultTreatmentPanel(ATP) guidelines.8 A10yearCHDFRS>20%,observedin25%ofUSadults,9 is consideredhighrisk.Theintermediateriskcategoryisalternativelydefinedasa CHDFRSof1020%6 or520%,9 thelattercomprising40%oftheadultpopulation.9 Themostrecentconsensusdocumentdetailingcardiovascularriskassessmentin asymptomaticadultsproposedanintermediateriskcategoryof1020%.6 Finally,a riskscoreof<10%or<5%,observedin35%ofUSadults,9 classifiespatientsinto thelowriskcategory. Theseriskthresholds,thougharbitrarilydefined,10providethestructuretoidentify patientswhowarrantintensificationoflipidloweringtherapy.The2004NCEPATPIII updaterecommendedminimumLDLCtargetsforhighrisk,intermediaterisk,and lowriskgroupsof<100mg/dl,<130mg/dl,and<160mg/dl.11 Weaknessesofthe10yearhardCHDFRSincludeitsfocusonCHDeventstothe exclusionofotheratherothromboticoutcomesthelimitedgeneralizabilityoffindings fromasinglecenter,predominantlyCaucasianstudyexposedtoadifferentrisk factormilieuthancontemporarycohortsthedominanteffectofageleadingto underestimationofriskinyoungergroupsandoverestimationofriskintheelderly therelativelyshort10yeartimeframegiventheslowevolutionofatherosclerosis overdecadesandtheexclusionofknowncausativeriskfactorssuchasfamily historyandobesity.12 Arguablythemostworrisomelimitationofthe10yearhardCHDFRSliesinits suboptimaldetectionofhighriskpatientswhogoontosufferanMI,individualsin whomfailuretoimplementintensivepreventivetherapyrepresentsasignificant missedopportunity.Inaretrospectivestudyof222youngerpatientshospitalizedfor acuteMI,only12%weredeemedathighriskby10yearhardCHDFRS.13Ina secondstudyexamining355consecutivepatientspresentingwithSTelevationMI,14 only6%wereclassifiedashighriskusingthe10yearhardCHDFRS.
Table3

SummaryofSelectedClinicalRiskScores Table3 CHD=coronaryheartdiseaseCVD=cardiovasculardiseaseFRS=FraminghamriskscoreHDLC=highdensitylipoproteincholesterolMI= myocardialinfarction. References: 1. WilsonPW,D'AgostinoRB,LevyD,BelangerAM,SilbershatzH,KannelWB.Predictionofcoronaryheartdiseaseusingriskfactor categories.Circulation199897:183747. 2. D'AgostinoRBSr,VasanRS,PencinaMJ,etal.Generalcardiovascularriskprofileforuseinprimarycare:theFraminghamHeartStudy. Circulation2008117:74353. 3. PencinaMJ,D'AgostinoRBSr,LarsonMG,MassaroJM,VasanRS.Predictingthe30yearriskofcardiovasculardisease:the Framinghamheartstudy.Circulation2009119:307884. 4. LloydJonesDM,LeipEP,LarsonMG,etal.Predictionoflifetimeriskforcardiovasculardiseasebyriskfactorburdenat50yearsofage. Circulation2006113:7918.

ClinicalRiskScoresforPrimaryPrevention (2of2)
RiskScoresIncorporatingBroaderEndpointsandLongerTimeFrames Inanefforttoexpandtheapplicabilityoftheclinicalriskscore,amoreextensive inclusionofriskfactorssuchasfamilyhistoryaswellasbroadlydefinedendpoints maybetterillustrateindividualrisk.The10yearFRSforgeneralCVDovercomes severalofthelimitationsofthehardCHDFRSbyusingamoreinclusiveendpoint, incorporatingnotonlyfatalCHDandMIbutcoronaryinsufficiency,angina, cerebrovasculardisease(ischemicstroke,hemorrhagicstroke,transientischemic attack),peripheralarterydisease(intermittentclaudication),andheartfailure(Figure 1).15 Inputsintothealgorithmincludediabetesaswellastheindependentvariablesof the10yearhardCHDFRS.Tablesareavailableonlinetofacilitatecalculation (http://www.framinghamheartstudy.org/risk/gencardio.html).Useofan encompassingmetricacknowledgessharedriskfactorsandsimilarpreventive measuresforthecomponentCVDs.Moreover,suchanapproachmayimproverisk communicationandavoidundertreatmentofpatientsathighriskfornoncoronary events.Forexample,femalehypertensivesmokersmayexhibita10yeargeneral CVDFRSoverthreetimeshigherthana10yearhardCHDFRSduetothe contributionofexcessheartfailureandstroke.16 Morerecentlydevelopedriskindicesincorporatealongertermperspectiveinorder tomotivateyoungeratriskpatientstoinitiateandadheretolifestylechangesand, whenneeded,pharmacotherapy(Figure1).The30yearFRSforhardCVDestimates the30yearriskforthedevelopmentofcoronarydeath,MI,andstrokebasedonthe standardriskfactorsofthe10yeargeneralCVDFRS.17Lifetimeriskscoresextend thefollowupdurationfurther,providingestimatesoftheriskofatheroscleroticCVD assumingabaselineageof50yearsandsurvivalto95years.18Alsoderivedfrom Framinghamcohortdata,thelifetimeriskalgorithmutilizesgender,systolicblood pressure,diastolicbloodpressure,smokingstatus,totalcholesterol,anddiabetes statustocalculatetheriskofcardiovasculardeath,MI,coronaryinsufficiency,angina pectoris,atherothromboticstroke,andintermittentclaudication. Discrepanciesbetweenlongandshorttermriskestimatescanbestriking.For example,fora25yearoldfemalehypercholesterolemicsmoker,the10year generalCVDFRSisonly1.4%,butthecorresponding30yearhardCVDFRS reaches12%.17A50yearoldnonsmoking,nondiabeticmanwithtotalcholesterol of250mg/dl,HDLcholesterolof60mg/dl,anduntreatedsystolicbloodpressureof 160mmHghasanestimated10yearhardCHDFRSof7%,butanaveragelifetime riskforCVDapproaching70%.18Simpleonlinetoolsarenotyetavailablefor calculating30yearhardCVDorlifetimeCVDrisk.
Figure1

CardiovascularRiskAssessmentforaHypotheticalCaseUsingFraminghamRiskScoresfor10YearGeneralCVDand30YearHardCVD Figure1 BP=bloodpressureCVD=cardiovasculardiseaseHDL=highdensitylipoproteinHTN=hypertensionRF=riskfactor. ReproducedwithpermissionfromVasanRS,KannelWB.Strategiesforcardiovascularriskassessmentandpreventionoverthelifecourse: progressamidimperfections.Circulation2009120:3603.

LimitationsofClinicalRiskScores
Limitationsofthe10yearhardCHDFRSweredescribedearlier.Clinicalriskequationsutilizingbroaderendpointsand longertimehorizonsappeartoofferadvantagesoverthetraditionalriskassessmentapproach.However,itremains uncertainhowthesenewermethodsshouldbeincorporatedintoclinicalmanagement,includingwhichnumerical thresholdsmaybeassignedtodefinetreatmentrelevantriskcategories.Longtermriskestimatesmaybemostuseful forpromotinglifestylemodificationamongyoungerpatientsandforidentifyingappropriatetargetpopulationsforpublic healthinitiatives.Finally,althoughuseofclinicalriskequationsrepresentsawellacceptedapproach,thereislimited directevidencefromrandomizedclinicaltrialsthatcalculationandcommunicationofglobalclinicalriskscoresalters patientandphysicianbehaviororimprovespatientoutcomescomparedtoriskfactorcountingoranadhocunifactor basedapproach.19

CoronaryHeartDiseaseRiskEquivalents
TheNCEPATPIIIintroducedtheconceptofCHDriskequivalents,diseasestatesconferringariskofincidentMIequalto theriskofrecurrentMIamongpatientswithestablishedCHD,thataregreaterthan2%peryear.8 Inadditiontoa10year hardCHDFRSabove20%,fourdiseasesweredeemedCHDriskequivalentsbasedonnumerousobservationalcohort studiesindicatinganannualCHDeventrateexceeding2%:lowerextremityperipheralarterydisease,symptomatic carotidarterydisease,asymptomaticcarotidarterydiseasewithstenosisexceeding50%,diabetesmellitus,and abdominalaorticaneurysm. TheCHDriskequivalentdesignationwascreatedtoincreaseawarenessofnoncoronaryconditionsathighriskforCHD eventsandtointensifymanagementamongthisgrouptoasecondarypreventionapproach,includingsettingaggressive lowdensitylipoproteincholesterol(LDLC)goalsof70100mg/dlorbelow.Whilerandomizedcontrolledclinical outcometrialsdonotexistsupportingthesetargetsamongpatientswithasymptomaticcarotidarterydiseaseand abdominalaorticaneurysm,suchanapproachseemsjustifiedinlightofthecentraltenetofprevention,matching intensityoftherapytodegreeofrisk.

EmergingRiskRefinementMethods (1of2)
Thepastdecadehaswitnessedaproliferationofadjunctiveriskpredictiontools aimingtofurtherimprovecardiovascularriskassessment.Subclinical atherosclerosisimagingtechniques,circulatinginflammatorybiomarkers, noninvasivemetricsofendothelialfunction,additionallipoproteintesting,andmost recentlypanelsofgeneticvariationsorsinglenucleotidepolymorphismshavebeen advancedaspotentialmethodstoaddressthesocalleddetectiongap1 inCVD prognosis.Fourofthebeststudiedriskrefinementtoolsaredescribedlater. GuidelinesareprovidedinTable4,andtestcharacteristicsaresummarizedin Table5.Norandomizedcontrolledtrialshaveyetestablishedthebenefit(orharm) associatedwithmanagementguidedbythesetestscomparedtotreatmentbased onclinicalriskscoresdescribedearlier. CReactiveProtein CRPisa110kDaproteinpredominantlysynthesizedbyhepatocytesinresponseto theinflammatorycytokinesinterleukin(IL)6andIL1.Moststudieshave demonstratedastatisticalrelationshipbetweenCRPandcardiovascularevents, althoughtheweightofevidencethusfararguesagainstacausativerolein atherosclerosis.20Aswithmeasuresofcholesterol,CRPdisplaysadegreeof intraindividualvariabilityforwhichtwoserialmeasurementsarerecommendedfora givenpatienttobetterassessthetruehomeostaticsetpointpriortomaking therapeuticdecisions.21Valueshigherthan3mg/Ldefinethehighriskcategory accordingtoanearlierconsensusstatement.21 Sincethen,resultshavebeenpublishedfortheJUPITER(JustificationfortheUseof StatinsinPrevention:AnInterventionTrialEvaluatingRosuvastatin)trial,which utilizedanhsCRPof2mg/Lorgreaterasaninclusioncriterion.IntheJUPITER trial,treatmentwithrosuvastatin20mgdailyforamedianof1.9yearswas associatedwithasignificant46%reductionintheincidenceofcardiovasculardeath, MI,stroke,hospitalizationforunstableangina,andrevascularizationcomparedto placebo.Ofnote,thestudywasnotdesignedtotesttheincrementalvalueofhs CRPforriskassessmentcomparedtotraditionalriskfactorsalone. CRPismodestlyassociatedwithworsenedcardiovascularoutcomeswitha multivariableadjustedriskratioforCHDandnonfatalMIof1.6,comparinghighestto lowesthsCRPtertilevalues.Discriminationandnetreclassificationdataare providedinTable5.AclinicalriskscorethatincludesCRP,calledtheReynolds RiskScore,hasbeendeveloped.22,23 Otherinputsincludeage,sex,smokingstatus,systolicbloodpressure,total cholesterol,andHDLCaswellasaparentalhistoryofMIbeforetheageof60. Statisticallysignificantbutmodestimprovementsindiscriminationandrisk reclassificationwerereportedcomparedtotraditionalriskfactorsalone(Table5).An onlinecalculatorfortheReynoldsRiskScorecanbefoundat http://www.reynoldsriskscore.org/. CriticsoftheReynoldsRiskScorecitetoomuchweightplacedonascorethat includesCRP,whichhasarelativelysmallincrementalprognosticvaluecompared totraditionalriskfactors.Anadditionalconcernisthefluctuationobservedinserial CRPmeasures. AnkleBrachialIndex ABI,anintegralcomponentofthediagnosticevaluationoflowerextremityperipheral arterydisease,yieldsimportantcardiovascularprognosticinformationinadditionto describinglimbmorbidity.AsdiscussedinChapter9,PeripheralArteryDisease,ABI fortheright(orleft)lowerextremityisbyconventiondefinedasthehigherofthe systolicpressuresintheright(orleft)dorsalispedisandposteriortibialarteries dividedbythehigherofthesystolicpressuresintherightandleftbrachialartery.In healthyindividuals,distalpulsewavereflectioncausesanklesystolicpressuresto be1015mmHghigherthanbrachialsystolicpressurestherefore,thenormalABI

Table4

Table5

exceeds1.0.24Ontheotherendofthespectrum,asupranormalABIabove1.4 alsoportendsaworsecardiovascularprognosis.Anklepressureselevatedtothis degreemaybeobservedinnoncompressible,calcifiedvesselsduetodiffuse atherosclerosisordiabetes. Alargeinternationalmetaanalysisexamining16populationcohortstudies,24,955 men,and23,339womenclarifiedtheincrementalvalueofABIaboveandbeyondthe traditionalFRS.25ComparedwithanABIof1.111.4,anABIbelow0.9was associatedwithahazardratioforcardiovascularmortalityandmajoreventsof2.34 formenand2.35forwomenafteradjustmentfortheFRS.AddingABIdatatothe FRSsignificantlyimproveddiscriminationamongwomen,increasingtheareaunder thecurvefrom0.605to0.658.Nochangewasnotedamongmen. InclusionoftheABIincardiovascularriskstratificationusingtheFRSwouldresultin reclassificationoftheriskcategoryandmodificationoftreatmentrecommendations inapproximately19%ofmenand36%ofwomen.Theprevalenceofanabnormal ABIamongasymptomaticadultswithoutCVDordiabeteshasbeenestimatedat 13%amongsubjectswithanintermediateFRS.26

2010ACCF/AHAGuidelineforAssessmentofCardiovascularRiskinAsymptomaticAdults:RecommendationsforRiskRefinementMethods Table4 CHD=coronaryheartdiseaseFRS=FraminghamriskscoreLDLC=lowdensitylipoproteincholesterol. ReproducedwithpermissionfromGreenlandP,AlpertJS,BellerGA,etal.2010ACCF/AHAguidelineforassessmentofcardiovascularriskin asymptomaticadults:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines.J AmCollCardiol201056:e50103.

OverviewofTestCharacteristicsofhsCRP,ABI,CACS,andCIMT Table5 ABI=anklebrachialindexAUC=areaunderthecurveCACS=coronaryarterycalciumscoreCHD=coronaryheartdiseaseCIMT=carotid intimamediathicknesscNRI=clinicalnetreclassificationindexFRS=FraminghamriskscorehsCRP=highsensitivityCreactiveproteinRR= relativerisk.


aComparinghsCRP>3and<1mg/L.Endpoint:CHDdeath,nonfatalmyocardialinfarction. bcNRIwas15%amongparticipantswith10yearhardCHDFRS520%usingfourriskcategories:<5%,5to<10%,10to<20%,20%.cNRIwas

9%amongparticipantswith10yearhardCHDFRS520%usingthreeriskcategories:<5%,5to<20%,20%.Endpoint:myocardialinfarction, coronaryrevascularization,stroke,andcardiovasculardeath. c cNRIwas16%amongparticipantswith10yearhardCHDFRS520%usingfourriskcategories:<5%,5to<10%,10to<20%,20%.cNRIwas 12%amongparticipantswith10yearhardCHDFRS520%usingthreeriskcategories:<5%,5to<20%,20%.Endpoint:myocardialinfarction, coronaryrevascularization,stroke,andcardiovasculardeath. dComparingABI<0.9to1.111.4.Endpoint:cardiovascularmortalityandmajorevents. eNosignificantdifferenceinAUCamongmen. f Netreclassificationindexcalculatedfrompublisheddata,definingabnormalABIas<0.9and>1.4andutilizingthreeFraminghamriskstrata (<10%,1020%,>20%).ThepercentagesofpatientsinwhomABIwouldreclassifyriskandmodifytreatmentrecommendationswere19% amongmenand36%amongwomen. gComparingtopandbottomquantile,usuallyquartile.Endpoint:coronarydeath,nonfatalmyocardialinfarction,surgicalorpercutaneouscoronary revascularizationprocedures,nonhemorrhagicstroke,andperipheralarterialsurgery. hAmongparticipantswith5yearhardCHDFRS310%usingthreeriskcategories:<3%,3%to<10%,10%.Endpoint:CHDdeath,myocardial infarction,cardiacarrest,angina,andcoronaryrevascularization. iAmongparticipantswith10yearhardCHDFRS1020%usingthreeriskcategories:<10%,1020%,>20%. jComparingtopandbottomquantile,usuallyquartile.Endpoint:variable,systematicreviewincludedstudiesofmyocardialinfarctionalone,stroke alone,andallcardiovascularoutcomes. k cNRIwas22%amongparticipantswith10yearhardCHDFRS520%usingfourriskcategories:<5%,5to<10%,1020%,>20%.Endpoint: CHDdeath,myocardialinfarction,andcoronaryrevascularization. References:

1. BuckleyDI,FuR,FreemanM,RogersK.HelfandM.Creactiveproteinasariskfactorforcoronaryheartdisease:asystematicreview andmetaanalysesfortheU.S.PreventiveServicesTaskForce.AnnInternMed2009151:48395. 2. CookNR,BuringJE,RidkerPM.TheeffectofincludingCreactiveproteinincardiovascularriskpredictionmodelsforwomen.AnnIntern Med2006145:219. 3. RidkerPM,PaynterNP,RifaiN,GazianoJM.CookNR.Creactiveproteinandparentalhistoryimproveglobalcardiovascularrisk prediction:theReynoldsRiskScoreformen.Circulation2008118:224351. 4. AnkleBrachialIndexCollaboration,FowkesFG,MurrayGD,ButcherI,etal.AnklebrachialindexcombinedwithFraminghamRiskScore topredictcardiovasculareventsandmortality:ametaanalysis.JAMA2008300:197208. 5. PolonskyTS,McClellandRL,JorgensenNW,etal.Coronaryarterycalciumscoreandriskclassificationforcoronaryheartdisease prediction.JAMA2010303:16106. 6. NambiV,ChamblessL,FolsomAR,etal.Carotidintimamediathicknessandpresenceorabsenceofplaqueimprovespredictionof coronaryheartdiseaserisk:theARIC(AtherosclerosisRiskInCommunities)study.JAmCollCardiol201055:16007.

EmergingRiskRefinementMethods (2of2)
CoronaryArteryCalcium CACscanningquantifiestheaggregateamountofcalciumdepositedinthewallsof theepicardialcoronaryarteriesandservesasaproxyfortheextentofcoronary atherosclerosis(Figure2).27Calcificationofthecoronaryarteriesissynonymous withintimalatherosclerosiswithtwoinfrequentexceptions:1)medialcalcification rarelyobservedinpatientswithdiabetesorchronickidneydisease,and2) calcificationoftheinternalelasticlaminaseeninpatientswiththehuman immunodeficiencyvirus.28Ofnote,pathologicexaminationandintravascular ultrasoundofatheromahavedemonstratedthatcalcifiedplaqueaccountsforonly 20%oftotalplaqueburden,theremainderattributedtolipiddepositionand fibrosis.29 Electronbeamcomputedtomography(EBCT),socalledultrafastCT,wasthefirst imagingmodalityusedtomeasureCAC.Theacquisitionprotocolinvolves nonoverlapping3mmslicesfromthecarinatothecaudalextentoftheheart.The referenceAgatstonmethoddefinesanareaofcalcificationasanareawithinthe coronaryarteriesmeasuringatleast1mm2 withadensityof130Hounsfieldunits (HU)orgreater.Eachareaismultipliedbyafactorof14dependingonpeak.The totalCACscoreisthenobtainedthroughsummationofscoresforalltransaxial images. ImprovementsinscannertechnologynowpermitCACevaluationusingmulti detectorCT(MDCT).Asimilaracquisitionandquantificationmethod,calledthe AgatstonalgorithmforMDCT,providesscorescomparabletothatofEBCT.CAC scoresexceeding100Agatstonunits(AU)or75thpercentileareconsideredhigh riskforcoronaryevents,andvaluesabove400AUor90thpercentileareclassified asveryhighrisk.29 TestcharacteristicsforCACaresummarizedinTable5.Aconsistentfindinginlarge populationstudieshasbeenthelongterm,benignprognosticprofileofpatientswith azeroCACscore.TheabsenceofCACasquantifiedbytheAgatstonmethod confersaverylowriskofevents,anannualizedcardiovasculareventrateof0.11% over4years,30andamortalityrateof0.5%over10years.31 RadiationexposurerepresentstheleadingconcernwithCACscanning. Prospectivelytriggeredacquisitionyieldseffectivedosesof0.91.1mSv,although higherdosesmayresultfromretrospectiveimaging.27Verylowdoseprotocolshave beendevelopedthatreduceradiationexposurebelow1mSv. Onemulticenterstudyofclinicalpracticesindicatedahigheraverageradiation exposureof2.3mSv(0.810.5mSv).32AppropriateuseofCACrequiresconstant vigilancetominimizeradiationexposure,tailoringimageacquisitionprotocolsto eachandeverypatient.Asecondimportantissueisthatmacrocalcificationdetected byCTisarelativelylatefindingintheatheroscleroticprocess.Asaresult,the sensitivityofCACscoreforsubclinicaldiseaseishighlydependentonpatientage. Inonestudyofyoungerpatients(meanage49years)withoutdocumentedCVD, subclinicalatherosclerosisbycarotidultrasoundwasdetectedin47%ofpatients withazeroCACscore.33TheproposedminimumagethresholdsfortheuseofCAC is45yearsformenand55yearsforwomen34however,appropriateagecutoffs remainuncertain.Inadditiontoyoungerpatients,patientswithdiabetesmayalso developcoronaryplaquewithoutsignificantcalcification. CarotidIntimaMediaThickness Screeningcarotidultrasoundforcardiovascularriskrefinementincorporatesboth measurementofCIMTandassessmentforcarotidplaque.35IMTismeasuredas thedistancebetweenthelumenintimainterfaceandthemediaadventitiainterface, visualizedastwoparallelechobrightlinesonultrasound(Figure3).Current
Figure2

Table5

Figure3

guidelinesfromtheAmericanSocietyofEchocardiographyandtheSocietyof VascularMedicinerecommendmeasurementofIMTinthefarwallofthedistal1cm ofthecommoncarotidarteries.35Althoughtheearliestdevelopmentof atherosclerosisfrequentlyoccursatthecarotidbulbandtheoriginoftheinternal carotidartery,thecommoncarotidarterywaschosenasthetargetsegment becausethesiteisfrequentlyeasiertovisualizeandtoacquireimagesforIMT assessment. Plaqueisdefinedaseitherafocalwallthickeningatleast50%greaterthanthatof thesurroundingarterialwallorafocalregionofIMTthickeninggreaterthan1.5mm thatprotrudesintothelumenandisdistinctfromtheadjacentboundary.The presenceofanycarotidplaqueoranIMTexceedingthe75thpercentileusingan age,sex,andethnicspecificreferencepopulationconfersahigherriskofCVD, independentoftraditionalriskfactors.TestcharacteristicsareprovidedinTable5. TheprimarylimitationofCIMTistherequiredtechnicalproficiencytoachieve consistentsubmillimetermeasurements.Onestudy,however,demonstratedthe abilityofnonsonographerclinicianstoperformaccurateCIMTassessmentusing semiautomatedborderdetectionsoftwareafterabrief2daytrainingprogram.36 AnadditionalconcernhasbeenthebiologicaldissimilaritybetweenIMTand atherosclerosis.37IMTislargelydrivenbymedialthickening,attributedto hypertensionandage,whereasearlyatherosclerosisisanintimalprocess.The higherfrequenciesrequiredtoisolatethethinintimallayer,however,cannot penetratetothedepthneededtoassessthecarotidartery.Mediallayeraside, pathologyofatheroscleroticlesionsatvariousstagesofevolutionsuggeststhat pathologicintimalthickening,characterizedbytheformationoflipidpools,doesnot necessarilyprogresstoplaque,aphenotypedefinedbytheformationofanecrotic core.Ontheotherhand,providedCIMTtrackswellwithcardiovascularoutcomes, theeffectivenessofthesurrogatemarkerneednotrelyonidentical pathophysiologicalunderpinnings.

RepresentativeMultiDetectorComputedTomographyAxialImageTakenFromaPatientWithaHighRiskCoronaryArteryCalciumScoreof250 Figure2 ReproducedwithpermissionfromRumbergerJA.Coronaryarterycalciumscanningusingcomputedtomography:clinicalrecommendationsfor cardiacriskassessmentandtreatment.SeminUltrasoundCTMR200829:2239.

OverviewofTestCharacteristicsofhsCRP,ABI,CACS,andCIMT Table5 ABI=anklebrachialindexAUC=areaunderthecurveCACS=coronaryarterycalciumscoreCHD=coronaryheartdiseaseCIMT=carotid intimamediathicknesscNRI=clinicalnetreclassificationindexFRS=FraminghamriskscorehsCRP=highsensitivityCreactiveproteinRR= relativerisk. a. ComparinghsCRP>3and<1mg/L.Endpoint:CHDdeath,nonfatalmyocardialinfarction. b. cNRIwas15%amongparticipantswith10yearhardCHDFRS520%usingfourriskcategories:<5%,5to<10%,10to<20%,20%. c. NRIwas9%amongparticipantswith10yearhardCHDFRS520%usingthreeriskcategories:<5%,5to<20%,20%.Endpoint: myocardialinfarction,coronaryrevascularization,stroke,andcardiovasculardeath. d. cNRIwas16%amongparticipantswith10yearhardCHDFRS520%usingfourriskcategories:<5%,5to<10%,10to<20%,20%. cNRIwas12%amongparticipantswith10yearhardCHDFRS520%usingthreeriskcategories:<5%,5to<20%,20%.Endpoint: myocardialinfarction,coronaryrevascularization,stroke,andcardiovasculardeath. e. ComparingABI<0.9to1.111.4.Endpoint:cardiovascularmortalityandmajorevents. f. NosignificantdifferenceinAUCamongmen. g. Netreclassificationindexcalculatedfrompublisheddata,definingabnormalABIas<0.9and>1.4andutilizingthreeFraminghamrisk strata(<10%,1020%,>20%).ThepercentagesofpatientsinwhomABIwouldreclassifyriskandmodifytreatmentrecommendations were19%amongmenand36%amongwomen. h. Comparingtopandbottomquantile,usuallyquartile.Endpoint:coronarydeath,nonfatalmyocardialinfarction,surgicalorpercutaneous coronaryrevascularizationprocedures,nonhemorrhagicstroke,andperipheralarterialsurgery. i. Amongparticipantswith5yearhardCHDFRS310%usingthreeriskcategories:<3%,3%to<10%,10%.Endpoint:CHDdeath, myocardialinfarction,cardiacarrest,angina,andcoronaryrevascularization. j. Amongparticipantswith10yearhardCHDFRS1020%usingthreeriskcategories:<10%,1020%,>20%. k. Comparingtopandbottomquantile,usuallyquartile.Endpoint:variable,systematicreviewincludedstudiesofmyocardialinfarctionalone, strokealone,andallcardiovascularoutcomes. l. cNRIwas22%amongparticipantswith10yearhardCHDFRS520%usingfourriskcategories:<5%,5to<10%,1020%,>20%. Endpoint:CHDdeath,myocardialinfarction,andcoronaryrevascularization.

References: 1. BuckleyDI,FuR,FreemanM,RogersK.HelfandM.Creactiveproteinasariskfactorforcoronaryheartdisease:asystematicreview andmetaanalysesfortheU.S.PreventiveServicesTaskForce.AnnInternMed2009151:48395.

2. CookNR,BuringJE,RidkerPM.TheeffectofincludingCreactiveproteinincardiovascularriskpredictionmodelsforwomen.AnnIntern Med2006145:219. 3. RidkerPM,PaynterNP,RifaiN,GazianoJM.CookNR.Creactiveproteinandparentalhistoryimproveglobalcardiovascularrisk prediction:theReynoldsRiskScoreformen.Circulation2008118:224351. 4. AnkleBrachialIndexCollaboration,FowkesFG,MurrayGD,ButcherI,etal.AnklebrachialindexcombinedwithFraminghamRiskScore topredictcardiovasculareventsandmortality:ametaanalysis.JAMA2008300:197208. 5. PolonskyTS,McClellandRL,JorgensenNW,etal.Coronaryarterycalciumscoreandriskclassificationforcoronaryheartdisease prediction.JAMA2010303:16106. 6. NambiV,ChamblessL,FolsomAR,etal.Carotidintimamediathicknessandpresenceorabsenceofplaqueimprovespredictionof coronaryheartdiseaserisk:theARIC(AtherosclerosisRiskInCommunities)study.JAmCollCardiol201055:16007.

ExampleofCarotidIntimaMediaThicknessMeasurementPerformedintheFarWalloftheDistalCommonCarotidArtery Figure3 cIMT=carotidintimamediathicknessRCCA=rightcommoncarotidartery. ReproducedwithpermissionfromSteinJH,KorcarzCE,HurstRT,etal.Useofcarotidultrasoundtoidentifysubclinicalvasculardiseaseand evaluatecardiovasculardiseaserisk:aconsensusstatementfromtheAmericanSocietyofEchocardiographyCarotidIntimaMediaThickness TaskForce.EndorsedbytheSocietyforVascularMedicine.JAmSocEchocardiogr200821:93111.

FutureDirections
Furtherresearchwilldeterminetheappropriateclinicalroleofnewerriskequations,includingassessmentof lifetimerisk. Futureclinicalriskscoresmayofferadditionaladvantagessuchasexclusionofagewithintheriskmodelby limitinganalysistonarrowwindowsofageorinclusionofmultipleethnicities,asintheMESA(MultiEthnicStudy ofAtherosclerosis). Randomizedclinicaltrialscomparingclinicaloutcomesandcosteffectivenessofvariousriskassessment strategies,includingthoseincorporatingsubclinicalatherosclerosisimagingmodalities,areneeded.

KeyPoints
Globalcardiovascularriskassessment,thecornerstoneofpreventivecare,servestoguidetheintensityof medicalmanagement. Limitationsofthe10yearhardCHDFRSasaclinicalriskassessmenttechniqueincludeitsfocusonCHD eventstotheexclusionofotheratherothromboticoutcomesthelimitedgeneralizabilityoffindingsfromasingle center,predominantlyCaucasianstudyexposedtoadifferentriskfactormilieuthancontemporarycohortsthe dominanteffectofageleadingtounderestimationofriskinyoungergroupstherelativelyshort10yeartimeframe giventheslowevolutionofatherosclerosisoverdecadesandtheexclusionofknowncausativeriskfactorssuch asfamilyhistory. Newerclinicalriskscores,suchasthe10yeargeneralcardiovascularriskscoreandlifetimeriskassessment, incorporatebroaderendpointsandlongertimeframestoovercomeseverallimitationsofthetraditionalFRS. Lowerextremityperipheralarterydisease,symptomaticcarotidarterydisease,asymptomaticcarotidartery diseasewithstenosisexceeding50%,diabetesmellitus,andabdominalaorticaneurysmarenoncoronary diseasesdesignatedasCHDriskequivalentswarrantingintensivepreventivetherapyakintosecondary preventiongroups. HsCRPlevelsgreaterthan3mg/Ldefinethehighriskcategory. ABIsbelow1.1orabove1.4areassociatedwithanincreasedriskforcardiovascularevents. CACscoresexceeding100AUor75thpercentileareconsideredhighriskforcoronaryevents. ThepresenceofanycarotidplaqueoranIMTexceedingthe75thpercentiledefinesthehighriskcategoryforCVD.

References
1. PasternakRC,AbramsJ,GreenlandP,SmahaLA,WilsonPW,HoustonMillerN.34thBethesdaConference: Taskforce#1Identificationofcoronaryheartdiseaserisk:isthereadetectiongap?JAmCollCardiol 200341:186374. 2. VasanRS,KannelWB.Strategiesforcardiovascularriskassessmentandpreventionoverthelifecourse: progressamidimperfections.Circulation2009120:3603. 3. CooneyMT,DudinaAL,GrahamIM.Valueandlimitationsofexistingscoresfortheassessmentofcardiovascular risk:areviewforclinicians.JAmCollCardiol200954:120927. 4. JacksonR,LawesCM,BennettDA,MilneRJ,RodgersA.Treatmentwithdrugstolowerbloodpressureandblood cholesterolbasedonanindividual'sabsolutecardiovascularrisk.Lancet2005365:43441. 5. RobinsonJG,StoneNJ.Identifyingpatientsforaggressivecholesterollowering:theriskcurveconcept.AmJ Cardiol200698:14058. 6. GreenlandP,AlpertJS,BellerGA,etal.2010ACCF/AHAguidelineforassessmentofcardiovascularriskin asymptomaticadults:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociation TaskForceonPracticeGuidelines.JAmCollCardiol201056:e50103. 7. WilsonPW,D'AgostinoRB,LevyD,BelangerAM,SilbershatzH,KannelWB.Predictionofcoronaryheartdisease usingriskfactorcategories.Circulation199897:183747. 8. NationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation,andTreatmentofHigh BloodCholesterolinAdults(AdultTreatmentPanelIII).ThirdReportoftheNationalCholesterolEducation Program(NCEP)ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(Adult TreatmentPanelIII)finalreport.Circulation2002106:3143421. 9. GreenlandP,SmithSCJr,GrundySM.Improvingcoronaryheartdiseaseriskassessmentinasymptomatic people:roleoftraditionalriskfactorsandnoninvasivecardiovasculartests.Circulation2001104:18637. 10. LloydJonesDM.Cardiovascularriskprediction:basicconcepts,currentstatus,andfuturedirections.Circulation 2010121:176877. 11. GrundySM,CleemanJI,MerzCN,etal.onbehalfoftheNationalHeart,Lung,andBloodInstituteAmerican CollegeofCardiologyFoundationAmericanHeartAssociation.Implicationsofrecentclinicaltrialsforthe NationalCholesterolEducationProgramAdultTreatmentPanelIIIguidelines.Circulation2004110:22739. 12. LloydJonesDM.Shorttermversuslongtermriskforcoronaryarterydisease:implicationsforlipidguidelines. CurrOpinLipidol200617:61925. 13. AkosahKO,SchaperA,CogbillC,SchoenfeldP.Preventingmyocardialinfarctionintheyoungadultinthefirst place:howdotheNationalCholesterolEducationPanelIIIguidelinesperform?JAmCollCardiol200341:1475 9. 14. SpositoAC,AlvarengaBF,AlexandreAS,etal.onbehalfoftheBrasiliaHeartStudyGroup.Mostofthepatients presentingmyocardialinfarctionwouldnotbeeligibleforintensivelipidloweringbasedonclinicalalgorithmsor plasmaCreactiveprotein.Atherosclerosis2011214:14850. 15. D'AgostinoRBSr,VasanRS,PencinaMJ,etal.Generalcardiovascularriskprofileforuseinprimarycare:the FraminghamHeartStudy.Circulation2008117:74353. 16. MarmaAK,LloydJonesDM.SystematicexaminationoftheupdatedFraminghamheartstudygeneral cardiovascularriskprofile.Circulation2009120:38490. 17. PencinaMJ,D'AgostinoRBSr,LarsonMG,MassaroJM,VasanRS.Predictingthe30yearriskofcardiovascular disease:theFraminghamheartstudy.Circulation2009119:307884. 18. LloydJonesDM,LeipEP,LarsonMG,etal.Predictionoflifetimeriskforcardiovasculardiseasebyriskfactor burdenat50yearsofage.Circulation2006113:7918. 19. SheridanSL,CrespoE.Doestheroutineuseofglobalcoronaryheartdiseaseriskscorestranslateintoclinical benefitsorharms?Asystematicreviewoftheliterature.BMCHealthServRes20088:60. 20. ElliottP,ChambersJC,ZhangW,etal.GeneticLociassociatedwithCreactiveproteinlevelsandriskofcoronary heartdisease.JAMA2009302:3748. 21. PearsonTA,MensahGA,AlexanderRW,etal.Markersofinflammationandcardiovasculardisease:applicationto clinicalandpublichealthpractice:AstatementforhealthcareprofessionalsfromtheCentersforDiseaseControl andPreventionandtheAmericanHeartAssociation.Circulation2003107:499511. 22. 22. CookNR,BuringJE,RidkerPM.TheeffectofincludingCreactiveproteinincardiovascularriskpredictionmodels forwomen.AnnInternMed2006145:219. 23. RidkerPM,PaynterNP,RifaiN,GazianoJM.CookNR.Creactiveproteinandparentalhistoryimproveglobal cardiovascularriskprediction:theReynoldsRiskScoreformen.Circulation2008118:224351. 24. HirschAT,HaskalZJ,HertzerNR,etal.ACC/AHA2005guidelinesforthemanagementofpatientswithperipheral arterialdisease(lowerextremity,renal,mesenteric,andabdominalaortic):executivesummaryacollaborative reportfromtheAmericanAssociationforVascularSurgery/SocietyforVascularSurgery,SocietyforCardiovascular AngiographyandInterventions,SocietyforVascularMedicineandBiology,SocietyofInterventionalRadiology,and theACC/AHATaskForceonPracticeGuidelines(WritingCommitteetoDevelopGuidelinesfortheManagementof PatientsWithPeripheralArterialDisease)endorsedbytheAmericanAssociationofCardiovascularand

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PulmonaryRehabilitationNationalHeart,Lung,andBloodInstituteSocietyforVascularNursingTransAtlantic InterSocietyConsensusandVascularDiseaseFoundation.JAmCollCardiol200647:1239312. AnkleBrachialIndexCollaboration,FowkesFG,MurrayGD,ButcherI,etal.Anklebrachialindexcombinedwith FraminghamRiskScoretopredictcardiovasculareventsandmortality:ametaanalysis.JAMA2008300:197208. DhanganaR,MurphyTP,AhnSH.Prevalenceofabnormalanklebrachialindexamongsubjectswithlow intermediateFraminghamriskscore.SocietyofInterventionalRadiology35thAnnualScientificMeeting,Tampa, FL:2010Abstract43. BudoffMJ,AchenbachS,BlumenthalRS,etal.Assessmentofcoronaryarterydiseasebycardiaccomputed tomography:ascientificstatementfromtheAmericanHeartAssociationCommitteeonCardiovascularImaging andIntervention,CouncilonCardiovascularRadiologyandIntervention,andCommitteeonCardiacImaging, CouncilonClinicalCardiology.Circulation2006114:176191. AlexopoulosN,RaggiP.Calcificationinatherosclerosis.NatRevCardiol20096:6818. RumbergerJA.Coronaryarterycalciumscanningusingcomputedtomography:clinicalrecommendationsfor cardiacriskassessmentandtreatment.SeminUltrasoundCTMR200829:2239. SarwarA,ShawLJ,ShapiroMD,etal.Diagnosticandprognosticvalueofabsenceofcoronaryarterycalcification. JACCCardiovascImaging20092:67588. BlahaM,etal.Absenceofcoronaryarterycalcificationandallcausemortality.JACCCardiovascImaging 20092:692700. KimKP,EinsteinAJ,BerringtondeGonzalezA.Coronaryarterycalcificationscreening:estimatedradiationdose andcancerrisk.ArchInternMed2009169:118894. LesterSJ,EleidMF,KhandheriaBK,HurstRT.Carotidintimamediathicknessandcoronaryarterycalciumscore asindicationsofsubclinicalatherosclerosis.MayoClinProc200984:22933. NaghaviM,FalkE,HechtHS,etal.FromvulnerableplaquetovulnerablepatientPartIII:Executivesummaryofthe ScreeningforHeartAttackPreventionandEducation(SHAPE)TaskForcereport.AmJCardiol200698:2H15H. SteinJH,KorcarzCE,HurstRT,etal.Useofcarotidultrasoundtoidentifysubclinicalvasculardiseaseand evaluatecardiovasculardiseaserisk:aconsensusstatementfromtheAmericanSocietyofEchocardiography CarotidIntimaMediaThicknessTaskForce.EndorsedbytheSocietyforVascularMedicine.JAmSoc Echocardiogr200821:93111quiz18990. KorcarzCE,HirschAT,BruceC,etal.Carotidintimamediathicknesstestingbynonsonographerclinicians:the officepracticeassessmentofcarotidatherosclerosisstudy.JAmSocEchocardiogr200821:11722. FinnAV,KolodgieFD,VirmaniR.Correlationbetweencarotidintimal/medialthicknessandatherosclerosis:a pointofviewfrompathology.ArteriosclerThrombVascBiol201030:17781.

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4.2:LipidManagement
Author(s): ElizabethA.Jackson,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Recallcurrentguidelines/statementsrelevanttolipidmanagement. 2. Describelandmarktrialsoflipidloweringtherapies. 3. Discussclinicalimplicationsofcurrentrecommendationsandevidenceinregardtolipidmanagement.

Introduction
Anestimated16.2%ofadultsresidingintheUnitedStateshavetotalcholesterollevelsof240mg/dlorgreater.1 This translatesintoover33millionadultswithelevatedcholesterol,placingthematincreasedriskforcardiovasculardisease. Althoughthenumberofadultswhoreporthavinghadtheirlipidscheckedhasincreasedfrom68.6%in19992000to 74.8%in20052006,thereremainsubstantialgapsinpatients'awarenessofhavingelevatedcholesterol.Womenand minoritiesremainlessawareoftheirconditioncomparedtomenandnonminorities.1,2Amongpatientswithheart disease,currently<20%areattheirrecommendedlowdensitylipoproteincholesterol(LDLC)goal,and<50%of patientswithsymptomaticcoronaryheartdisease(CHD)aretakinglipidloweringtherapy.1

AdultTreatmentProgramIIIGuidelines
TheNationalCholesterolEducationalPanel(NCEP)haspublishedguidelinesfor lipidmanagementperiodically,startingin1988.35Themostcurrent recommendations,theAdultTreatmentProgramIII(ATPIII),werepublishedin2001 andupdatedin2004.5,6Thecurrentguidelinesarebasedonalargebodyof evidence,whichdemonstratesthatloweringLDLCresultsinstatisticallysignificant reductionsincardiovascularevents.Basedonthesetrials,guidelinesinclude establishedcriteriaforriskassessmentandtreatmentofadults. ThefollowingsectionwilloutlinethekeypointsofATPIIIrelatedtoriskassessment andrelatedtreatmentgoals.KeytrialsuponwhichtheATPIIIrecommendations werebased,inadditiontokeytrialspublishedsincethepublicationofATPIII,willbe reviewed.Last,thissectionwillreviewpharmacotherapyrelatedtoLDLCandnon highdensitylipoprotein(HDL)managementandtheuseofadditionaltestingwhere appropriate. RiskAssessmentandLowDensityLipoproteinCholesterolGoals Forbothprimaryandsecondaryprevention,LDLCistheprimarytargetforthe majorityofpatients.MajorclinicaltrialsthatsupportLDLCloweringtoreduce cardiovasculardiseaseeventsinclude:HPS,PROSPER,ALLHATLLT,ASCOTLLA, PROVEITTIMI22,VAHIT,TNT,REVERSAL,IDEAL,andASTERIOD. TheATPIIIguidelinescategorizepatientsintothreeriskcategories:1)established CHDandCHDriskequivalents,2)multipleriskfactors,and3)01riskfactor.CHD riskequivalentsincludediabetes,symptomaticcarotidarterydisease,peripheral arterialdisease(includingtheaorta),andmultipleriskfactors,witha10yearriskfor CHDof>20%.Majorriskfactorsincludecigarettesmoking,hypertension,lowHDL cholesterol(HDLC),afamilyhistoryofprematureCHD,andage(Table1). UseoftheFraminghamriskscore(FRS)iscentraltotheidentificationofthoseat highriskandintermediateriskofCHD.PatientswitheitherCHDorCHDrisk equivalentsareconsideredhighrisk,andtherefore,havearecommendedgoal LDLCof<100mg/dl.Amongpatientsconsideredveryhighrisk(i.e.,thosewithboth CHDandriskfactorssuchasdiabetes,orwithuncontrolledriskfactorssuchas smoking),theATPIIIupdaterecommendedthatareasonablegoalwouldbean LDLClevel<70mg/dl(Table2). ForpatientswithoutclinicallyapparentCHD,butwithtwoormoreriskfactors,the updatedATPIIIguidelinescallfortheuseoftheFRStodeterminewhichofthose patientswouldbeconsideredhighrisk.Patientswith2+riskfactorswhohavea10 yearriskofCHD>20%areconsideredtohaveaCHDriskequivalent,andtherefore, areathighrisk.Forsuchpatients,agoalLDLC<100mg/dlisreasonable. Patientswith2+riskfactorswhohavea10yearriskofCHD<20%arefurther categorizedintointermediaterisk(FRSbetween10%and20%)andlowrisk(FRS <10%).Forbothgroups,anLDLCgoal130mg/dlisappropriate.Insuchpatients, guidelinesallowforinitiationoflipidloweringmedicationssuchasstatinsaftera trialofdietarytherapy.Ifthe10yearriskofCHDis<10%,LDLCtherapycanbe considerediftheLDLis160mg/dlonmaximaldietarytherapy. Themajorityofpatientswith01riskfactorshavealowFRS(i.e.,<10%).Forthese lowriskadults,agoalLDLC<160mg/dlisconsideredreasonable.Diettherapy shouldbeinitiatedwhentheLDLCis160mg/dl,andiftheLDLCis190mg/dl afteratrialofdietarymodification,thenpharmacotherapyshouldbeconsidered.ATP IIIguidelineauthorssuggestedthatinthepresenceofa"severeriskfactor,"earlier initiationoflipidloweringmedicationcanbeconsidered. NonLowDensityLipoproteinGoals AlthoughLDLCremainstheprimarytargetoftherapyforamajorityofpatients,once theLDLCgoalhasbeenmet,considerationofnonHDLtargetsisthesecond therapeuticconcernamongpatientswithtriglyceridelevels200mg/dl.NonHDLC includesbothveryLDL(VLDL)andLDL,whichrepresentpotentialadditionalrisk
Table3

Table1

Table2

Table4

duetoatherogenicremnantlipoproteins. NonHDLgoalsare30mg/dlabovetheLDLCgoal.Forexample,apatientwhose LDLCgoalis<100mg/dlwouldhaveanonHDLgoalof<130mg/dl.Apatientwith anLDLCgoalof<70mg/dlwouldhaveanonHDLgoalof<100mg/dl.Atthetimeof publication,theATPIIIauthorsdidnotbelievethattherewasenoughevidencefor inclusionofagoalHDLC.CurrentmanagementoptionsforincreasingHDLC beyondlifestyleincludefibratesandnicotinicacid,bothofwhichwillbedescribed laterinthismodule. TheprimaryexceptiontoaninitialLDLCtargetisamongpatientswithelevated triglycerides.Amongpatientswithtriglyceridelevels500mg/dl,triglycerides becometheinitialtarget,whileLDLCisconsideredasasecondarytarget.The mainstayoftherapyisdietaryintervention,whichcanresultinsubstantial improvementintriglyceridelevels(Table3). Factorsassociatedwithelevatedtriglyceridesincludeobesity,uncontrolled diabetes,physicalinactivity,cigarettesmoking,andexcessivealcoholintake. Lifestylemodificationcanleadtoasignificantreductionintriglyceridelevels.For patientswithhightriglycerides,24gramsofeicosapentaenoicacid(EPA)+ docosahexaenoic(DHA)foundinfishoil,togetherwithdietarymodification,can assistinloweringtriglyceridelevels. Alcoholconsumptionshouldbelimitedto1drinkforwomenand12drinksformen. Increasedintakeofalcoholcancontributetoincreasedtriglyceridelevelstherefore, accurateassessmentofbothalcoholintakeanddietaryfactorsshouldbeincluded incliniciandiscussionsregardingpreventionefforts. Additionally,drugssuchascorticosteroids,estrogens,retinoids,andbetablockers cancontributetoelevationsintriglycerides.Thesefactorsalsoareassociatedwith reductionsinHDLCaswell.Therefore,acarefulhistoryofcomorbidities, medications,andlifestylefactorsisrecommendedamongallpatients,and particularlythosewithelevatedtriglycerides. TheMetabolicSyndrome TheATPIIIguidelinesplacedincreasedemphasisonthemetabolicsyndromewith goodreason.Thepresenceofcomponentsofthemetabolicsyndromesignificantly increasestheriskforbothdiabetesandheartdisease.6 CalculationofnonHDLor thetotalcholesteroltoHDLCratiocanassistinidentifyingpatientswiththe metabolicsyndromebecausethesepatientsoftenhavealowerHDLCandthus elevatednonHDLcholesterol. Forexample,amalepatientatintermediatecardiovasculardiseaseriskwhohasan LDLof125mg/dl,HDLof30mg/dl,andtotalcholesterolof200mg/dlhasmethis LDLgoalof<130mg/dl.However,hisnonHDLof170mg/dlisabovehisgoalof 160mg/dl.HislowHDLisonecriterionforthemetabolicsyndrome.Bymeasuring fastingglucose,waistcircumference,andtriglycerides,hishealthcareprovidermay confirmadditionalcriteriaofthemetabolicsyndrome.Theclinicianshouldbeaware ofthecriteriaandbeabletoeasilyidentifypatientswhomeetcriteriaofthe metabolicsyndrome,astheyconstituteagroupatriskforCHDregardlessoftheir FRS(Table4).

MajorRiskFactorsThatModifyLDLCholesterolGoals(AdultTreatmentPanelIII) Table1 CHD=coronaryheartdiseaseHDL=highdensitylipoproteinLDL=lowdensitylipoprotein

ThreeCategoriesofRiskforCHDThatModifyGoalsandModalitiesofLDLCLoweringTherapy Table2 CHD=coronaryheartdiseaseLDLC=lowdensitylipoproteincholesterol

LifestyleRecommendationstoLowerTriglycerides Table3 BMI=bodymassindex

ClinicalIdentificationoftheMetabolicSyndrome Table4 HDLC=highdensitylipoproteincholesterol

DietandExerciseGuidelines/Recommendations
TheAmericanHeartAssociation(AHA)ScientificStatementonDietandLifestyle RecommendationsRevision2006,7 providesrecommendationsondietrelatedto lipidmodification.Inbrief,thisstatementrecommendsabalancedcaloricintake, togetherwithregularphysicalactivity,toassistintheachievementofahealthybody weight.Adietrichinvegetableandfruits,wholegrains,andhighfiberis recommended.Saturatedfatsshouldbelimitedto<7%ofenergy.Transfatsshould beavoidedwheneverpossible(Table5).Thestrongestdietaryfactorsassociated withincreasedLDLincludedietarysaturatedfatsandtransfats. SolublefiberandsoyproteincanmodestlyreduceLDLC.Plantstanols/sterolshave beenshowntolowerLDLCupto15%.Maximumeffectsareobservedwithintakes ofapproximately2g/day.Redyeastrice,afermentedriceproductthatcontains monacolinswhichhavehydroxymethylglutarylcoenzymeA(HMGCoA)reductase inhibitoractivity,hasbeenshowntoreduceLDLCcomparedtoplacebo.Thetotal monacolincontentcanvarysignificantlyindifferentavailablepreparations,andthe lackoflongtermsafetydataandregulationbytheUSFoodandDrugAdministration (FDA)limitpotentialforinclusioninfutureguidelinerecommendations. LowHDLlevelsareoftenrelatedtolifestylefactorsincludingexcessweight (particularlycentralobesity),smoking,andsedentarybehaviors.Verylowfatdiets (<10%fat)havealsobeenlinkedtoloweringHDLlevels.ForpatientswithlowHDL, recommendationsforweightloss,regularexercise(increasingthedoseofexercise overtime),andsmokingcessationarecentraltoraisingHDLlevelsthroughlifestyle modification.Asdiscussedpreviously,forpatientswithelevatedtriglycerides, additionoffishoiland/orfiber,togetherwithreduction(oravoidance)ofalcoholand controlofglucose,willassistinloweringtriglycerides.Additionalrecommendations includeconsuminglowfatdairyproductssuchasmilk,whilelimitingbeverages withaddedsugar,whichiscentraltoreducingemptycalories.

Table5

ExamplesofDietaryPatternsConsistentWithAHARecommendations Table5 *DASH=DietaryApproachestoStopHypertension. TLC=Therapeuticlifestylechanges. #Wholegrainfoodsarerecommendedformostgrainservingstomeetfiberrecommendations. Thisnumbercanbelessormoredependingonotherfoodchoices,tomeet2,000calories. AdaptedwithpermissionfromLichtensteinAH,AppelLJ,BrandsM,etal.Dietandlifestylerecommendationsrevision2006:ascientificstatement fromtheAmericanHeartAssociationNutritionCommittee.Circulation2006114:8296,Table4.

MajorClinicalTrialsUponWhichtheATPIII2004UpdateWas Based
LandmarktrialsuponwhichcurrentATPIIIguidelineswerebasedincludetheHPS (HeartProtectionStudy),8 PROSPER(PROspectiveStudyofPravastatininthe ElderlyatRisk),9 ALLHATLLT(AntihypertensiveandLipidLoweringTreatmentto PreventHeartAttackTrialLipidLoweringTrial),10ASCOTLLA(AngloScandinavian CardiacOutcomesTrialLipidLoweringArm),11andPROVEITTIMI22(Pravastatin orAtorvastatinEvaluationandInfectionThrombolysisinMyocardialInfarction22).12 ThesetrialsformedthebasisfortheupdatestoATPIII,publishedin2004.6 Itis beyondthescopeofthismoduletodiscussallthemajorstudiestherefore,abrief discussionoftrialsuponwhichtheATPIII2004updateswerebasedwillbe provided,inadditiontosomeofthekeytrialspublishedsince2004. HPS(HeartProtectionStudy) TheHPSwasaclinicaltrialincluded20,536adults,ages4080years,whowere consideredhighriskforcardiovasculardiseaseevents.8 Subjectsincludedthose withahistoryofCHDandCHDriskequivalents(noncoronaryocclusivearterial diseaseanddiabetes).Subjectswererandomizedto40mgofsimvastatinor placeboandfollowedforaprimaryoutcomeoftotalmortality,andsecondary outcomesoffatalandnonfatalvascularevents.Averagelipidvaluesatbaseline weretotalcholesterol228mg/dl,triglycerides186mg/dl(nonfasting),HDLC41 mg/dl,nonHDLC187mg/dl,anddirectLDLC131mg/dl. Amongsubjectsrandomizedtosimvastatin,totalmortalitywasreducedby13%(p= 0.003).Reductionswereobservedformajorvascularevents(24%),coronarydeath (18%),nonfatalmyocardialinfarction(MI)andcardiacdeath(27%),nonfatalorfatal stroke(25%),andcardiovascularrevascularization(24%),ascomparedto placebo.Thebenefitswereobservedforboththeprimarypreventiongroup(i.e., thosewithnopriorhistoryofCHD)andthesecondarypreventiongroup(i.e.,those withahistoryofCHD).Similarreductionswerenotedforbothmenandwomen,and forthoseunderandover70yearsofageatbaseline. AkeyfindingoftheHPSwastheriskreductionobservedwithsimvastatinatall baselinelevelsofLDLC,includingsubjectswithLDLClevels<100mg/dl.An additionalimportantfindingwasthesignificantriskreductionobservedamong diabetics.In2,426diabeticsubjectswithapretreatmentLDLC<116mg/dl,event rateswere27%lowerinthesimvastatingroupcomparedtotheplacebogroup.No significantadverseeffectsofsimvastatintherapywerereported,includingany significantincreaseinmyopathy,cancerincidence,orhospitalizationforanyother nonvascularcause(Figure1). PROSPER(ProspectiveStudyofPravastatinintheElderlyatRisk) ThemajoraimofthePROSPERtrialwastoexaminethepotentialforCVDrisk reductionrelatedtostatintherapyamongtheelderly.9 Atotalof5,804menand women,ages7082years,withahistoryofvasculardiseaseorcardiovascular diseaseriskfactors,wererandomizedtopravastatin40mg/dayorplacebo.The primaryendpointwascombinedcoronarydeath,nonfatalMI,andfatalornonfatal stroke.Overanaveragefollowupof3.2years,pravastatinreducedLDLClevelsby 34%.Theprimaryendpointwasreducedby15%amongthepravastatingroup comparedtothecontrolgroup(p=0.014). Riskreductionswereobservedforsecondaryendpoints,includingmajorcoronary events(i.e.,nonfatalMIandCHDdeath).CHDmortalitywasreducedby24%inthe statingroupcomparedtotheplacebogroup.Noreductioninstrokewasobserved however,transientischemicattacks(TIAs)werereducedby25%.Diagnosisofnew cancerwasunexpectedlyfoundtobe25%moreofteninsubjectsonpravastatin treatment(p=0.020).Pravastatintherapydidnotimprovecognitivefunction,nordid itretardprogressionofcognitiverelateddisabilities.ThekeyfindingofPROSPER wasthesignificantbenefitofstatintherapyinthehighriskelderly.

Figure1

ASCOTLLA(AngloScandinavianCardiacOutcomesTrialLipidLoweringArm) IntheASCOTLLAstudy,19,342hypertensivepatients,ages4079yearsold,with threeormorecardiovascularriskfactorsinadditiontohypertension,were randomizedtooneoftwoantihypertensiveregimens.11Atotalof10,305subjects werealsorandomlyassignedtoatorvastatin10mg/dayorplacebo.LDLClevels averaged132mg/dlatbaselineandwerereducedbyanaverageof42mg/dl(29%) intheatorvastatintreatedgroupattheendofthestudy. Thetrialwasstoppedearlyforasignificantreductionintheprimarycombined endpointofnonfatalMIandfatalCHD.Atthattime,100primaryeventshadoccurred intheatorvastatingroupcomparedwith154eventsintheplacebogroup(hazard ratio[HR],0.64p=0.0005).Intheatorvastatingroup,fatalandnonfatalstrokewere reducedby27%(p=0.024),totalcardiovasculareventsby21%(p=0.0005),and totalcoronaryeventsby29%(p=0.0005).Therewasanonsignificanttrendtowarda reductionintotalmortalityintheatorvastatingroup(13%p=0.16).Thekeyfindingof ASCOTLLAwasthesignificantbenefitofstatintherapyinprimarypreventionamong patientswithhypertension. PROVEITTIMI22(PravastatinorAtorvastatinEvaluationandInfectionTherapy ThrombolysisinMyocardialInfarction22)Trial ThePROVEITTIMI22studywasdesignedtocompareintensiveLDLClowering comparedtostandardtherapytoreducemajorcoronaryeventsamonghighrisk patients(i.e.,recentacutecoronarysyndrome[ACS]).12Theintensivetherapyarm wasatorvastatin80mg/daycomparedtostandardtherapyofpravastatin40mg/day. Atotalof4,162patientsrecentlyhospitalizedforanACS(withinthepreceding10 days)wererandomizedtotwotreatmentarms.Theprimaryendpointofthetrialwas acompositeofdeathfromanycause,MI,documentedunstableanginarequiring rehospitalization,revascularization(performedatleast30daysafterrandomization), andstroke.Meanfollowuptimewas24months. AgreaterreductioninLDLClevelwasattainedinthegrouprandomizedto80mgof atorvastatin(62mg/dl),ascomparedtothosewhoreceivedpravastatin40mg(95 mg/dl).Attheendof2yearfollowup,asignificantreductionintheprimary compositecardiovascularendpointwasobservedfortheatorvastatingroup comparedtothepravastatingroup(p<0.005).Nonsignificanttrendswereobserved inpatientsonatorvastatintherapyfortotalmortality(p<0.07)andfordeathorMI(p< 0.06).Thehighdoseofatorvastatinwaswelltolerated,andnocaseofsevere myopathy(rhabdomyolysis)wasobservedineithertreatmentgroup.Greaterthan threefoldelevationsofalanineaminotransferase(ALT)wereobservedin3.3%of patientstreatedwithatorvastatinversus1.1%onpravastatin(p<0.003). ThekeyfindingofthePROVEITTIMI22studywasthereductionincardiovascular diseaseeventsamongpatientswithrecentACSeventsrandomizedtointensive dosestatintherapy.

TheHeartProtectionTrial:MajorVascularEventsbyLDLCholesterol Figure1 CI=confidenceintervalLDL=lowdensitylipoproteinSE=standarderror. ReproducedwithpermissionfromHeartProtectionStudyCollaborativeGroup.MRC/BHFHeartProtectionStudyofcholesterolloweringwith simvastatinin20,536highriskindividuals:arandomisedplacebocontrolledtrial.Lancet2002360:722.

LandmarkTrialsSincetheAdultTreatmentPanelIIIUpdate
REVERSAL(ReversalofAtherosclerosisWithAggressiveLipidLowering)Trial Subjects(n=502)intheREVERSALtrialwererandomizedtoeitheraggressivelipidloweringtherapywithatorvastatin80 mg/dayormoderatelipidloweringwithpravastatin40mg/day.13Intravascularultrasound(IVUS)wasperformedat baselineandat18months.MeanLDLClevelsatbaselineweresimilarinbotharms(152.2mg/dl),whilefollowupLDL Cwaslowerintheaggressivetherapyarm(79mg/dlvs.110mg/dl).ByIVUS,atheromavolumehadsignificantly increasedinthegrouprandomizedtopravastatin40mg/day,whereassubjectsrandomizedtoatorvastatin80mg/day demonstratednochange. InaposthocanalysisamongsubjectsrandomizedtopravastatinwhoseLDLwas<100mg/dl,thepercentchangein atheromastilldemonstratedprogressionofatherosclerosis.Creactiveprotein(CRP)levelsdecreasedmoreinthe atorvastatinarm,ascomparedwiththepravastatinarm(36.4%vs.5.2%,p<0.0001).Nodifferencewasobservedin adverseevents,death,orMIbetweenthetwotreatmentgroups.Thisstudysuggeststhatalthoughnodifferencewas observedforhardendpointssuchasMI(thetrialwasnotpoweredtodetectsuchendpoints),intensivedosestatins preventprogressionofatheroma,asmeasuredbyIVUS. IDEAL(IncrementalDecreaseinEndPointsThroughAggressiveLipidLowering)Trial TheIDEALstudycomparedhighdosestatinswithmoremoderatedosing.14TheIDEALstudyfoundnodifferenceinthe primarycompositeendpointofmajorcoronaryeventsorsecondaryendpointsofCHDdeath,orcardiacarrestbetween thoserandomizedtoatorvastatin80mg/dayorsimvastatin20mg/day.LowerratesofnonfatalMIwereobservedfor subjectsonatorvastatincomparedwithsubjectsonsimvastatin. TNT(TreatingtoNewTargets)Trial TheTNTstudyrandomizedsubjectstoeitheratorvastatin80mg/dayoratorvastatin10mg/day(aftercompletionofan8 weekopenlabeledruninperiodwhereallsubjectswereonatorvastatin10mg/day).15OntreatmentmeanLDLCwas 77mg/dlamongthoserandomizedtoatorvastatin80mg/dayand101mg/dlamongthoserandomizedtoatorvastatin10 mg/day. Theprimaryendpoint(CHDdeath,nonfatalMI,resuscitatedcardiacarrest,andfatalornonfatalstroke)waslowerinthe intensivelytreatedgroup,ascomparedtothosetreatedwithatorvastatin10mg/day(8.7%vs.10.9%,p<0.001). Secondaryendpoints,includingnonfatalMIandstroke,werealsoreducedinthegrouprandomizedtoatorvastatin80 mg/day.Thesedatasuggestthatintensivestatindosesmaybebeneficialamongpatientswithstablecoronaryartery disease. JUPITER(JustificationfortheUseofStatinsinPrevention:AnInterventionTrialEvaluatingRosuvastatin) TheJUPITERtrial,arandomizedtrialofrosuvastatininthepreventionofcardiovasculareventsamong17,802apparently healthymenandwomenwithelevatedlevelsofhighsensitivityCRP(hsCRP),wasalandmarktrialpublishedin2008.16 SubjectswithlowLDLC(<130mg/dl)andhsCRP2mg/Lwererandomizedtoeitherrosuvastatin20mg/dayor placebo.Additionalinclusioncriteriawereage50yearsformen,60yearsforwomen,andnocardiovasculardisease ordiabetes.Thetrialwasstoppedearlyduetoasignificantreductionintheprimaryendpoint(MI,stroke,unstable angina/revascularization,andcardiovasculardeath)observedintherosuvastatingroupcomparedtoplacebo(hazard ratio[HR],0.5695%confidenceinterval[CI],0.460.69). ReductionsinnonfatalandfatalMI,stroke,andrevascularizationwereobservedamongthoserandomizedtostatin therapy.Thebenefitsofrosuvastatinwerenotedforallsubgroups.Amodestincreaseindevelopmentofdiabeteswas observedwithstatintherapy(HR,1.2595%CI,1.051.54).ThekeyfindingofJUPITERwasthebenefitofstatintherapy forprimarypreventionamongpatientswithoutsignificantelevationsofLDLCatbaseline. ACCORD(ActiontoControlCardiovascularRiskinDiabetes)Trial TheACCORDstudyexaminedcombinationtherapywithastatinplusfibratecomparedtostatintherapyalonetoreduced cardiovasculardiseaseeventsamongsubjectswithtype2diabetes.17Atotalof5,518subjectswererandomizedto openlabelsimvastatinwitheithermaskedfenofibrateorplacebo.Theprimaryoutcomewasfirstoccurrenceofnonfatal MI,nonfatalstroke,orcardiovasculardiseasemortality.Meanfollowupwas4.7years. Thecombinationoffenofibrateandstatindidnotreduceratesoffatalcardiovasculardiseaseevents,nonfatalMI,or nonfatalstrokecomparedtostatintherapyalone.Thesedatasuggestthatforamajorityofdiabeticpatients,additionofa fibratetostatintherapyisnotassociatedwithsignificantbenefitintermsofreducingfuturecardiovasculardisease events.

PharmacotherapyforLowDensityLipoprotein
BasedonATPIIIguidelines,theprimarygoalformostpatientsfocusesonLDLC levels.Basedonthepresenceorabsenceofcoronaryarterydiseaseand/or coronaryarterydiseaseriskequivalent,andconcomitantriskfactors,anLDLtarget isdetermined.TheresultsofstudiessuchasHPSandPROVEITsupportalower LDLCgoalthanhadbeenrecommendedinearlierguidelines.Thus,forpatientsat veryhighrisksuchasthosepatientswithcoronaryarterydiseaseanddiabetes,itis reasonabletotargetLDLforagoalof<70mg/dl.Statintherapyisthefirstlineagent forLDLloweringbasedonthenumeroustrials,severalofwhichareoutlinedinthis module. Afterinitiationofstatintherapy,arepeatLDLCandliverenzymetestsareperformed. Statindoseisadjustedorcombinationtherapyisinitiatedifthepatientisnotatgoal (Table6).AfterthetargetLDLClevelsareobtained,LDLlevelsandliverenzymes arecheckedevery46monthsthereafter.Allpatientsshouldbeinstructedin therapeuticlifestyleincludingregularexercise,andadiethighinfiberandlowin saturatedfats,alongwithmaintenanceofahealthyweightandavoidanceof smoking,whicharecentraltolipidmanagement. WhenpatientscannotachievetheirLDLgoalwithstatinsasmonotherapy, considerationforcombinationtherapyisrecommended.Optionsforcombination therapyincludeuseofezetimide,bileacidsequestrants,ornicotinicacid.Additional nonpharmacologicinterventionsincludetheuseofplantstanols/sterolsin combinationwithastatin.Additionoffiberandsoymayalsobeconsidered. Bileacidsequestrantsbindtobileacidsinthegut,thusreducingreabsorption.The subsequentreductioninintrahepaticcholesterolleadstoanincreaseinthe synthesisofapoB/Ereceptors,whichbindLDLfromtheplasma,thusresultingin furtherreductionsinLDLC.Bileacidcanbeusedincombinationwithstatins, nicotinicacid,andpsylliumtoachieverecommendedLDLgoals.Sideeffects includinggastrointestinalsymptoms(nausea,bloating,andcramping),andthe effectsonabsorptionofotherdrugssuchaswarfarin,limititsuse.Liverenzymes shouldbemonitoredevery46monthsorwithchangesinmedications.Nicotinic acidandfibratesarediscussedinthefollowingsection. EzetimideisalsousedincombinationwithstatinsforloweringLDLC.However,to date,dataforezetimidehavenotbeenshowntoreducesignificantoutcomes,such asMI.Givenevidenceofnonsignificantchangesinintimamediathickness measureswithezetimideandsimvastatincomparedtosimvastatinalone,current recommendationscallforezetimideasasecondorthirdlineagent,ratherthanan initialtreatmentchoice.

Table6

LDLCAverageReductionWithStandardDosesofCurrentlyAvailableStatins Table6 LDLC=lowdensitylipoproteincholesterol

PharmacotherapyforNonHighDensityLipoprotein
AlthoughcurrentguidelinesdonotidentifyHDLClevelsforspecifictreatmentgoals,lowHDLClevelsareassociated withincreasedcardiovasculardiseaseriskandareakeycomponentofthemetabolicsyndrome.Acombinationofstatin withniacincanresultinareductioninLDLCalongwithariseinHDLC.TheconcurrentLDLloweringwithHDL increasingresultsinasignificantCHDriskreduction.PriorclinicaltrialssupporttheuseofniacintobothreduceLDLand increaseHDL. Niacin TheHATS(HDLAtherosclerosisTreatmentStudy)trialrandomizedsubjectstofourtreatmentarms1)simvastatin/niacin, 2)antioxidants,3)simvastatin/niacin+antioxidants,and4)placebo.18LDLandHDLlevelsdidnotchangeinthe antioxidantgrouportheplacebogroup.Inthesimvastatin/niacingroup,LDLlevelsdecreasedby42%,whereasHDL levelsincreasedby26%.Similarchangeswereobservedamongthoserandomizedtoantioxidantswith simvastatin/niacin.Cardiovasculardiseaseeventsweresignificantlyloweramongthoserandomizedto simvastatin/niacin(3%),comparedtoantioxidant+simvastatin/niacin(14%),antioxidantsalone(21%),amdplacebo alone(24%). Thesefindingssupporttheuseofcombinationstatin/niacinforcardiovasculardiseaseriskreduction,whileadding furtherdatatosuggestantioxidantsdolittletoreducecardiovasculardiseaserisk.Asaresultofthesedataandother studies,theFDAhasapprovedastatin/niacincombination. NiacininhibitsVLDLsynthesisintheliver,resultinginlowerLDLClevels.ItalsoraisesHDLCbyreducingthetransfer ofcholesterolfromHDLtoVLDL,andbyreducingHDLclearance.Amajorsideeffectofniacinisprostaglandin medicatedflushing.Pretreatmentofaspirin30minutespriortotakingniacincanreducesymptomsofflushing,and pruritus.Flushingoftendiminishesovera7to10dayperiodafterinitiationordoseincrease.Liverenzymesshouldbe monitoredwithdosechangesorevery46months.Increaseinuricacidprecipitatinggoutispossiblethus,among patientswithahistoryofgout,nicotinicacidshouldbeavoidedorusedwithcaution.Patientsandtheirprovidersshould alsobeawareofthepotentialforincreaseinglucoselevelswithnicotinicacid. NoflushoverthecounterpreparationsareineffectiveforHDLraising(orLDLlowering),astheycontainnicotinamide,the inactiveformofthevitamin,ratherthannicotinicacid.Nicotinicacidshouldbeusedwithcautioninpatientswithliver disease,andmaynotbeappropriateforthosewithgoutorpepticulcerdisease. Fibrates PriorclinicaltrialswithfibratessuggestedariskreductionforCHDeventsinpatientswithhightriglyceridesandlowHDL C,particularlyamongpatientswithdiabetesorcriteriaforthemetabolicsyndrome.19However,recentresultsfrom theACCORDstudydonotconfirmsuchbenefitsamongpatientswithtype2diabetes.17 Riskforadverseevents,inparticularmyopathy,relatedtostatinuseincreaseswithuseofcombinationtherapysuchas fibrates.Fenofibrateisrecommendedsinceitdoesnotinterferewiththecatabolismofstatins,andthus,reducestherisk formyopathiesinpatientsonstatintherapy.Cautionshouldbeusedwhenprescribingfibratesinpatientswithliveror renaldysfunction,andthosewithgallbladderdisease. LipidTreatmentAdverseEffects Absolutecontraindicationstostatintherapyincludeactiveliverdiseaseandpregnancy,whereasrelative contraindicationsincludeuseofcyclosporine,gemfibrozil,macrolideantibiotics,antifungals,andcytochromeP450 inhibitors.Forpatientstakingcyclosporine,pravastatinisthepreferredstatin.Monitoringforadverseeffectsincludes checkingliverfunctiontests(ALT/AST)atbaseline,68weeksafterdosechanges,and46monthswhenonastable dose. Elevatedhepatictransaminasescanbeseeninupto2%ofpatientstakingstatins.Abnormallevelsareassociatedwith increaseddosesofstatins,andcannormalizewithreduceddosesorholdingstatintherapy.Statinshavenotbeen associatedwithpooroutcomesamongpatientswithhepatitisBorC.However,activeorchronicliverdiseaseis consideredacontraindicationtostatintherapy.Pregnancyisalsoanabsolutecontraindicationforstatintherapy.For womenofchildbearingage,counselingpriortoconceptionisrecommended,withcessationofthestatinpriorto conception. TheAmericanCollegeofCardiology(ACC)/AHA/NationalHeart,Lung,andBloodInstitute(NHLBI)ClinicalAdvisoryonthe UseandSafetyofStatinsrecommendsthatcliniciansbeawareoffactorsthatcanincreaseriskforstatinassociated myopathy.20Thesefactorsincludeadvanceage,particularlyinwomen,smallbodyframeandfrailty,multisystemdisease includingchronicrenalinsufficiencyduetodiabetes,hypothyroidism,andmultiplemedications.Concomitantuseof medications,includingfibrates,cyclosporine,azoleantifungals,itraconazoleandketoconazole,macrolideantibiotics,

erythromycinandclarithromycin,humanimmunodeficiencyvirusproteaseinhibitors,nefazodone,verapamil, amiodarone,andalcoholabuse,canincreasetheriskformyopathy.Intakeofgrapefruitjuiceoveronequartperdaycan alsoincreasetheriskforstatinassociatedmyopathy. Creatinephosphokinase(CPK)shouldbedrawnatbaseline,withrepeatmeasuresonlywhensignificantmuscleaches arereported.StatindoseshouldbereducedordiscontinuedforaCPKlevel>10timesnormal.Sinceahypothyroidstate canpredisposepatientstomyopathy,athyroidstimulatinghormone(TSH)shouldbechecked.Rhabdomyolysisisrare, andisassociatedwithanincreasedriskofmortality(~10%).Only1per3,000deathsoccurredinpatientstakingbotha statinandfibrate.NonspecificmuscleacheswithminorornoCPKelevationsarepresentinapproximately5%of patients,whichisasimilarrateobservedamongsubjectsrandomizedtoplaceboinseveraltrials.Inthepast,concern hasbeenraisedregardingpotentialdangersofreducingLDLCtoverylowlevelshowever,inalargebodyofclinical trials,nosignificantsideeffectsfromLDLloweringhavebeenidentified.

KeyPoints
PatientsarecategorizedbyATPIIIintothreeriskcategories:1)establishedCHDandCHDriskequivalents,2) multiple(2+)riskfactors,and3)zerotooneriskfactor.CHDriskequivalentsincludenoncoronaryformsofclinical atheroscleroticdisease,diabetes,andmultipleriskfactors(2+)witha10yearsriskforCHD>20%.Allpersons withCHDorCHDriskequivalentscanbecalledhighrisk. LDLCremainstheprimarytargetoflipidtreatment.Randomizedcontrolledtrialsusingstatinssuggesta significantbenefittostatintherapytolowerLDLC.Recenttrialssuggestbenefittointensivedosestatintherapy forpatientsathighorveryhighriskforcardiovasculardiseaseevents. Recenttrialssuggestabenefittointensivedosestatintherapyforpatientsathighorveryhighriskfor cardiovasculardiseaseevents.Thus,evidenceisapplicabletopatientgroupsincludingwomen,theelderly, diabetics,minorities,andthosewithhypertension. LipidtreatmentthatfailstoproduceasizableLDLCreductionwillnotyieldasignificantreductionin cardiovasculardiseaserisk.Forthoseathighrisk,anLDLCgoalof<70mg/dlisreasonable. Therapeuticlifestylechangesincludingexercise,dietarymodification,andsmokingcessationcanleadto substantialimprovementsinlipids.Allpatientsshouldbecounseledregardingahealthylifestyle. CurrentATPIIIguidelinesrecommendthatcliniciansplaceincreasedemphasisonthemetabolicsyndromein patientswhoarealreadyreceivingLDLCloweringtherapybyadditionallytargetingtheloweringoftriglycerides andraisingHDLC. ThecombinationofastatinwithniacincanproduceamarkedreductioninLDLC,alongwithasignificantriskin HDLC,leadingtoreductionsinCHDrisk.

References
1. RogerVL,GoAS,LloydJonesDM,etal.,onbehalfoftheAmericanHeartAssociationStatisticsCommitteeand StrokeStatisticsSubcommittee.Heartdiseaseandstrokestatistics2011update:areportfromtheAmerican HeartAssociation.Circulation2011123:e18e209. 2. PleisJ,Lucas,L.SummaryHealthStatisticsforUSAdultsNationalHealthInterviewSurvey,2007.Hyattsville,MD: USDepartmentofHealthandHumanServices,CentersforDiseaseControlandPrevention,NationalCenterfor HealthStatistics,2010.VitalandHealthStatistics,Series10,No.249,DHHSpublicationNo.20091568. 3. [Noauthorslisted].Cholesteroltreatmentrecommendationsforadults.Highlightsof1987report,National CholesterolEducationProgramAdultTreatmentPanel.MdMedJ198837:245. 4. [Noauthorslisted].SummaryofthesecondreportoftheNationalCholesterolEducationProgram(NCEP)Expert PanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelII). JAMA1993269:301523. 5. ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.ExecutiveSummaryof theThirdReportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection,Evaluation, andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII).JAMA2001285:248697. 6. GrundySM,CleemanJI,MerzCN,etal.,onbehalfoftheNationalHeart,Lung,andBloodInstituteAmerican CollegeofCardiologyFoundationAmericanHeartAssociation.Implicationsofrecentclinicaltrialsforthe NationalCholesterolEducationProgramAdultTreatmentPanelIIIguidelines.Circulation2004110:22739. 7. LichtensteinAH,AppelLJ,BrandsM,etal.Dietandlifestylerecommendationsrevision2006:ascientific statementfromtheAmericanHeartAssociationNutritionCommittee.Circulation2006114:8296. 8. HeartProtectionStudyCollaborativeGroup.MRC/BHFHeartProtectionStudyofcholesterolloweringwith simvastatinin20,536highriskindividuals:arandomisedplacebocontrolledtrial.Lancet2002360:722. 9. ShepherdJ,BlauwGJ,MurphyMB,etal.,onbehalfofthePROSPERStudyGroup.PROspectiveStudyof PravastatinintheElderlyatRisk.Pravastatininelderlyindividualsatriskofvasculardisease(PROSPER):a randomisedcontrolledtrial.Lancet2002360:162330. 10. ALLHATOfficersandCoordinatorsfortheALLHATCollaborativeResearchGroup.TheAntihypertensiveandLipid LoweringTreatmenttoPreventHeartAttackTrial.Majoroutcomesinmoderatelyhypercholesterolemic, hypertensivepatientsrandomizedtopravastatinvsusualcare:TheAntihypertensiveandLipidLowering TreatmenttoPreventHeartAttackTrial(ALLHATLLT).JAMA2002288:29983007. 11. SeverPS,DahlofB,PoulterNR,etal.,onbehalfoftheASCOTInvestigators.Preventionofcoronaryandstroke eventswithatorvastatininhypertensivepatientswhohaveaverageorlowerthanaveragecholesterol concentrations,intheAngloScandinavianCardiacOutcomesTrialLipidLoweringArm(ASCOTLLA):a multicentrerandomisedcontrolledtrial.Lancet2003361:114958. 12. CannonCP,BraunwaldE,McCabeCH,etal.,onbehalfofthePravastatinorAtorvastatinEvaluationandInfection TherapyThrombolysisinMyocardialInfarction22Investigators.Intensiveversusmoderatelipidloweringwith statinsafteracutecoronarysyndromes.NEnglJMed2004350:1495504. 13. NissenSE,TuzcuEM,SchoenhagenP,etal.,onbehalfoftheREVERSALInvestigators.Effectofintensive comparedwithmoderatelipidloweringtherapyonprogressionofcoronaryatherosclerosis:arandomized controlledtrial.JAMA2004291:107180. 14. PedersenTR,FaergemanO,KasteleinJJ,etal.,onbehalfoftheIncrementalDecreaseinEndPointsThrough AggressiveLipidLowering(IDEAL)StudyGroup.Highdoseatorvastatinvsusualdosesimvastatinforsecondary preventionaftermyocardialinfarction:theIDEALstudy:arandomizedcontrolledtrial.JAMA2005294:243745. 15. LaRosaJC,GrundySM,WatersDD,etal.,onbehalfoftheTreatingtoNewTargets(TNT)Investigators.Intensive lipidloweringwithatorvastatininpatientswithstablecoronarydisease.NEnglJMed2005352:142535. 16. RidkerPM,DanielsonE,FonsecaFA,etal.,onbehalfoftheJUPITERStudyGroup.Rosuvastatintoprevent vasculareventsinmenandwomenwithelevatedCreactiveprotein.NEnglJMed2008359:2195207. 17. GinsbergHN,ElamMB,LovatoLC,etal.,onbehalfoftheACCORDStudyGroup.Effectsofcombinationlipid therapyintype2diabetesmellitus.NEnglJMed2010362:156374. 18. BrownBG,ZhaoXQ,ChaitA,etal.Simvastatinandniacin,antioxidantvitamins,orthecombinationforthe preventionofcoronarydisease.NEnglJMed2001345:158392. 19. KeechA,SimesRJ,BarterP,etal.Effectsoflongtermfenofibratetherapyoncardiovasculareventsin9795 peoplewithtype2diabetesmellitus(theFIELDstudy):randomisedcontrolledtrial.Lancet2005366:184961. 20. PasternakRC,SmithSCJr,BaireyMerzCN,GrundySM,CleemanJI,LenfantC.ACC/AHA/NHLBIClinicalAdvisory ontheUseandSafetyofStatins.Circulation2002106:10248.

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4.3:NutritionandObesity
Author(s): AmitKhera,MD,MSc,FACC AnandRohatgi,MD,MSCS,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Applythe2006AmericanHeartAssociation(AHA)dietandlifestylerecommendationstoimproveriskfactorsandhealth outcomesinpatientswithcardiovasculardisease(CVD)andthoseatriskforCVD.1 2. Recognizewhichdietaryfactorsareandarenotrecommendedforimprovingcardiovascular(CV)health. 3. UtilizetheNationalInstitutesofHealth(NIH)PracticalGuiderecommendationsforpromotingweightlossinoverweight andobesepatients.2 4. Describetheappropriateuseofpharmacologictherapyandbariatricsurgeryastherapeuticoptionsforobesity management.

Introduction
DespitemajoradvancesinmedicaltherapiesforreducingCVevents,dietandlifestylechangesremainthemosteffective waystoreducetheburdenofCVDinthegeneralpublic.Unfortunately,currentdietarypatterns,alongwithdecreasing physicalinactivity,haveledtoepidemicsinobesityanddiabetes.Obesityanddiabetesarebothmajorriskfactorsfor CVD. Amajorityoftheresearchhasfocusedonindividualnutrients,butithasbecomeincreasinglyclearthatoverallhealthy eatingpatternsensureadequatenutrientintakeandenergybalance.Consistentwiththesefindings,theAHAhasset goalsforoptimalhealthyeatingbehaviors.1 Inaddition,theNationalHeart,Lung,andBloodInstitute(NHLBI)has synthesizedtheevidencetoprovidepracticalrecommendationsfortheapproachtoobesitymanagement.2

NutritionGuidelines
In2006,theAHANutritionCommitteerevisedthedietandlifestyle recommendationstoemphasizeanoverallhealthyeatingpattern,ratherthan focusingonaspecificnutrientorfood.1 Inadditiontoconsumingahealthydiet,other goalstoreduceCVriskinclude:1)aimingforahealthybodyweight2)maintaining recommendedlevelsoflowdensitylipoproteincholesterol(LDLC),highdensity lipoproteincholesterol(HDLC),andtriglyceridesand3)maintainingnormalblood pressure(BP)andbloodglucoselevels.Otherrecommendationsinclude:1)being physicallyactive,and2)avoidingexposuretotobaccoproducts.Thespecificdietary recommendationsareshowninTable1.Theseconsistofabalanceddietwiththe followinglimitations:1)saturatedfatintaketo<7%ofdailycalories,2)transfatto <1%ofdailycalories,and3)cholesterolto<300mg/day.Therecommendations encourageincreasedconsumptionofoilyfish,vegetables,fruits,andwholegrain. Saltandalcoholconsumptionshouldbelimited. Goalsforahealthybodyweighttargetabodymassindex(BMI)inthenormalrange (i.e.,18.524.9kg/m2 )(Table2).Increasingemphasishasbeenplacedon preventionofweightgainduringchildhoodandthesubsequentadultyears.Thisis becauseobesityisastrongriskfactorforthedevelopmentofCVDriskfactorsand forCVDitself,andbecauseweightlosscanbechallenging. LDLClevelsarelinearlyrelatedtoanincreasingCVDrisk,andLDLremainsthe primarylipoproteintargetforCVriskreduction.OptimalLDLClevelsare<100mg/dl (Table2).Borderlinehighlevelsare130159mg/dl,highlevelsare160189mg/dl, andveryhighlevelsare190mg/dl.ThestrongestdietarydeterminantsofLDLC levelsaredietarysaturatedfattyacidandtransfattyacidintake.HDLCand triglyceridesarealsoaffectedbydietarypatternsandbodyweight.Thecriteriaforthe metabolicsyndromeincludeHDLClevels<40mg/dlinmenand<50mg/dlin women,aswellastriglyceridelevels>150mg/dl. OptimalBPisasystolicBP<120mmHgandadiastolicBP<80mmHg(Table2). However,theriskofCVDandrenaldiseaseincreasesthroughouttherangeofBPs withoutaspecificthreshold.DietaryfactorshaveacentralroleinaffectingBP,as discussedinthefollowingsections.Theoptimalbloodglucoselevelis100mg/dl, withdiabetesdefinedasafastingglucoselevel126mg/dl.Modestweightloss throughreducingcaloricintakeandincreasingphysicalactivitycanimproveglucose control,delaytheonsetofdiabetes,andpossiblypreventtheincidenceofdiabetes bymorethan50%.3

Table1

Table2

AmericanHeartAssociation2006DietandLifestyleRecommendationsforCardiovascularDiseaseRiskReduction Table1 ReproducedwithpermissionfromLichtensteinAH,AppelLJ,BrandsM,etal.Dietandlifestylerecommendationsrevision2006:ascientific statementfromtheAmericanHeartAssociationNutritionCommittee.Circulation2006114:8296.

OptimalTargetsforReducingCardiovascularDiseaseRisk Table2 BMI=bodymassindexBP=bloodpressureLDLC=lowdensitylipoproteincholesterol. ReproducedwithpermissionfromLichtensteinAH,AppelLJ,BrandsM,etal.Dietandlifestylerecommendationsrevision2006:ascientific statementfromtheAmericanHeartAssociationNutritionCommittee.Circulation2006114:8296.

CardiovascularEffectsofSpecificDietaryPatterns
LowFatDiet Observationalstudiesandsmallerrandomizedtrialshavesuggestedthatdietslowerinfats,particularlysaturatedfats, couldresultinimprovedCVoutcomes.ThelargestrandomizedtrialtodatetotestthishypothesisistheWomensHealth InitiativeDietaryModificationTrial.Thistrialincludedapproximately48,000womenwhowererandomizedtoadiet targetingreducedtotalfatintake,aswellasincreasedfruits,vegetables,andgrains,versusnodietarychange.4 Despite an8.2%lowerfatintake,womeninthedietaryinterventionarmhadnosignificantdifferenceinratesofCVevents.These nullresultsmaybeattributedtoinsufficientreductionsinsaturatedfats(i.e.,2.9%)intheinterventionarm,duringanera withgenerallyloweroverallsaturatedfatintake.However,itwasalsosuggestedthataglobaldietarypatternchangemay benecessarytoimpactCVevents,ratherthanaprimaryfocusononemacronutrient. MediterraneanDiet SeverallargeobservationalstudieshavedemonstratedareductionintotalmortalityandCVDmortalitywiththe Mediterraneanstylediet.Thisdietconsistsofanincreasedintakeofmonounsaturatedfat,plantprotein,wholegrains, andfishmoderateconsumptionofalcoholandlowconsumptionofredandprocessedmeat,wholefatdairyproducts, andsweets. Inadditiontoobservationalstudies,therandomizedsecondarypreventionLyonHeartStudydemonstratedfewerfataland nonfatalCVeventswiththeMediterraneandiet,ascomparedwiththelowfatdiet.5 Severalrecentsubstudiesofthe ongoingrandomizedPREDIMED(PrevencionconDietaMediterranean)trialoftwoMediterraneandietsversusalowfat diethaveelucidatedthesalutaryeffectsoftheMediterraneandietonCVriskfactors.Thisdietarypatternresultedin significantlylowerplasmaglucoselevels,lowersystolicanddiastolicBP,andalowertotalcholesteroltoHDLCratio,but littlechangeinLDLC.6 Morerecently,thePREDIMEDinvestigatorsalsoreportedgreaterresolutionofthemetabolic syndromeandalowerincidenceofdiabetesinthoseassignedtotheMediterraneandiet.7 DietaryApproachestoStopHypertensionDiet TheoriginalrandomizedDASH(DietaryApproachestoStopHypertension)trialcomparedacontroldiettoadietrichin fruits,vegetables,andlowfatdairyfoods,andwithreducedsaturatedandtotalfatintake.Theresultsdemonstratedthat thoseontheDASHdiethadasignificantlygreaterreductioninsystolicanddiastolicBP(i.e.,5.0and3.5mmHg, respectively).8 Thereductionwasmoresubstantialamongthosewithdiagnosedhypertension(i.e.,11.4and5.5mmHg, respectively).Subsequently,theDASHstudygroupdemonstratedthatalowsodiumdietandtheDASHdieteachhad beneficialeffectsonBP,butthattheeffectsweregreatestwhenbothdietswerecombined.9 ThemostrecentdietaryguidelinesfromtheUSDepartmentofHealthandHumanServicesrecommendadailysodium intakeof<2300mg/dayforalladults,and<1500mg/dayforthosewhohavehypertensionorareatriskofhypertension. Theatriskgroupsincludethoseovertheageof50,AfricanAmericans,andthosewithdiabetesorchronickidney disease.10However,adailyintakeof<1500mgmaybeareasonabletargetforeveryone.

DietaryFactorsPotentiallyAffectingRiskFactorsandCardiovascularRisk
Omega3FattyAcids Multipleobservationalstudieshaveconsistentlydocumentedtheassociationbetweenfishintakeandadecreasedriskof CVD.TheAHArecommendsthatindividualswithoutcoronaryheartdisease(CHD)consumefishatleasttwiceweekly, specificallyoilyfishsuchastuna,mackerel,trout,orsalmon.ForpatientswithCHD,atotalof1goflongchainomega3 fattyacidsincludingeicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA)perdayisrecommended,through consumptionofoilyfishand/orsupplements.1 Higherdosesof24gdailyofEPA/DHAarerequiredfortreatmentof hypertriglyceridemia. Fiber Inobservationalstudies,increasedtotaldietaryfiberconsumptionhasbeenassociatedwithareducedriskofCHDand coronarydeath.11Solubleorviscousfiberfoundinoats,barley,flax,psyllium,beans,peas,andnutscanmodestlylower LDLClevels.Thisisaccomplishedbyincreasingshortchainfattyacidsynthesisandthusreducingendogenous cholesterolsynthesis,aswellasbyincreasingbileacidproduction.12Insolublefiberfoundinwholewheat,wholegrains, greenbeans,andleafyvegetables,canenhancesatietyandslowgastricemptying.Currently,>25g/dayoftotalfiberis recommendedforpossiblyimprovingCVDoutcomes,and1025g/dayofsolublefiberisrecommendedforlipidlowering therapy.TheAHArecommendationscallforatleasthalfofthegrainintaketocomefromwholegrains.1 PlantStanols/Sterols PlantsterolsarechemicallysimilartoanimalcholesterolandcanlowerLDLCbyupto15%,primarilybyreducing cholesterolabsorptionintheintestines,butalsothroughdownstreambiochemicaleffectsofreceptorbinding.The maximaleffectiveintakeisapproximately2g/day.1 Plantstanols/sterolsareavailableinanumberofdifferenttypesof foodproductswithvaryingcaloricandnutrientcontent.Whetherintakeofplantstanols/sterolsisassociatedwith decreasedriskremainstobedetermined.Forexample,araregeneticformofadiseaseinvolvingseverelyincreased plantsterollevels,sitosterolemia,resultsinprematureCHD. Alcohol Whilealcoholuseisnotencouraged,forthosecurrentlyconsumingalcohol,theAHArecommendsalimitedintakeof2 servings/dayinmenand1serving/dayinwomen.1 Oneservingequatestoonehalfounceofalcohol,whichisthecontent ofone12oz.bottleofbeer,a4oz.glassofwine,anda1.5ozshotof80proofspirits.Epidemiologicdatasuggestthat thisquantityofalcoholmaybeassociatedwithaloweredriskofCVD.However,itisnotknownwhetherinitiating consumptionofalcoholinthosewhohavepreviouslyabstainedwilllowerCVDevents.12

DietaryFactorsWithUnprovenEffects
AntioxidantSupplements ObservationalstudiessuggestthereisabenefitofahighintakeofantioxidantvitaminsforloweringCVDrisk.However, clinicaltrialsofantioxidantsupplementsincludingvitaminsCandEhavenotconfirmedthisbenefit,despitewitnessing significantlyhigherbloodlevelsinthoserandomizedtotakingthesesupplements.13Importantly,someantioxidantshave beenassociatedwithanincreasedriskoflungcancer(i.e.,betacarotene)aswellasheartfailureandtotalmortality(i.e., vitaminE).14Whiletheuseofantioxidantsupplementsisnotsupported,foodsourcescontainingantioxidantnutrients arerecommended.Theseincludefruits,vegetables,wholegrains,andvegetableoils.1 FolicAcidandOtherBvitamins HigherhomocysteinelevelshaveconsistentlybeenlinkedtomodestlyhigherratesofCVD.15Nevertheless,arecent metaanalysisofeightlarge,randomizedtrialsinvolving37,485individualsfoundnosignificanteffectoffolicacid supplementation(withorwithoutvitaminsB12andB6)onanyoftheCVDendpoints,eventhoughtherewasanaverage 25%reductioninhomocysteinelevelsinthesestudies.16Thus,theAHAdoesnotrecommendfolicacidandBvitamin supplementationforCVDriskreduction.1 SoyProtein EarlystudiessuggestedafavorableeffectofsoyproteinonimprovingLDLClevels.Thiswaspossiblybecausesoy proteinreplacedanimalproteinthatwasrichinsaturatedfat,orduetofavorableeffectsonLDLreceptors.However,the aggregateofevidence,includingnewerstudies,demonstratesthatevenlargeamountsofsoyproteinconsumptionhave minimaleffectsonLDLC(approximately3%reduction)ascomparedtomilkandotherproteins.Ithasnosignificant effectonHDLC,triglycerides,lipoprotein,orBP.17Similarly,soyisoflavoneshavenotbeenfoundtohaveanysignificant CVbenefitsinrandomizedstudies.Nevertheless,soyproteinmaybeagoodvegetablebasedproteinandanalternative toanimalanddairyproductswhichcontainhighersaturatedfat. Omega6PolyunsaturatedFattyAcidsRestriction Linoleicacidistheprimarydietaryformofomega6polyunsaturatedfattyacid(PUFA)(i.e.,vegetableoils).Itisconverted toarachidonicacid,whichisthesubstrateforahostofbothproandantiinflammatorymolecules.Decreasedintakeof linoleicacidhasbeenadvocatedbysometoreducearachidonicacidproductionandtherebyreducetheinflammatory stimulusforatherosclerosisandCHD. However,evidencefrombothrandomizedtrialsandobservationalstudiesconsistentlyshowsthatanintakeof510%of energyfromomega6PUFAresultsinadecreasedCHDriskcomparedwithlowerintake.Studiesalsoshowthata higherintakeissafeandpossiblymorebeneficial.18TheAHArecommendsatleast510%ofenergyintheformof dietaryomega6PUFAs.The20012002NationalHealthandNutritionExaminationSurveyfoundthattheaverageUS intakeoflinoleicacid,basedona2000kcal/daydiet,was6.7%ofenergy(14.8g/day).

Obesity (1of2)
Obesityistermedanepidemicduetoitsdramaticriseinprevalenceoverthepast4 decades,fromjust15%ofthepopulationtonowover30%ofthepopulation.19 CurrentclassificationschemesuseBMIcategoriesof18.5to<25kg/m2 asnormal weight,25to<30kg/m2 asoverweight,and30kg/m2 asobese,withfurther subcategoriesoftheobesegroup.TheseschemeshavebeendevelopedbytheNIH andsupportedbytheAHAandWorldHealthOrganization(WHO)(Table3).20 ThemostrecentestimatesfortheadultUSpopulationdemonstratethattheoverall prevalenceofobesityisnow33.9%,withahigherprevalenceamongwomenas comparedwithmen(35.5%vs.32.2%).Thehighestratesofobesityareamong AfricanAmericans(44%),followedbyHispanics(38%),andthenCaucasians (33%).21Importantly,overweightandobesityratestogethercompriseovertwothirds (68%)ofthepopulation. WhileBMIisthemostcommonlyusedanthropometricmeasurement,waist circumferencecanalsoidentifythoseatahigherriskofadversemetabolic consequencesofadiposity.Thisisduetoitsclosecorrelationwithtotalabdominal andvisceralfat.TheNHLBIdefineshigherriskwaistcircumferencevaluesasthose >102cm(40inches)formenand>88cm(35inches)forwomen.20 CardiovascularConsequencesofObesity SeveralCVriskfactorstrackwithobesityandcontributetotheincreasedriskofCVD eventsinobesepatients.Obeseindividualsareapproximatelythreetimesmore likelytohavehypertensionandtype2diabetesmellitusthannormalweight individuals,andtheyalsomoreoftenhavedyslipidemia,metabolicsyndrome,and obstructivesleepapnea.22,23Independentoftheseriskfactors,obesityconveysan increasedriskofallcausemortality,CVdeath,stroke,andCHD.24These associationsaremanifestevenwithobesitymeasuredinadolescence.25 However,inpatientswithknowncoronaryarterydiseaseormyocardialinfarction, overweightandobesitymaybeassociatedwithimprovedoutcomes,particularlyfor theoverweightgroup.Thisobservationistermedtheobesityparadox.26Additional physiologicchangesaccompanyingobesityincludeincreasedcirculatingblood volumeandcardiacoutput,highercardiacwallstress,andincreasedfilling pressures.Assuch,obeseindividualsaremorepronetoleftventricularhypertrophy, diastolicfillingabnormalities,atrialfibrillation,andcardiomyopathy.27 GuidelineRecommendations DietaryTherapy ThePracticalGuidedevelopedbytheNHLBIin2000remainsthemainstayfor weightlossrecommendations.2 Thisguiderecommendsweightlosstherapyforall individualswithaBMI>30kg/m2 .Weightlosstherapyisalsorecommendedfor thosewithaBMI2529.9kg/m2 ,oranincreasedwaistcircumferenceandtwoor moreriskfactors.Theinitialtargetgoalforweightlossis10%ofbodyweightover6 months,accomplishedbylosing12poundsperweek.Thisamountcanbe achievedbyreducingcalorieintakeby5001000kcal/day(i.e.,500kcal/dayx7days =3500kcal=1pound).Thisresultsinatargetcalorieintakeof10001200kcal/day formostwomen,and12001600kcal/dayformostmen.Aftertheinitialweightloss period,themaingoalisweightmaintenance,withpossibleadditionalweightloss afteraperiodofstability. BehavioralTherapy Inadditiontodietarytherapy,behaviortherapyandincreasedphysicalactivityarethe majorcomponentsofweightlosstherapy.Severalbehavioralstrategieshavebeen evaluated,andtheevidencesuggeststhatweightlosssuccessinvolves

Table3

incorporatingtwoormorestrategies.Thesestrategiesincludegoalsetting,self monitoring,feedbackandreinforcement,enhancingselfefficacy,problemsolving, modelingbehavior,andfrequentandprolongedcontact.28Oneparticularlyeffective behavioralstrategyismotivationalinterviewingwhichinvolveselicitingthemotivation tochange,ratherthanimposingit,upontheindividual.Thisisdonebyhavingthe counselorhelpdirecttheindividualtoresolvehisorherownambivalence. PhysicalActivity Currentrecommendationsspecifythatalladultsshouldengageinatleast30 minutesadayofmoderateintensityphysicalactivityatleast5daysaweek.This amountofphysicalactivitycanbothimproveCVhealthandcontributetowardsa negativecaloriebalanceforweightloss.29However,60minutesormoremaybe requireddailyforweightlossorweightmaintenance.29Thisvolumeofphysical activitymaybeaccumulatedinbriefincrementsthroughoutthedayratherthaninone setting. Severelyobeseindividualsorthosewholeadaverysedentarylifestylemayneedto startwithverylightorlightactivities,suchashouseholdchoresorslowwalking.It shouldbenoted,however,thatmoreweightlossoccursduetoreducingcaloric intakethanincreasedphysicalactivitythelattermaybemoreeffectiveinpreventing weightgain.2

ClassificationofOverweightandObesitybyBodyMassIndexWaistCircumferenceCategories Table3 Diseaseriskfortype2diabetes,hypertension,cardiovasculardisease. *Increasewaistcircumferenceis>102cm(40inches)inmenand>88cm(35inches)inwomen. **Increasedwaistcircumferencecanstratifyriskprimarilyamongthosewithbodymassindex(BMI)2534.9kg/m2,andcanalsobeamarkerfor increasedriskeveninpersonsofnormalweight. ReproducedwithmodificationfromNationalInstitutesofHealth.ClinicalGuidelinesontheIdentification,Evaluation,andTreatmentofOverweight andObesityinAdultsTheEvidenceReport.ObesRes19986(Suppl2):51S209S.

Obesity (2of2)
WeightLossDiets Althoughcaloricreductionisthemajordietarycontributortoweightloss,thereis muchinterestinwhetherdietsinvolvingspecificmacronutrientpatternswillresultin moreweightlossthanothers.Severalrecentstudieshavedirectlycompareddietsof varyingmacronutrientcomposition.TheAtoZStudy(AtoZ:AComparativeWeight LossStudy)comparedfourcommerciallyavailablediets:Atkins(verylow carbohydrate),Zone(lowcarbohydrate),LEARN(lowfat,highcarbohydrate),and Ornish(lowfat,veryhighcarbohydrate).Thesubjectswere311overweightand obesepostmenopausalwomen.ThestudyreportedthattheAtkinsdietledtothe mostweightlossat12months.30 TheDIRECT(DietaryInterventionRandomizedControlledTrial)studycompared threedietarypatterns,ratherthancommercialdiets.Thesewere:1)Mediterranean, restrictedcalorie2)lowfat,restrictedcalorieand3)lowcarbohydrate,nonrestricted calorie.Thesubjectswere322overweight/obeseindividuals.31After2years,the Mediterraneanandlowcarbohydrategroupslostsignificantlymoreweightthanthe lowfatdietgroup.ThegreatestincreasesinHDLandreductionsintriglycerides occurredinthelowcarbohydrategroup.However,thelowcarbohydrategroup actuallyhadlowercaloricintakethantheothers,andthelowfatgrouphadhigherfat intakethanadvised. Amorerecentrandomizedtrialevaluatedtheimpactoffourdietswithvarying amountsoffat,protein,andcarbohydratesin811overweight/obesemenand womenovera2yearperiod.Similarfoodswereusedinthedietstomaintainthe doubleblinddesign.32Theoverallweightlosswassimilarbetweenthedifferent dietsregardlessofnutrientcomposition.However,acrossthegroups,therewasa strongassociationbetweenadherencetogroupcounselingsessionsandweight loss.Itcanbeconcludedfromthistrialthatthemacronutrientcompositionofadiet probablyisnotascriticalascaloricrestrictionandadherencetoaweightloss program.CVriskfactorsimproveingeneralwithdiverseweightlossdiets,despite minordifferencesinriskfactorchangesrelatedtothespecificcompositionofthe diet. Currently,therearenolargerandomizedstudiesevaluatingtheeffectsofweight lossonclinicalCVDoutcomes.However,theLookAHEAD(ActionforHealthin Diabetes)trialof5,100individualswithdiabetesandaBMI>25kg/m2 (meanBMI ~36kg/m2 )hasprovidedsomevaluableinsightintothepotentialimprovementsin CVDriskfactorswithintensivelifestyleinterventions.33Ascomparedwithusual care,theintensiveinterventionresultedinamean8.6%weightlossat1year,which wasaccompaniedbysignificantlygreaterimprovementsinglycatedhemoglobin( 0.50%),systolicBP(4.0mmHg),HDLC(+2.0mg/dl)andtriglycerides(15.7 mg/dl).Thus,amodestamountofweightlosswithdietandlifestyleinterventions canbeassociatedwithmeaningfulbeneficialchangesinmultiplemetabolic parameters. PharmacologicTherapy PharmacotherapycanbeconsideredforthosewithaBMI30kg/m2 .Itcanalsobe consideredforthosewithaBMIof27kg/m2 andaweightrelatedcomorbidity,who donothavesufficientweightlossafter6monthsoflifestylechanges(Table4).2 Currently,onlyonemedication,orlistat,isapprovedbytheUSFoodandDrug Administration(FDA)forlongtermtreatmentofobesity.34Theotheragentpreviously approved,sibutramine,wasrecentlywithdrawnfromthemarketbytheFDAdueto evidenceofincreasedCVriskinpatientswithestablishedCVD.Orlistatanditsless potentoverthecounterform,Alli,workbyinhibitinggastricandpancreaticlipase, thusreducingdietaryfatabsorptionbyapproximately30%.Thistherapyresultsina modest~3%weightloss.Comparedwithaplacebo,orlistathasbeenshownto slightlyimproveLDLClevels,BP,andfastingglucose.However,thecommon gastrointestinalsideeffectsfromfatmalabsorptionlimititslongtermtolerability.
Table4

Figure1

SeveralsympathomimeticagentsareFDAapprovedonlyforshorttermtreatmentof obesity(i.e.,12weeks).Phentermineanddiethylpropionarethemostcommonly prescribedoftheseagents.34Theseamphetaminederivativeshelpsuppressthe appetitebyenhancingthereleaseofdopamineandnorepinephrine.Theyare contraindicatedinindividualswithCVDandmoderatetoseverehypertension, hyperthyroidism,andglaucoma.Recently,threedifferentagentsindevelopmentfor potentialweightlossindicationsfailedtogainFDAapproval,duetosideeffectsor lackoflongtermsafetydata. BariatricSurgery Currently,theNIHsupportsbariatricsurgeryasanoptionforpatientswithaBMI>40 kg/m2 .ItisalsoanoptionforpatientswithaBMI>35kg/m2 whohaveserious comorbidconditionsincludinghypertension,diabetes,sleepapnea,andcoronary arterydisease.20Itismostappropriateinthosewhohavefailedattemptsatlifestyle andmedicaltherapy,andwhoareatacceptableoperativerisk. Theoperationsincludeeitherrestrictiveproceduresthatreducethegastricsizeand delaygastricemptying,ormalabsorptiveproceduresthatbypassportionsofthe smallintestine.Thethreemostcommonproceduresincludethelaproscopic adjustablegastricbanding,verticalsleevegastrectomy,whicharebothrestrictive procedures,andRouxenYgastricbypass,whichisacombinedrestrictiveand malabsorptiveprocedure(Figure1).35Ingeneral,allthreeproceduresare reasonablysafe,withamajorcomplicationrateofapproximately4%.Thereisa slightlyhigherriskofmortalitywiththegastricbypassandverticalsleeve gastrectomy(0.5%),ascomparedwiththeadjustablebandprocedure(0.1%).35 However,weightlossisusuallyslowerandofalesseramountwiththeadjustable bandprocedure. Inadditiontomeaningfulweightloss,bariatricsurgeryleadstonotable improvementsinBP,lipids,andespeciallydiabetes.Forexample,several observationalstudieshavedemonstratedathreetofourfoldgreaterresolutionof clinicaldiabetesinthoseundergoingbariatricsurgeryascomparedwithusualcare, withapproximately75%showingremissionintheearlyperiod.36Triglyceridesare alsosignificantlyreducedandHDLCismodestlyincreased,butthereislittle changeinLDLClevelswiththeseprocedures. Afewrecentlarge,observationalstudieshaveconfirmedandextendedthefindings ofpriorsmallerstudies,whichshowedthatbariatricsurgerymayconferasurvival benefit.TheSOS(SwedishObeseSubjects)studywasaprospective,matched, observationalstudyof4,047subjects.Thestudydemonstrateda27%relativerisk reductionindeathinthebariatricsurgerygroupafterameanof10.9years,witha numericalreductioninCVdeaths.37Duetothesalutaryeffectsonweight,risk factors,andpossiblymortality,thereisinterestinextendingthescopeofbariatric surgerytoincludetheBMIcategoryof3034.9kg/m2 .However,currentdataare insufficienttofirmlysupportthispractice.

RecommendationsforTreatmentStrategiesbyBodyMassIndexCategory Table4 ReproducedwithpermissionfromNationalInstitutesofHealthNationalHeart,Lung,andBloodInstituteandNorthAmericanAssociationforthe StudyofObesity.2000.ThePracticalGuide:Identification,Evaluation,andTreatmentofOverweightandObesityinAdults.Availableat: http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf.Accessed11/07/2011.

CommonTypesofBariatricSurgeryProcedures Figure1 ReproducedwithpermissionfromDeMariaEJ.Bariatricsurgeryformorbidobesity.NEnglJMed2007356:217683.

KeyPoints
TheAHADietandLifestyleRecommendationsemphasizeanoverallhealthyeatingpattern,ratherthanfocusing onaspecificnutrientorfood. Specificdietaryrecommendationsconsistofabalanceddietwithlimitationsofsaturatedfatintaketo<7%ofdaily calories,transfatto<1%ofdailycalories,andcholesterolto<300mg/day.Recommendationsalsoinclude increasedconsumptionofoilyfish,vegetables,fruits,andwholegrain,andlimitationofsaltandalcohol. Alladultsshouldconsume2servingsofoilyfishperweekthatarerichinlongchainomega3fattyacids(EPA andDHA).OnegramperdayofEPAandDHAisrecommendedinthosewithestablishedCHD. Antioxidantvitaminsupplements(i.e.,vitaminsCandE)andfolicacidsupplementationhavenotbeenshownto reduceCVeventsandarenotrecommendedforCVriskreduction. ObesityisdefinedasaBMI>30kg/m2 ,whileoverweightisdefinedas2529.9kg/m2 ,andnormalweightis definedas18.524.9kg/m2 . Anincreasedwaistcircumferenceof>40inchesformenand>35inchesforwomenisassociatedwithahigher riskofadversemetabolicconsequencesofadiposity,eveninthosewhoarenotobese. AccordingtotheNHLBIPracticalGuide,aninitialapproachtoweightlossshouldincludeagoalof12lbsper weekbyreducingcaloricintakeby5001000kcal/day,withaninitialweightlossgoalof10%ofbodyweightin6 months. Caloricrestrictionandadherencetoaweightlossprogramaremoreimportantthanthespecificmacronutrient compositionofaweightlossdiet. Inadditiontodietarytherapy,behavioraltherapyandincreasedphysicalactivityarethemajorcomponentsof weightlosstherapy. PharmacologictherapymaybeappropriateforthosewithaBMI>27kg/m2withcomorbidity,orforthosewitha BMI>30kg/m2 .OrlistatiscurrentlytheonlyFDAapprovedagentforlongtermweightloss. BariatricsurgeryisconsideredanappropriateoptionforpatientswithaBMI>40kg/m2 orthosewithaBMI>35 kg/m2withseriouscomorbidconditionsincludinghypertension,diabetes,sleepapnea,andcoronaryartery disease. Bariatricsurgerycanleadtosignificantimprovementsinbodyweight,lipids,andparticularlyindiabetes,with possibleimprovementsinmortality.

References
1. LichtensteinAH,AppelLJ,BrandsM,etal.Dietandlifestylerecommendationsrevision2006:ascientific statementfromtheAmericanHeartAssociationNutritionCommittee.Circulation2006114:8296. 2. NationalInstitutesofHealthNationalHeart,Lung,andBloodInstituteandNorthAmericanAssociationforthe StudyofObesity.2000.ThePracticalGuide:Identification,Evaluation,andTreatmentofOverweightandObesityin Adults.Availableat:http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf.Accessed11/07/2011. 3. KnowlerWC,BarrettConnorE,FowlerSE,etal.Reductionintheincidenceoftype2diabeteswithlifestyle interventionormetformin.NEnglJMed2002346:393403. 4. HowardBV,VanHornL,HsiaJ,etal.Lowfatdietarypatternandriskofcardiovasculardisease:theWomen's HealthInitiativeRandomizedControlledDietaryModificationTrial.JAMA2006295:65566. 5. deLorgerilM,RenaudS,MamelleN,etal.Mediterraneanalphalinolenicacidrichdietinsecondarypreventionof coronaryheartdisease.Lancet1994343:14549. 6. EstruchR,MartnezGonzlezMA,CorellaD,etal.EffectsofaMediterraneanstyledietoncardiovascularrisk factors:arandomizedtrial.AnnInternMed2006145:111. 7. SalasSalvadJ,BullM,BabioN,etal.Reductionintheincidenceoftype2diabeteswiththeMediterraneandiet: resultsofthePREDIMEDReusnutritioninterventionrandomizedtrial.DiabetesCare201134:149. 8. AppelLJ,MooreTJ,ObarzanekE,etal.Aclinicaltrialoftheeffectsofdietarypatternsonbloodpressure.DASH CollaborativeResearchGroup.NEnglJMed1997336:111724. 9. SacksFM,SvetkeyLP,VollmerWM,etal.EffectsonbloodpressureofreduceddietarysodiumandtheDietary ApproachestoStopHypertension(DASH)diet.DASHSodiumCollaborativeResearchGroup.NEnglJMed 2001344:310. 10. U.S.DepartmentofAgricultureandU.S.DepartmentofHealthandHumanServices.DietaryGuidelinesfor Americans,2010.7thEdition,Washington,DC:U.S.GovernmentPrintingOffice,December2010. 11. PereiraMA,O'ReillyE,AugustssonK,etal.Dietaryfiberandriskofcoronaryheartdisease:apooledanalysisof cohortstudies.ArchInternMed2004164:3706. 12. VanHornL,McCoinM,KrisEthertonPM,etal.Theevidencefordietarypreventionandtreatmentofcardiovascular disease.JAmDietAssoc2008108:287331. 13. HeartProtectionStudyCollaborativeGroup.MRC/BHFHeartProtectionStudyofantioxidantvitamin supplementationin20,536highriskindividuals:arandomisedplacebocontrolledtrial.Lancet2002360:2333. 14. MillerERIII,PastorBarriusoR,DalalD,RiemersmaRA,AppelLJ,GuallarE.Metaanalysis:highdosagevitamin Esupplementationmayincreaseallcausemortality.AnnInternMed2005142:3746. 15. HomocysteineStudiesCollaboration.Homocysteineandriskofischemicheartdiseaseandstroke:ameta analysis.JAMA2002288:201522. 16. ClarkeR,HalseyJ,LewingtonS,etal.EffectsofloweringhomocysteinelevelswithBvitaminsoncardiovascular disease,cancer,andcausespecificmortality:Metaanalysisof8randomizedtrialsinvolving37485individuals. ArchInternMed2010170:162231. 17. SacksFM,LichtensteinA,VanHornL,HarrisW,KrisEthertonP,WinstonM.Soyprotein,isoflavones,and cardiovascularhealth:asummaryofastatementforprofessionalsfromtheamericanheartassociationnutrition committee.ArteriosclerThrombVascBiol200626:168992. 18. HarrisWS,MozaffarianD,RimmE,etal.Omega6fattyacidsandriskforcardiovasculardisease:ascience advisoryfromtheAmericanHeartAssociationNutritionSubcommitteeoftheCouncilonNutrition,PhysicalActivity, andMetabolismCouncilonCardiovascularNursingandCouncilonEpidemiologyandPrevention.Circulation 2009119:9027. 19. KumanyikaSK,ObarzanekE,StettlerN,etal.Populationbasedpreventionofobesity:theneedforcomprehensive promotionofhealthfuleating,physicalactivity,andenergybalance:ascientificstatementfromAmericanHeart AssociationCouncilonEpidemiologyandPrevention,InterdisciplinaryCommitteeforPrevention(formerlythe expertpanelonpopulationandpreventionscience).Circulation2008118:42864. 20. NationalInstitutesofHealth.ClinicalGuidelinesontheIdentification,Evaluation,andTreatmentofOverweightand ObesityinAdultsTheEvidenceReport.ObesRes19986(Suppl2):51S209S. 21. FlegalKM,CarrollMD,OgdenCL,CurtinLR.PrevalenceandtrendsinobesityamongUSadults,19992008. JAMA2010303:23541. 22. BrownCD,HigginsM,DonatoKA,etal.Bodymassindexandtheprevalenceofhypertensionanddyslipidemia. ObesRes20008:60519. 23. MokdadAH,FordES,BowmanBA,etal.Prevalenceofobesity,diabetes,andobesityrelatedhealthriskfactors, 2001.JAMA2003289:769. 24. KurthT,GazianoJM,BergerK,etal.Bodymassindexandtheriskofstrokeinmen.ArchInternMed 2002162:255762. 25. TiroshA,ShaiI,AfekA,etal.AdolescentBMItrajectoryandriskofdiabetesversuscoronarydisease.NEnglJMed 2011364:131525. 26. RomeroCorralA,MontoriVM,SomersVK,etal.Associationofbodyweightwithtotalmortalityandwith cardiovasculareventsincoronaryarterydisease:asystematicreviewofcohortstudies.Lancet2006368:66678. 27. PoirierP,GilesTD,BrayGA,etal.Obesityandcardiovasculardisease:pathophysiology,evaluation,andeffectof

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weightloss:anupdateofthe1997AmericanHeartAssociationScientificStatementonObesityandHeart DiseasefromtheObesityCommitteeoftheCouncilonNutrition,PhysicalActivity,andMetabolism.Circulation 2006113:898918. ArtinianNT,FletcherGF,MozaffarianD,etal.Interventionstopromotephysicalactivityanddietarylifestylechanges forcardiovascularriskfactorreductioninadults:ascientificstatementfromtheAmericanHeartAssociation. Circulation2010122:40641. HaskellWL,LeeIM,PateRR,etal.Physicalactivityandpublichealth:updatedrecommendationforadultsfrom theAmericanCollegeofSportsMedicineandtheAmericanHeartAssociation.Circulation2007116:108193. GardnerCD,KiazandA,AlhassanS,etal.ComparisonoftheAtkins,Zone,Ornish,andLEARNdietsforchangein weightandrelatedriskfactorsamongoverweightpremenopausalwomen:theATOZWeightLossStudy:a randomizedtrial.JAMA2007297:96977. ShaiI,SchwarzfuchsD,HenkinY,etal.Weightlosswithalowcarbohydrate,Mediterranean,orlowfatdiet.NEngl JMed2008359:22941. SacksFM,BrayGA,CareyVJ,etal.Comparisonofweightlossdietswithdifferentcompositionsoffat,protein,and carbohydrates.NEnglJMed2009360:85973. LookAHEADResearchGroup,PiSunyerX,BlackburnG,etal.Reductioninweightandcardiovasculardisease riskfactorsinindividualswithtype2diabetes:oneyearresultsofthelookAHEADtrial.DiabetesCare 200730:137483. PowellTM,KheraA.Therapeuticapproachestoobesity.CurrTreatOptionsCardiovascMed201012:38195. PoirierP,CornierMA,MazzoneT,etal.Bariatricsurgeryandcardiovascularriskfactors:ascientificstatementfrom theAmericanHeartAssociation.Circulation2011123:16831701. BuchwaldH,EstokR,FahrbachK,etal.Weightandtype2diabetesafterbariatricsurgery:systematicreviewand metaanalysis.AmJMed2009122:248256. SjstrmL,NarbroK,SjstrmCD,etal.EffectsofbariatricsurgeryonmortalityinSwedishobesesubjects.N EnglJMed2007357:74152.

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4.4:SmokingCessation
Author(s): DonnaM.Polk,MD,MPH,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Discussthecontributionoftobaccoabuseasamodifiablecardiovascularriskfactorinthedevelopmentof atherosclerosisandcardiovascularevents. 2. Explainhowtoimproveabstinenceratesthroughsystematicidentificationofsmokersandthroughprovidingtoolstohelp smokersquit. 3. Identifythepharmacologicagentsusedtohelpimproveabstinencerates.

Introduction
Tobaccouseisassociatedwithsignificantmorbidityandmortality,andintheUnitedStates,over435,000deathsare attributedtoitsuseannually.1 AlthoughthenumberofsmokersintheUnitedStateshasdeclinedoverthelastdecade, nearly19.3%ofalladultsovertheageof18arecurrentcigarettesmokers,withsignificantregional,age,gender,and ethnicdifferences.2 Morementhanwomenarecurrentsmokers(21.5%vs.17.3%).2 Amongvariousethnicgroups,AmericanIndianorAlaskanNativeadults(31.4%)havethehighestratesofsmoking, whereasAsian(9.2%)andHispanicadults(12.5%)aretheleastlikelytosmokecigarettes.2 Adultsages65yearsare theleastlikelytobecurrentsmokers(9.5%).Withmorethan70%ofcurrentsmokershavingexpressedadesiretoquit, thesystematicidentification,assistancewithcessation,andfollowupofsmokersallowstheclinicianatremendous opportunitytogreatlyimpactthehealthofsmokers.

SmokingandCardiovascularRisk
Cigarettesmokingisamajormodifiableriskfactorinthedevelopmentofatherosclerosis,myocardialinfarction(MI),and mortalityafterrevascularization.35SmokingcessationimprovesoutcomesinpatientspostMIandpostrevascularization. IntheOASIS(OrganizationtoAssessStrategiesinAcuteIschemicSyndromes)trial,whichincluded>18,000patients withacutecoronarysyndrome,quittingsmokingwasassociatedwithanoddsratio(OR)of0.57(95%confidenceinterval [CI],0.360.89)forMIascomparedwithcontinuedsmoking.6 InpatientswithleftventriculardysfunctionafterMI,patients whostoppedsmokinghada40%lowerhazardofallcausemortalityanda30%lowerhazardofdeathorrecurrentMIor deathorheartfailurehospitalizationat42monthfollowupintheSAVE(SurvivalandVentricularEnlargement)trial.7 Inalongtermfollowupof1,521patientsafterMI,therewasahazardratio(HR)of0.63(95%CI,0.480.82)forpatients whoquitaftertheMI,andareductioninmortalityforthosewhoreducedtheamounttheysmoked:an18%declinein mortalityforeveryreductionoffivecigarettes.8 Inpatientswhohavebeenrevascularized,thereisahighertotalmortality rate(allcausemortalityrelativerisk[RR],1.6895%CI,1.332.13andcardiacdeathrisk,RR,1.7595%CI,1.302.37), aswellashigherratesofrepeatrevascularization(RR,1.4195%CI,1.021.94),asseenina20yearfollowupstudy aftercoronaryarterybypassgrafting.9 Overtime,quittingsmokingafterMIreducestheriskofrecurrenteventstothatofanonsmokerwithin3years.10Ina systemicreviewbyCritchleyandcolleagues,thereductionofallcausemortalityfromsmokingcessationholdstrue regardlessofage,gender,typeofcardiacevent,andcountrystudied.11

Pathophysiology
Thereareseveralmechanisticpathwayswherebycigarettesmoking,eitheractiveor passiveexposure,leadstothedevelopmentofatherosclerosisandcardiovascular disease(CVD).Theseincludevasomotorandendothelialdysfunction,inflammatory responses,adverseeffectonlipids,plateletdysfunction,andchangesin coagulation(Figure1).3,1220 Endothelialdysfunctionisaprecursortoatherosclerosisandexposuretotobacco impairsnitricoxideavailabilityandendothelialfunction.3,12,13Thisdysfunctionis associatedwithacute,chronic,andpassiveexposuretotobaccosmoke.12,13 Smokingcessationleadstoimprovedendothelialfunction,aswellasreduced arterialstiffness.14,15Acuteexposuretocigarettesmokingcancauseacute vasospasmandincreasedtotalcoronaryvascularresistance,andthus,increase themyocardialoxygendemandinsmokers.16 Inflammationalsoplaysaroleintheactivationofleukocytesandthedevelopmentof atherosclerosis.3 Circulatingleukocytesandmultipleinflammatorymarkers includingCreactiveprotein(CRP),interleukin6,andtumornecrosisfactorare elevatedinsmokers.3,17Exposuretotobaccosmokealsoincreasesthelevelsof vascularcelladhesionmolecule(VCAM)1,intercellularadhesionmolecule(ICAM) 1,andEselectin,thusincreasingthecelltocellinteraction,recruitmentof leukocytes,andthedevelopmentofatherosclerosis.3 Thefibinolytic/thrombogenicbalanceisalsoimpairedinsmokers.3 Platelets becomeactivated,fibrinogenlevelsareincreased,endothelialcellsproduceless tissueplasminogenactivatorandplasminogenactivatorinhibitor1,andthereis reducedthrombolyticcapacityduringacutecoronaryeventsinsmokers.3,18,19 Cigarettesmokingisassociatedwithalessfavorablelipidprofile,withsmokers havinghighertotalcholesterol,triglycerides,lowdensitylipoproteincholesterol (LDLC)levels,andlowerhighdensitylipoproteincholesterol(HDLC)levels.3,20 ThereareincreasedlevelsofoxidizedLDLCparticlesandantibodiesagainst oxidizedLDLCinsmokers.3,21SmokingcessationimproveslevelsofHDLC,but nottheLDLCnumberorparticlesize.20

Figure1

PotentialPathwaysandMechanismsforCigaretteSmokingMediatedCardiovascularDysfunction Figure1 METC=mitochondialelectrontransportchainNADPH=nicotinamideadenosinedinucleotidephosphateNO=nitricoxideNOS=nitricoxide synthaseONOO=peroxinitrate. ReproducedwithpermissionfromAmbroseJA,BaruaRS.Thepathophysiologyofcigarettesmokingandcardiovasculardisease:Anupdate.J AmCollCardiol200443:17317.

SmokingCessation
Ofthemorethan43millionsmokersintheUnitedStates,nearly70%wanttoquit smoking.2,22Unaided,theirsuccessrateisonly47%.22Smokerswithrecent diagnosesofstroke,cancer,lungdisease,heartdisease,ordiabetesmellituswere 3.2timesmorelikelytoquitsmokingandthosewithmultiplediagnoseswere6.1 timesmorelikelytoquit.23Assistancewithcessationintheformofquitlines,group andindividualcounseling,nicotine,andprescriptionagentscansignificantly increasequitrates.Eachinteractionasmokerhaswiththehealthcareprovideris anopportunitytopromotesmokingcessation.Aphysician'sadvicetoquitsmoking increasescessationratesby30%.22 Tobaccouseisachronichealthissue,andsmokersoftenmakemultipleattempts atquitting,soitisimportantforeachinteractionwiththehealthcaresystemto identifysmokersandtheirreadinesstoquit.Asystematicapproachtoallsmokers canimprovecessationrates.The"5A's"(ask,advise,assess,assist,andarrange followup)isaneffectivemodelforthispurpose(Table1).24 Patientsshouldbeaskedateveryencounterabouttobaccouse.Theidentificationof smokersisthefirststepinsmokingcessation.Often,systemicremindersare requiredtohelpidentifysmokersforthebusyhealthcareprovider.Oneexampleis toincludesmokingstatusinthevitalsignssothatsmokingstatusisreadily identifiable(Table2).24Documentationofsmokersthroughelectronichealthrecord reminderssignificantlyincreasedtheidentificationofsmokers(17%vs.11%p25 Thenextstepistoadviseeverysmokertoquit,withpersonalizedinformation regardingthehealthbenefitsofcessation. Thenextcriticalstepinsuccessfulsmokingcessationistoassessthesmoker's readinesstoquit.TheProchaskastagesofchangemodelforbehaviorchangeisa usefultoolinassessingasmoker'sabilitytoquit.26Individualsaredescribedas beingatapointinthestagesofchangemodelfromprecontemplation, contemplation,preparation,action,tomaintenance.Itisimportanttoidentifywhere theyaretohelpthemadvancetosuccessfulcessation. Intheprecontemplationstage,individualsdonotintendtomakeachangeinthe next6months.Contemplationisthenextstage,whereasmokerisseriously thinkingaboutchanginginthenext6months.Thoseinpreparationintendtochange inthenextmonth.Oftentheseindividualshavetriedtoquitwithinthelastyearand aretakingstepstowardaction,suchascuttingdownontobaccouse.Thosethat havequitsmokingwithinthelast6monthsareintheactionstageandareat greatestriskforrelapse.Maintenanceisthecontinuationofahealthierlifestyle. Identificationofthestageasmokerisinwillhelpfocustheprovider'sintervention, suchaseducationofaprecontemplatororprovidingcounselingand/or pharmaceutictherapiestoapersoninthepreparationstage.Itisimportantto continuallyassessthereadinessofthepatientstomakelifestylechangesandto assistthemastheymovealongthespectrumofthestagesofchangemodel.For thosesmokerswhoarenotreadytoquit,cliniciansshouldassessbarriersto changeaswellasprovideinformationabouttherelevance,risks,andrewardsthat resultfromsmokingcessation(Table3).24 Thenextstepinthe"5A's"modelistoassistthepatientinquittingthrough resources,counseling,andmedication.Settingaquitdateinthenearfuturecan helpfocustheactionstrategy.Preparations,suchasmakingthehomesmokefree, canhelpwithasmoker'ssuccessfulquitattempt.Clinicianscanhelpsmokers utilizethetimepriortothequitdatetoidentifytriggersandchallengesandtodevelop copingstrategiesforthem.Ifpharmacologictherapyispartofthequitplan,itshould bestartedduringthisphase. Arrangingfollowupforsmokerswhoarequittingiscriticalinhelpingthemremain abstinent.Mostrelapsesoccurwithinthefirst3months.Earlycontactwithinthefirst week,eitherbyphoneorinperson,shouldbearrangedwithasecondfollowupin thefirstmonthtomaximizesuccessrates.22
Table3

Table1

Table2

The5AsModelforTreatingTobaccoUseandDependence Table1 ReproducedwithpermissionfromFioreMC,JanCR,BakerTB,etal.Treatingtobaccouseanddependence:2008update.Quickreference guideforclinicians.Rockville,MD:U.S.DepartmentofHealthandHumanServices,PublicHealthService2009.

IdentificationofTobaccoUsers Table2 aRepeatedassessmentisnotnecessaryinthecaseoftheadultwhohasneverusedtobaccoorhasnotusedtobaccoformanyyearsandfor whomthisinformationisclearlydocumentedinthemedicalrecord.


bAlternativestoexpandingthevitalsignsincludeusingtobaccousestatusstickersonallpatientchartsorindicatingtobaccousestatusvia

electronicmedicalrecordsorcomputerizedremindersystems. ReproducedwithpermissionfromFioreMC,JanCR,BakerTB,etal.Treatingtobaccouseanddependence:2008update.Quickreference guideforclinicians.Rockville,MD:U.S.DepartmentofHealthandHumanServices,PublicHealthService2009.

EnhancingMotivationtoQuitTobaccoThe5Rs Table3 ReproducedwithpermissionfromFioreMC,JanCR,BakerTB,etal.Treatingtobaccouseanddependence:2008update.Quickreference guideforclinicians.Rockville,MD:U.S.DepartmentofHealthandHumanServices,PublicHealthService2009.

SmokingCessationSupport
Physicaldependenceaswellaspsychosocialfactorscontributestotheaddictivenatureoftobacco,andthecombination ofpharmacotherapyandcounselingcanbeeffectiveforsmokingcessation.Counselingalonecanimprovequitrates andcanbeaslittleasabriefcounselingsessionbyaphysicianduringanofficevisit.27Cessationratescanbe increasedby30%with3minutesorlessofcounseling.22Effectivecounselingcanbeperformedbytrainedcounselors individuallyoringroups,facetoface,byphone,phoneandInternet,orviamobiletextmessaging.22,2830 Inametaanalysisof16,050smokersand13,499controls,therewasasignificanteffectofwebbasedandcomputer basedinterventionsonincreasingcessationrates(RR,1.4495%CI,1.271.64)withlongterm(12month)cessation ratesof9.9%(95%CI,8.910.9)versus5.7%(95%CI,5.16.3).30 Althoughsomestudiesshowhigherabstinencerateswithmorecomprehensiveinterventions,notallcounselingstudies haveshownincreasedlongtermquitrates.31In16randomizedcontrolledtrialsreviewed,therewasheterogeneity betweentrials,butoverall6to12monthabstinencerateswereimprovedwithbehavioraltherapiesandselfhelp materials(OR,1.4495%CI,0.992.11).32Theadditionofpharmacologictreatmentincreaseslongtermabstinence ratesinsmokers.22,31

Pharmacotherapy
NicotineReplacement TheFoodandDrugAdministration(FDA)hasapprovedfivedifferenttypesofnicotine replacementtherapy(NRT):transdermalpatch,gum,lozenge,nasalspray,and inhaler.Thesehavebeenthemainstayofsmokingcessationaidsbecausetheyare readilyavailableoverthecounter.Theuseofthesetherapiescandoublelongterm abstinenceratesand,aswithallpharmacotherapiesusedtoassistsmoking cessation,successisenhancedwiththeadditionofcounseling.22,33 Cigarettesdeliveraspikeofnicotinetothesmokerandthusreinforcetheaddictive natureofnicotine(Figure2).Nicotinereplacementsdelivernicotineinlowerlevels andinamoretimereleasedfashion.Nicotinepatchescomeinseveraldosesand aneffectivestartingdosecanbeestimatedbythenumberofcigarettesusedper day.Themostcommonsideeffectsarelocalskinreactions,insomnia,andvivid dreams.Patchesshouldbeplacedontheskineachmorningandcanberemoved atbedtimeforindividualswhoexperiencesideeffects.Durationoftreatmentis8 weeks. Nicotinegumcanbeusedaloneorinconjunctionwithanicotinepatch.Thereare twodosesavailable:a2mgdoseappropriateforthosewhosmoke<25cigarettesa day,anda4mgdoseforthosewhosmoke>25cigarettesperday.22Smokershave bettersuccessiftheyusetheguminascheduledmanner(atleast1pieceevery12 hours).34Itisimportanttoinstructpatientsintheproperuseofthenicotinegumin ordertopreventthemostcommonsideeffects,suchasmouthsoreness,jawache, dyspepsia,andhiccups.Thegumshouldbechewedslowlyuntilapepperytasteis sensed,andthenparkedbetweenthecheekandthegumforafewminutes,then chewedagainovera30minuteperiod.22Durationoftreatmentis812weeks. Nicotinelozengescanbeusedwithorwithoutconcurrenttransdermalnicotine.Itis availablein2or4mgdosesandshouldbedissolvedinthemouth.Recommended doseisninelozengesaday,withamaximumof20perdayandtaperedovertime. Mostcommonsideeffectsaredyspepsia,hiccups,nausea,headache,andcough. Recommendeddurationoftreatmentisupto12weeks. Thenicotinenasalsprayhasaninitialspikeofnicotinethatislowerthanthat deliveredbyacigarettebutfasterthananyofthenicotinedeliverysystems(Figure2). Becauseofrapiddeliveryofnicotine,ithasthehighestdependencypotential.22Itis availablebyprescriptiononly.Thedoseis1mg(0.5mgpernostril),with12doses perhour.Maximumtreatmentiseightdosesperday.Mostcommonsideeffectsare nasalcongestion,nasalirritation,andchangesintasteandsmell,allofwhich usuallyimproveafterthefirstweekoftreatment.Durationoftreatmentisupto6 months. Nicotineinhalerisavailablebyprescriptiononly,andvaporizednicotineisdelivered tothebuccalmucosawitheachpuff.Ittakesapproximately80puffsover20minutes todeliver24mgofnicotine,andtherecommendeddailydoseis616cartridgesper day.Themostcommonsideeffectsarelocalirritationandcough.Recommended durationofuseisupto6months. NRTisnotassociatedwithincreasedCVriskinpatientswithandwithoutcoronary arterydisease.22,35,36TheNRTpackageinsertsdo,however,cautiontheuseof theseproductsinindividualswithin2weeksafterMI,inunstableangina,orin patientswithseriousarrhythmias.22 NonNicotineTherapy SustainedReleaseBupropion Bupropionisamonocyclicantidepressantthatinhibitsthereuptakeofdopamine andnorepinephrine,andisFDAapprovedforsmokingcessation.Initialtherapy shouldbestartedat150mg/dfor3days,andthenincreasedto150mgtwicedaily. Bupropiontherapyshouldbegin1weekpriortothequitdate,butcanbeusedwithin
Figure2

thefirst2weeksafteranMI.22Itiscontraindicatedinindividualswithahistoryof seizuresoreatingdisorders.Mostcommonsideeffectsareinsomnia,drymouth, andoccasionalhypertension.Durationoftreatmentis712weeks,butcanbeused inlowerdosesforupto6months. Varenicline Vareniclineisan42nicotinicacetylcholinereceptorpartialagonistthatisFDA approvedforuseinsmokingcessation.37Initialtherapy,started1weekbeforethe quitdate,is0.5mgoncedailyfor3days,then0.5mgtwicedailyfor4days,andthen 1mgtwicedaily.Patientswithkidneydiseaseorwhoareondialysisshouldreceive lowerdoses.22 AnadditionalwarninghasbeenaddedbytheFDAtoalerthealthcareprovidersto changesinmood,behavior,orsuicidalideation.Sideeffectsincludenausea, troublesleeping,andvividdreams.Vareniclinehasrecentlybeenstudiedinpatients withCVDanddidnotincreaseCVeventsormortality.38Durationoftherapyis3 months,butthismaybeextendedto6months. Clonidine ClonidineisasecondlineagentforthetreatmentoftobaccoabuseandisnotFDA approvedforthisuse.Itcanbegivenorally(0.150.75mg/d)ortransdermally(0.1 0.2mg/d)startingupto3daysbeforethequitdate.22Itshouldnotbestopped abruptlyinordertoavoidreboundhypertension.Sideeffectsincludedrymouth, drowsiness,dizziness,andconstipation.22 Nortriptyline Nortriptylineisatricyclicantidepressantthatcanbeusedasasecondlineagentfor smokingcessation,butisnotFDAapprovedforthisuse.Theusualdoseis75150 mg/d.Mostcommonsideeffectsaredrymouth,sedation,anddizziness.Becauseof theriskofcardiacarrhythmias,itshouldbeusedwithcautionwithpatientswith CVD.Usualdurationoftherapyis12weeks,butthiscanbeextendedto6months.

PlasmaNicotineLevels Figure2 Plasmanicotinelevelsafterasmokerhassmokedacigarette,receivednicotinenasalspray,begunchewingnicotinegum,orappliedanicotine patch.Theamountofnicotineineachproductisgiveninparentheses.Thepatternproducedbytheuseofthenicotineinhaler(notshown)is similartothatfornicotinegum. ReproducedwithpermissionfromRigottiNA.Treatmentoftobaccouseanddependence.NEnglJMed2002346:50612.

AbstinenceRates
NRTnearlydoublestheabstinencerateoverplacebobothasamonotherapyandin combinationwithprescriptiontherapies,asseeninametaanalysisbyFioreand colleagues(Table4).22Thehighestquitratesat6monthswereinsmokerswho usedlongtermnicotinepatches(>14weeks)withadlibnicotinegumorspray(OR, 3.695%CI,2.55.2).22Theaverage6monthabstinencerateinthesethreestudies was36.5%(95%CI,28.645.3).Theuseofvareniclineasamonotherapyproduced quitratesof33.2%(95%CI,28.937.8),withanORof3.1(95%CI,2.53.8).22 Thelowestquitrateswereseeninthe15studiesthatutilizednicotinegumwithan ORof1.5(95%CI,1.21.7).Inarecentstudycomparingtheeffectivenessoffive smokingcessationpharmacotherapies,patchpluslozengeresultedin6month carbondioxideconfirmedabstinenceof40.1%ascomparedwith33.2%for bupropionpluslozenge,34.4%forpatch,33.5%forlozenge,31.8%forbupropion, and22.2%forplacebo.39Regardlessoftheinterventionutilized,frombrief counselingtopharmacologictherapy,abstinenceratesareincreasedinsmokers whoareidentifiedandofferedassistanceintheireffortstoquit.

Table4

MetaAnalysis:EffectivenessandAbstinenceRatesforSmokingCessationTherapies Table4 Gotowww.surgeongeneral.gov/tobacco/gdlnrefs.htmforthearticlesusedinthismetaanalysis. CI=confidenceintervalNRT=nicotinereplacementtherapySR=sustainedrelief. ReproducedwithpermissionfromFioreMC,JanCR,BakerTB,etal.Treatingtobaccouseanddependence:2008update.Quickreference guideforclinicians.Rockville,MD:U.S.DepartmentofHealthandHumanServices,PublicHealthService2009.

OpportunitiesforIntervention
Inadditiontoofficevisits,thereareotheropportunitiestopromotereduceduseoftobacco,suchasintheworkplace, throughcommunitysmokingbans,oratthetimeofhospitalization.Inamatchedcontrolledstudy,SeoandTorabi showedthattherewasasignificantdecreaseinhospitalizationsforacuteMIinnonsmokersinthe44monthsafterpublic smokingbanordinancewasenacted.40Smokerswhoarehospitalizedareoftenmotivatedtoquitregardlessoftheir diagnosisatthetimeofpresentation. AssessmentofsmokingstatusisarequirementbytheJointCommissiononAccreditationofHealthcareOrganizations, andthroughidentificationofsmokers,itprovidesanopportunityforintervention.Inametaanalysisof33trialsbyRigotti etal.,cessationsuccessinhospitalizedpatientswasrelatedtotheintensityoftheinterventionandtothecritical componentoffollowupgreaterthan1monthpostdischarge.41 Thosewhoreceivedthelowestintensityintervention(briefinpatientintervention)hadanORof1.16(95%CI,0.081.67)of quitting,whereasthosewithlongerinpatientcontactbutnofollowuphadanORof1.08(95%CI,0.891.29),astrategy thatwasnomoreeffectivethanusualcare.Thesixstudiesthatlookedatpatientswithinpatientinterventionandfollowup forupto1monthafterdischargedidnotshowincreasedquitrates(OR,1.0995%CI,0.911.30).Itwasthosepatients thatreceivedthemostintensiveinterventionandfollowupforlongerthan1monthpostdischargethathadimprovedquit rates(OR,1.6595%CI,1.441.77),thusillustratingthatarrangingforoutpatientfollowupafterhospitalizationiscrucial inimprovingquitratesinhospitalizedsmokers. InthePREMIER(ProspectiveRegistryEvaluatingOutcomesAfterMyocardialInfarction)study,hospitalbasedsmoking cessationprogramsandcardiacrehabilitationwerestronglyassociatedwithincreasedcessationrates.42

Summary
DespitethedecreasingnumberofsmokersintheUnitedStates,over435,000deathsareattributedtotobaccoannually. Tobaccouseistheleadingmodifiablecauseofthedevelopmentofatherosclerosis,aswellasacontributortoacute coronaryevents.SmokingcessationisassociatedwithalowerriskofCVD,andeffortstopromotecessationand abstinenceshouldbeaddressedateachencounterwiththehealthcareprovider. Assessingthepatient'sreadinesstochangecanhelptheproviderprovideappropriatecounseling,resources,and followuptoenhancelongtermabstinence.UseofoverthecounterandprescriptionNRTsandpharmacologicagents, suchasbupropionandvarenicline,significantlyimprovequitrates.

KeyPoints
Tobaccouseisaleadingpreventablecauseofmorbidityandmortalityandcontributesto>435,000deaths annuallyintheUnitedStates. Cigarettesmokingisassociatedwithincreasedinflammation,endothelialdysfunction,unfavorablechangesin thelipidprofile,andincreasedthromboticfactors. Identificationoftobaccousersisthefirststepinimprovingratesofabstinence. The"5A's"(ask,advise,assess,assist,andarrangefollowup)isaneffectivetooltosystematicallyidentifyand promotesmokingcessation. NRTscandoubleabstinencerates. CombinationtherapywithnicotinepatchandsupplementalnicotineorbupropionandNRTsignificantlyincrease quitrates.

References

1. CentersforDiseaseControlandPrevention.Annualsmokingattributablemortality,yearsofpotentiallifelost,andproductivelosses UnitedStates,19972001.MMWRMorbMortalWklyRep200554:6258. 2. CentersforDiseaseControlandPrevention.VitalSigns:CurrentCigaretteSmokingAmongAdultsAged18YearsUnitedStates,20 2010.MMWRMorbMortalWklyRep201160:120712. 3. AmbroseJA,BaruaRS.Thepathophysiologyofcigarettesmokingandcardiovasculardisease:anupdate.JAmCollCardiol 200443:17317. 4. DollR,PetoR,WheatleyK,GrayR,SutherlandI.Mortalityinrelationtosmoking:40years'observationsonmaleBritishdoctors.BMJ 1994309:90111. 5. HasdaiD,GarrattKN,GrillDE,LermanA,HolmesDRJr.Effectofsmokingstatusonthelongtermoutcomeaftersuccessful percutaneouscoronaryrevascularization.NEnglJMed1997336:75561. 6. ChowCK,JollyS,RaoMelaciniP,FoxKA,AnandSS,YusufS.Associationofdiet,exercise,andsmokingmodificationwithriskofea cardiovasculareventsafteracutecoronarysyndromes.Circulation2010121:7508. 7. ShahAM,PfefferMA,HartleyLH,etal.Riskofallcausemortality,recurrentmyocardialinfarction,andheartfailurehospitalization associatedwithsmokingstatusfollowingmyocardialinfarctionwithleftventriculardysfunction.AmJCardiol2010106:9116. 8. GerberY,RosenLJ,GoldbourtU,BenyaminiY,DroryY,onbehalfoftheIsraelStudyGrouponFirstAcuteMyocardialInfarction.Smok statusandlongtermsurvivalafterfirstacutemyocardialinfarction:Apopulationbasedcohortstudy.JAmCollCardiol200954:2382 9. vanDomburgRT,MeeterK,vanBerkelDF,VeldkampRF,vanHerwerdenLA,BogersAJ.Smokingcessationreducesmortalityafter coronaryarterybypasssurgery:a20yearfollowupstudy.JAmCollCardiol200036:87883. 10. ReaTD,HeckbertSR,KaplanRC,SmithNL,LemaitreRN,PsatyBM.Smokingstatusandriskforrecurrentcoronaryeventsafter myocardialinfarction.AnnInternMed2002137:494500. 11. CritchleyJA,CapewellS.Mortalityriskreductionassociatedwithsmokingcessationinpatientswithcoronaryheartdisease:a systematicreview.JAMA2003290:8697. 12. NeunteuflT,HeherS,KostnerK,etal.Contributionofnicotinetoacuteendothelialdysfunctioninlongtermsmokers.JAmCollCard 200239:2516. 13. KallioK,JokinenE,SaarinenM,etal.Arterialintimamediathickness,endothelialfunction,andapolipoproteinsinadolescents frequentlyexposedtotobaccosmoke.CircCardiovascQualOutcomes2010196:196203. 14. JohnsonHM,GossettLK,PiperME,etal.Effectsofsmokingandsmokingcessationonendothelialfunction:1yearoutcomesfroma randomizedclinicaltrial.JAmCollCardiol201055:198895. 15. JatoiNA,JerrardDunneP,FeelyJ,MahmudA.Impactofsmokingandsmokingcessationonarterialstiffnessandaorticwavereflec inhypertension.Hypertension200749:9815. 16. QuillenJE,RossenJD,OskarssonHJ,MinorRLJr,LopezAG,WinnifordMD.Acuteeffectofcigarettesmokingonthecoronary circulation:constrictionofepicardialandresistancevessels.JAmCollCardiol199322:6427. 17. AsthanaA,JohnsonHM,PiperME,FioreMC,BakerTB,SteinJH.Effectsofsmokingintensityandcessationoninflammatorymarker alargecohortofactivesmokers.AmHeartJ2010160:45863. 18. BaruaRS,AmbroseJA,SahaDC,EalesReynoldsLJ.Smokingisassociatedwithalteredendothelialderivedfibrinolyticand antithromboticfactors:aninvitrodemonstration.Circulation2002106:9058. 19. NewbyDE,McLeodAL,UrenNG,etal.Impairedcoronarytissueplasminogenactivatorreleaseisassociatedwithcoronary atherosclerosisandcigarettesmoking:directlinkbetweenendothelialdysfunctionandatherothrombosis.Circulation2001103:193 41. 20. GepnerAD,PiperME,etal.Effectsofsmokingandsmokingcessationonlipidsandlipoproteins:outcomesfromarandomizedclini trial.AmHeartJ201116:14551. 21. ZaratinA,GidlundM,BoschcovP,CastilhoL,deFariaEC.Antibodiesagainstoxidizedlowdensitylipoproteininnormolipidemic smokers.AmJCardiol200290:6513. 22. FioreMC,JanCR,BakerTB,etal.TreatingTobaccoUseandDependence:2008Update.ClinicalPracticeGuideline.Rockville,MD U.S.DepartmentofHealthandHumanServices.PublicHealthService.May2008. 23. KeenanPS.Smokingandweightchangeafternewhealthdiagnosesinolderadults.ArchInternMed2009169:23742. 24. FioreMC,JanCR,BakerTB,etal.TreatingTobaccoUseandDependence:2008Update.QuickReferenceGuideforClinicians. Rockville,MD:U.S.DepartmentofHealthandHumanServices.PublicHealthService.April2009. 25. LinderJA,RigottiNA,SchneiderLI,KelleyJH,BrawarskyP,HaasJS.AnElectronichealthrecordbasedinterventiontoimprovetobac treatmentinprimarycare:aclusterrandomizedcontrolledtrial.ArchInternMed2009169:7817. 26. ProchaskaJO,GoldsteinMG.Processofsmokingcessation.ClinChestMed199112:72735. 27. RigottiNA.Clinicalpractice.Treatmentoftobaccouseanddependence.NEnglJMed2002346:50612. 28. GrahamAL,CobbNK,PapandonatosGD,etal.ArandomizedtrialofInternetandtelephonetreatmentforsmokingcessation.Arch InternMed2011171:4653. 29. FreeC,KnightR,RobertsonS,etal.Smokingcessationsupportdeliveredviamobilephonetestmessaging(tst2stop):asingleblin randomisedtrial.Lancet2011378:4955. 30. MyungSK,McDonnellDD,KazinetsG,SeoHG,MoskowitzJM.Effectsofwebandcomputerbasedsmokingcessationprograms:m analysisofrandomizedcontrolledtrials.ArchInternMed2009169:92937. 31. RanneyL,MelvinC,LuxL,McClainE,LohrKN.Systematicreview:smokingcessationinterventionstrategiesforadultsandadultsin specialpopulations.AnnInternMed2006145:84556. 32. BarthJ,CritchleyJA,BengelJ.Psychosocialinterventionsforsmokingcessationinpatientswithcoronaryheartdisease.Cochrane

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DatabaseofSystematicReviews2008,Issue1.Art.No.:CD006886.Availableat: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006886/abstractjsessionid=00C2B20E5890515B1DC112B75C318CE7.d02 Accessed02/22/2012. FioreMD,SmithSS,JorenbyDE,BakerTB.Theeffectivenessofthenicotinepatchforsmokingcessation:ametaanalysis.JAMA 1994271:19407. GoldsteinMG,NiauraR.Methodstoenhancesmokingcessationaftermyocardialinfarction.MedClinNorthAm200084:6380. GreenlandS,SatterfieldMH,LanesSF.Ametaanalysistoassesstheincidenceofadverseeffectsassociatedwiththetransdermal nicotinepatch.DrugSaf199818:297308. JosephAM,NormanSM,FerryLH,etal.Thesafetyoftransdermalnicotineasanaidtosmokingcessationinpatientswithcardiac disease.NEnglJMed1996335:17928. HayesJT,EbbertJO.Vareniclinefortobaccodependence.NEnglJMed2008359:201824. RigottiNA,PipeAL,BenowitzNL,ArteagaC,GarzaD,TonstadS.Efficacyandsafetyofvareniclineforsmokingcessationinpatients cardiovasculardisease:arandomizedtrial.Circulation2010121:2219. PiperME,SmithSS,SchlamTR,etal.Arandomizedplacebocontrolledclinicaltrialof5smokingcessationpharmacotherapies.Arc GenPsychiatry200966:125362. SeoDC,TorabiMR.Reducedadmissionsforacutemyocardialinfarctionassociatedwithapublicsmokingban:matchedcontrolled study.JDrugEduc200737:21726. RigottiNA,MunafoMR,SteadLF,etal.Smokingcessationinterventionsforhospitalizedsmokers:asystematicreview.ArchInternM 2008168:195060. DawoodN,VaccarinoV,ReidKJ,SpertusJA,HamidN,ParasharSPREMIERRegistryInvestigators.Predictorsofsmokingcessatio afteramyocardialinfarction:theroleofinstitutionalsmokingcessationprogramsinimprovingsuccess.ArchInternMed2008168:1 7.

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4.5:Diabetes
Author(s): StevenP.Marso,MD

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Describetheriskofcoronaryheartdisease(CHD)associatedwithtype2diabetesmellitus(T2DM). 2. RecognizethegoalsofhypertensionandhyperlipidemiamanagementinpatientswithT2DM. 3. DescribetheclinicalbenefitsofmanagingchronichyperglycemiainpatientswithT2DM.

Introduction
DiabetesistheseventhleadingcauseofdeathintheUnitedStatesandisassociatedwithanincreasedhazardfor cardiovascular(CV),nonCV,andcancerdeaths.1 Theoverallriskofdeathinpatientswithdiabetesistwicethatof patientswithoutdiabetes.WhileCVdisease(CVD)isthemostfrequentcauseofdeathamongallindividualsinthe UnitedStates,peoplewithdiabetesaredisproportionatelyaffected.Heartdiseaseisnotedonthedeathcertificatesof nearly70%ofpatientswithdiabetes.

Epidemiology
Diabetesmellitus(DM)affects25.8millionpeople(8.3%ofthepopulation)inthe UnitedStates,including7millionundiagnosedindividuals.Thefrequencyof diabetesincreaseswithage.Over25%ofpatients65yearshavediabetes.Each yearintheUnitedStates,2millionnewcasesdevelopinindividuals>20yearsof age.Diabetesistheleadingcauseofkidneyfailure,nontraumaticlowerlimb amputations,andnewcasesofblindness.Itisamajordeterminantofheart diseaseandstroke. DMisametabolicdisordercharacterizedbyinsufficientinsulinsecretionnecessary tomaintainnormalplasmaglucosevalues.Therearethreedistinctclassifications fordiabetes:1)T2DM,whichaccountsformorethan90%ofallcases2)type1DM (T1DM),whichgenerallydevelopsintheyoungand3)gestationaldiabetes,which developsduringpregnancy. Gestationaldiabetescomplicatesabout4%ofpregnanciesintheUnitedStates. Womenwhodevelopgestationaldiabeteshaveanincreasedriskofdeveloping T2DM,ascomparedwiththosewhohavenormalglycemiathroughoutpregnancy. Therelativerisk(RR)isapproximately7.4.Theriskismeasurablewithin5years, withaRRofapproximately4.7.Theriskmorethandoublesto9.3inthosewomen5 yearspostpartum.2 TheabsoluteriskofdevelopingT2DMinametaanalysisby BellamyLandcolleagueswas12.5%inpatientswithgestationaldiabetes.2 ThecurrentdiagnosticcriteriafordiabetesandprediabetesarelistedinTable1.In general,glycatedhemoglobin(HbA1c)isusedasascreeningtestfordiagnosis. Eitherfastingplasmaglucoseoranoralglucosetolerancetest(OGTT)shouldbe usedforadefinitivediagnosiswhendiabetesissuspectedbasedonanelevated HbA1cvalue. Prediabetesisastateindicatingincreasedriskfordevelopmentofdiabetes.Itis characterizedbyimpairedglucosetolerance(IGT)and/orimpairedfastingglucose (IFG).InadditiontothecriteriainTable1,anHbA1cof5.76.4%alsoqualifiesas prediabetes. SpecialPopulations Thefrequencyofdiabetesvariesincertainminoritypopulations.Ithasbeen estimatedthat14.2%ofAmericanIndiansandAlaskaNativeshavediabetes.3 While thefrequencyis10.2%innonHispanicwhites>20yearsold,itis18.7%innon Hispanicblackindividualsofthesameage.3 T2DMisincreasinginprevalence,particularlyamongyoungerpeopleintheUnited States.Approximately0.18%ofindividualsunderage20haveeitherT1DMorT2DM (i.e.,1in523).AccordingtoSearchforDiabetesinYouth,amultistateregistry trackingallnewcasesofdiabetesinadolescentsandchildren019yearsold, 15,600patientswerediagnosedwithT1DMand3,600withT2DMfrom20022005.4 Duringeachyear,18.6per100,000newcasesofT1DMwerediagnosedin adolescentsages1019.Inthesameagegroup,8.5per100,000newcasesof T2DMwerediagnosed.ThefrequencyofT2DMintheyoungisincreasing,andis disproportionatelyhigheramongyoungPacificIslandersandAmericanIndians.In contrast,newcasesofT1DMarediagnosedtoagreaterextentinnonHispanic whiteyouths.4 CostofDiabetes Medicalexpendituresassociatedwithdiabetesaremorethantwotimesthatof peoplewithoutdiabetes.Totalannualmedicalcostsin2003wereestimatedtobe $174billion,including$116billionindirectcosts.Indirectcoststotaled$58billion, andincludeddisability,lostproductivity,andprematuremortality.6

Table1

DiagnosticCriteriaforDiabetesandPrediabetes Table1 References: 1. AmericanDiabetesAssociation.Diagnosisandclassificationofdiabetesmellitus.DiabetesCare201134Suppl1:S629. 2. WorldHealthOrganization.DefinitionandDiagnosisofDiabetesMellitusandIntermediateHyperglycemia:ReportofaWHO/IDF Consultation.Geneva:WorldHealthOrganization2006.

MetabolicSyndromeandDiabetesRisk
Metabolicsyndrome(MetSyn),originallydescribedover80yearsago,isthe presenceofmultiplecardiometabolicdisorders,alsoreferredtointheliteratureas SyndromeXorinsulinresistancesyndrome.Whileseveralclinicaldefinitionsfor MetSynexist,insulinresistanceisacentralcomponent.In2001,theNational CholesterolEducationProgram(NCEP)AdultTreatmentPaneldevelopedclinically usefulcriteriaforidentifyingMetSyninclinicalpractice,andthepanelupdatedthe criteriain2005(Table2).6 TheprevalenceofMetSynincreaseswithage,affectingasmanyas40%of individualsolderthanage60.However,itisincreasinglybeingobservedinyoung andobeseindividuals.7 Whileprevalenceestimatesvaryaccordingtothedefinition used,datafromtheNationalHealthandNutritionExaminationSurveysuggestthat nearly50millionpeople(i.e.,24%ofthepopulation)intheUnitedStateshave MetSyn.7 MetSynisassociatedwithanexcessriskofdevelopingdiabetesandCVD,8 whichis notsurprising,sinceMetSynincludesIFGandmultiplefactorsassociatedwithCV risk.IntheDECODE(DiabetesEpidemiology:CollaborativeanalysisOfDiagnostic criteriainEurope)study,therewasanapproximatetwofoldincreaseinriskforall causeandCVmortality.9 Othershavereportedanassociationwithbothmyocardial infarction(MI)andstroke.10Treatmentisprimarilyfocusedonriskfactor modification,sincenospecificMetSyntherapiescurrentlyexist.Similartothosewith diabetes,MetSynpatientsoftenhaveatherogenicdyslipidemiaconsistingof elevatedtriglyceridesandapolipoproteinB,smalllowdensitylipoprotein(LDL) particles,andlowhighdensitylipoprotein(HDL)levels.

Table2

NCEPAdultTreatmentPanelIIIDiagnosticCriteriaforMetabolicSyndrome Table2 *ForpeopleofEuropeanethnicity,theInternationalDiabetesFederationrecommendscutpointsof>94cmformenand>80cmforwomen.For peopleofAsiandescent,therecommendedcutoffsare>90cmformenand>80cmforwomen. HDL=highdensitylipoproteinNCEP=NationalCholesterolEducationProgram Reference: 1. TheIDFConsensusWorldwideDefinitionoftheMetabolicSyndrome.Brussels:InternationalDiabetesFederation,2006.Availableat: http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf.Accessed:12/27/2011.

CoronaryHeartDiseaseRisk
Inpatientswithdiabetes,the10yearriskofCHDevents(MIordeath)isnearlyequal tothatofpatientswithaknownhistoryofCHD,butwithoutdiabetes.Accordingly, diabetesisrecognizedasaCHDriskequivalent.11Furtherunderscoringthis association,CHDistheprimarycauseofdeathinmanypatientswithdiabetes.In addition,fatalitiesfollowingMIareexcessiveinpatientswithDM,andtheirlongterm survivalingeneralispooroncediagnosedwithCHD.11Itisthecombinationof theseCVriskfactors,ratherthanhyperglycemiaalone,thatraisesdiabetestothe levelofaCHDriskequivalent. ManagementofconcomitantCVriskfactorsisrequisiteinpatientswithDM.Given thatDMisaCHDriskequivalent,manyriskfactorthresholdsandtreatmentgoals aresimilartothoseforpatientswithknownCHD(Table3).Attainmentofthese goalsisaclinicalpriority.

Table3

RiskFactorsandTreatmentGoalsforReducingCHDRiskinPatientsWithDiabetes Table3 CHD=coronaryheartdiseaseHbA1c=glycatedhemoglobinHDL=highdensitylipoproteinLDL=lowdensitylipoprotein. AdaptedwithpermissionfromHandelsmanY,MechanickJI,BlondeL,etal.AmericanAssociationofClinicalEndocrinologistsMedicalGuidelines forClinicalPracticefordevelopingadiabetesmellituscomprehensivecareplan.EndocrPract201117Suppl2:153.

Prevention
Diabetesisapreventablechronicdiseasethatcanbeavoidedordelayedthrough effectivelifestylemanagement,includingreducingcaloric,carbohydrate,andfat intaketoreachidealbodyweight,engaginginphysicalactivity,andavoiding smoking.Specificpreventionstrategiesincludea510%reductioninbodyweight, moderateexercise,andselectiveuseofmetformin.Sinceobesityisasignificantrisk factorforthedevelopmentofdiabetes,weightlossthroughdiet,exercise,and pharmacotherapymaybeappropriate. Gastricbypasssurgeryisalsoindicatedformorbidlyobese(i.e.,bodymassindex [BMI]>40kg/m2 )patientswithoutdiabetes.Itisalsorecommendedforthosewho haveaBMI>35kg/m2 withhighriskcomorbidities,includingdiabetes.12Specific riskfactorsfordiabetesareshowninTable4. Lifestylemodificationisparticularlyeffectiveatdelayingorpreventingtheonsetof diabetes.IntheDPS(FinnishDiabetesPreventionStudy),522overweight/obese subjectswithameanBMIof31kg/m2 andIGTwererandomizedtoanintervention consistingofdietaryandexercisecounselingtoreducebodyweightversusacontrol group.13Over4yearsoffollowup,thecumulativeincidenceofdiabeteswas58% lowerintheinterventiongroupcomparedwithcontrols(11%vs.23%,p<0.001). TheDPP(DiabetesPreventionProgram)trialincluded3,234overweightpatients withameanBMIof34kg/m2 andIFGorIGT.Patientswererandomlyassignedto eitherlifestyleintervention(i.e.,>7%weightlossand>150minutesweeklyphysical activity),metformin(i.e.,850mgbid),orplacebo.14Over3yearsoffollowup,lifestyle modificationwasassociatedwitha58%reductionintheincidenceofdiabetes comparedwithplacebo(4.8vs.11.0casesper100personyears),whilemetformin wasassociatedwitha31%reductioncomparedwithplacebo(7.8vs.11.0cases per100personyears).Thecumulativefrequencyofdiabetesat3yearsisshownin Figure1. IntheSTOPNIDDM(StudytoPreventNonInsulinDependentDiabetesMellitus) trial,1,429IGTpatientswererandomizedtothealphaglucosidaseinhibitor acarbose(100mgthreetimesdaily)orplacebo.PatientsreceivedannualOGTTsto assesstheincidenceofprogressiontoDM.15Treatmentwithacarbosewas associatedwitha25%reductioninRRofdiabetescomparedwithplaceboovera meanfollowupof3.3years(32%vs.42%,p=0.0015).Furthermore,morepatients whowererandomizedtoacarboseexperiencedareversalofIGTtonormoglycemia versuspatientswhowererandomizedtoplacebo(p<0.001).

Table4

Figure1

RiskFactorsforDiabetesMellitus Table4 AdaptedwithpermissionfromHandelsmanY,MechanickJI,BlondeL,etal.AmericanAssociationofClinicalEndocrinologistsMedicalGuidelines forClinicalPracticefordevelopingadiabetesmellituscomprehensivecareplan.EndocrPract201117Suppl2:153.

ThreeYearCumulativeIncidenceofDiabetesinDiabetesPreventionProgramTrial Figure1 Reference: 1. KnowlerWC,BarrettConnorE,FowlerSE,etal.Reductionintheincidenceoftype2diabeteswithlifestyleinterventionormetformin.N EnglJMed2002346:393403.

GlucoseManagement
Bydefinition,normoglycemicindividualshavepreprandialglucosevalues<99mg/dlorpostprandialvalues<120mg/dl. Epidemiologicalstudieshavedemonstratedelevatedglucosetobeassociatedwithgreaterriskformicrovascularand macrovascularcomplications.AnumberofthesestudieshaveshownalinearincreaseinCVDandmortality correspondingwithincreasingvaluesforfastingplasmaglucose,postprandialglucose,andHbA1c. GlucosecontrolisfundamentaltothemanagementofDM.AccordingtothecurrentglucoseguidelinesfromtheAmerican DiabetesAssociation(ADA),thetargetHbA1cthresholdforDMpatientsis<7.0%,butshouldbeindividualizedbasedon patientcharacteristics.Alowertargetcanbeconsideredinhighlyselectedindividualswhoareatlowerriskfor hypoglycemia.Lessstringenttreatmentgoalsmayalsobeappropriateforadultswithlimitedlifeexpectancyoradvanced vasculardisease. MicrovascularComplications Twoprospective,randomized,controlledtrialsofintensiveversusstandardglucosecontrolweretheDCCT(Diabetes ComplicationsandControlTrial)inT1DMpatientsandtheUKPDS(UnitedKingdomProspectiveDiabetesStudy)in T2DMpatients.16,17Thesetrialsdefinitivelyshowedthatimprovedglucosecontrolwasassociatedwithasignificant reductioninmicrovascularcomplications,namelyretinopathyandnephropathy. FollowupoftheDCCTandUKPDShasdemonstratedlongtermbenefitsofintensiveglucosecontrolwithrespectto microvascularcomplications.Anumberoftrialsofintensiveglucosecontrolthatweredesignedtodemonstratea reductioninmacrovasculareventshavealsoconfirmedareductioninmicrovascularcomplications.Acurvilinear relationshipexistsbetweenHbA1candmicrovascularcomplications,suggestingthatthegreatestmagnitudeofbenefitin reducingmicrovascularcomplicationsisinverypoorlycontrolledpatients(e.g.,HbA1c810%).Althoughtherecontinues tobealimitedbenefitforreducingmicrovascularcomplicationsbyloweringHbA1cfrom7%to6%,theabsolutebenefitis muchsmaller. MacrovascularComplications Theassociationbetweenintensiveglucosecontrolandmacrovascularcomplicationshasalsobeenexaminedinseveral largescalerandomizedcontrolledtrials.Incontrasttotheconsistentassociationbetweenglycemiccontroland microvascularcomplications,intensiveglucosecontrolhasnotbeenconsistentlylinkedtoimprovedCVoutcomesin thesetrials.Therewasmuchheterogeneityintheresults.Anoverviewofthemethodologyandfindingsfromafewof thesestudiesfollows. DCCTEDIC(DiabetesComplicationsandControlTrialEpidemiologyofDiabetesInterventionsand Complications)18:Therewere1,441patientswithT1DMandwithoutexistingCVDwhowererandomizedto intensiveglucosecontrol(i.e.,threetimesdailyinsulintoachievepreprandialglucose70120mg/dland postprandialglucose180mg/dl)versusconventionalglucosecontrol.Patientsweretreatedfor6.5yearsand werefollowedforanadditional10yearswithoutextendingthetreatmentassignment.Over90%ofpatientswere followedforatotalof17years,atwhichtimetherewasa42%RRreductioninCVeventsintheintensive treatmentgroupcomparedwithconventionaltherapy(0.38vs.0.80eventsper100patientyears,p=0.02)anda 57%reductioninriskofnonfatalMI,stroke,orCVdeath(p=0.02). UKPDS:Inover4,200T2DMpatientsrandomizedtointensiveglucosecontrol(i.e.,sulfonylurea,insulin,or metformin)orconventionalglucosecontrol,3,277weremonitoredforanadditional10yearsbutwerenotrequired tocontinuetreatmentaccordingtotheiroriginalrandomizationscheme.19During10yearsoffollowup, sulfonylureainsulinwasassociatedwitha13%reduction(RR,0.8795%confidenceinterval[CI],0.790.96)in allcausemortalityanda15%reduction(RR,0.8595%CI,0.740.97)inMIcomparedwithcontrols.Inthe metformingroup,theRRreductionsinallcausemortalityandMIcomparedwithconventionaltreatmentwere27% (RR,0.7395%CI,0.590.89)and33%(RR,0.5795%CI,0.510.89). ADVANCE(ActioninDiabetesandVascularDisease:PreteraxandDiamicronModifiedReleaseControlled Evaluation):11,140T2DMpatientswithexistingmacrovascularormicrovasculardiseasewererandomizedto glicazidewithorwithoutmetformin,thiazolidinediones(TZDs),acarbose,orinsulintoachieveHbA1c<6.5%versus standardglucosecontrol.20Althoughintensivecontrolresultedina10%reductionincombinedmacrovascular andmicrovascularevents(hazardratio[HR],0.9095%CI,0.820.98),thisbenefitwasmostlydrivenbya statisticallysignificantreductioninnephropathy(HR,0.7995%CI,0.660.93).Therewasnosignificantreduction inoverallmacrovascularevents(HR,0.9495%CI,0.841.06),includingnonfatalMI(HR,0.9895%CI,0.781.23). ThesepatientstypicallyhadadvancedstagesofdiabetesrelativetoUKPDS. ACCORD(ActiontoControlCardiovascularRiskinDiabetes):Thistrialwasprematurelydiscontinuedduetoan

excesshazardofmortalityassociatedwithintensiveglucosecontrol.21In10,251T2DMpatientswithHbA1c>7.5% andexistingCVD,intensiveglucosecontrolwasdefinedasatargetHbA1c<6%,whilestandardtherapywasa targetof77.9%.Althoughthecompositeoccurrenceofdeath,nonfatalMI,ornonfatalstrokewas10%lowerin patientsrandomizedtointensiveglucosecontrol(HR,0.9095%CI,0.781.04),therewere257deathsfromall causesintheintensivegroupcomparedwith203deathsincontrols(HR,1.2295%CI,1.011.46).After terminationofintensivetherapy,thesepatientswerefollowedfor5additionalyears.Duringthistime,meanHbA1c increasedfrom6.4%to7.2%intheintensivearm.AlthoughtheriskofnonfatalMIcontinuedtobelowerinthe intensivegroup(HR,0.8295%CI,0.700.96),astatisticallysignificanthazardformortalitypersistedinthese patients(HR,1.195%CI,1.031.38).22 VADT(Veteran'sAffairsDiabetesTrial):InthiscohortofUSMilitaryveteranswhohadT2DMforameandurationof 11.5years,intensiveglucosecontrolwasdefinedasanabsolutereductioninHbA1c>1.5%ascomparedwitha controlgroup.23Therewere1,791patientsrandomized.ThemeanHbA1cwas9.4%atbaselineinbothgroups. After6months,HbA1cwasreducedto6.9%intheintensivegroupand8.4%inthecontrolgroup.Overamedian followupof5.6years,intensivetherapywasassociatedwithanonsignificant12%reductioninprimarycomposite majoradverseCVevents(MACE)(HR,0.8895%CI,0.741.05).Theriskofallcausemortalitywasnumerically greaterintheintensivetherapygroupbutdidnotrisetothelevelofstatisticalsignificance(HR,1.0795%CI,0.81 1.42). Duetotheuncertaintyandheterogeneityinresultsfromindividualtrials,severalmetaanalyseshaverecentlybeen publishedthatcombinedresultsfromthesetrials.Oneofthesemetaanalysesincludedover33,000patientsand showeda17%reductioninRRfornonfatalMIassociatedwithintensiveglycemiccontrol(oddsratio[OR],0.8395%CI, 0.750.93)anda15%reductioninCHDevents(OR,0.8595%CI,0.770.93).Therewasnoeffectonstrokeorallcause mortality.24Twoadditionalmetaanalysessupportedthesefindings.24,26

DiabetesMedications
AccordingtotheCentersforDiseaseControlandPreventionreport,amongpatientswithdiabetesintheUnitedStates, 58%useoralmedications,14%useinsulinandoralmedications,12%useinsulinonly,and16%usenomedications.3 ClinicaltrialdataremainincompleteonspecificCVeffectsofmanyclassesofthesedrugs.TheADAsuggestslifestyle interventionormetforminasthefirstlinetherapytomanagehyperglycemia.27 Thiazolidinediones TZDsbindtoandactivatethenuclearreceptorknownasperoxisomeproliferatoractivatedreceptor(PPAR),whichis responsibleforregulatingtheexpressionofseveralmetabolicgenes.TZDsstimulateinsulinsensitivitythrough increasedinsulindependentglucosedisposalandreducedhepaticglucoseoutput.Althoughtheirprecisemechanism ofactionisunknown,itisbelievedthattheenhancedinsulinactionproducedbyTZDsismediatedbytranscriptional changesingeneexpression.Bothrosiglitazoneandpioglitazoneareassociatedwithincreasedfluidretentionandriskof congestiveheartfailure,aswellasanumericalexcessintheriskofbonefractures. Studieshaveshownthatpioglitazoneandrosiglitazoneexertdifferentialeffectsonplasmalipids.Specifically, rosiglitazoneuseisassociatedwithseveraladverseeffectsonlipids,asshowninaprospectivestudyof800patients withT2DMwhowererandomizedtoeitherpioglitazoneorrosiglitazonefor24weeks.Patientsrandomizedto rosiglitazonedemonstratedincreasedtriglyceridelevels,lowerincreasesinHDLcholesterollevels,greaterincreasesin LDLcholesterollevels,andincreasedLDLparticleconcentration.Incontrast,patientsrandomizedtopioglitazonehad reducedtriglyceridelevels,greaterincreasesinHDLcholesterol,lowerincreasesinLDLcholesterol,reducedLDL particleconcentration,andincreasedLDLparticlesizes.28OthergeneraleffectsofTZDsincludereducedblood pressure,markersofinflammation,carotidintimamedialthickness,aswellasreducedbonemineralization. TheCVsafetyofrosiglitazonehasbeendescribedinseveralmetaanalyses.2934Ingeneral,anexcessriskashighas 1.43fornonfatalMIhasbeendemonstrated.31OthershavereanalyzedthisworkanddemonstratedHRsrangingfrom 1.261.43fornonfatalMIand1.171.64forCVdeath.32,34MarketingofrosiglitazonewassuspendedbytheEuropean MedicinesAgencyinlate2010,andtheUSFoodandDrugAdministration(FDA)issueda"blackbox"warningfor rosiglitazoneinlate2007.Thiswarningstatedthatitsuseisassociatedwithanexcessriskofheartfailureand myocardialischemiaandisspecificallycontraindicatedinpatientswithNewYorkHeartAssociationclassIIIorIVheart failure.Subsequently,inearly2011thewarningwasrevisedtostatethatrosiglitazoneisassociatedwithincreasedrisk ofMIwhilenocomparableincreaseinriskhasbeendemonstratedwithuseofpioglitazone.Atthesametime,useof rosiglitazonewasrestrictedtoonlypatientscurrentlyusingitorthosenotachievingadequateglucosecontrolwithother antidiabeticmedications. Metformin MetforminisrecommendedasthefirstlinetherapyinoverweightpatientswithnewlydiagnosedT2DM.17However,its useiscontraindicatedinstage4and5chronickidneydisease.Althoughitisassociatedwithweightloss,itisalso associatedwithdyspepsiaanddiarrhea.IntheUKPDS,monotherapywithmetforminwasassociatedwitha30%RR reductioninmacrovascularevents,includingstatisticallysignificantreductionsinMI(RR,0.6195%CI,0.410.89)and allcausemortality(RR,0.6495%CI,0.450.91).Howevermetforminplussulfonylureawasassociatedwitha96% increaseinriskofdiabetesrelateddeath(p=0.039)anda60%increaseinriskofallcausemortality(p=0.041).17 Sulfonylureas Theglucoseloweringeffectsofsulfonylureasaremaximalat6monthsandtaperoffoverthecourseof3years. Combinedwithanyotherglucoseloweringagent,sulfonylureasareassociatedwithamultifoldincreaseinriskof hypoglycemia.TheyarealsoassociatedwithweightgaincomparabletothatofTZDs. OtherNovelAgents DipeptidylpeptidaseIV(DPPIV)isanenzymeexpressedinmultipleorgansandcells.Itinactivatestheguthormone glucagonlikepeptide1(GLP1),whichisresponsibleforinsulinstimulation,suppressionofglucagon,anddelayed gastricemptying.35SeveralorallyadministeredDPPIVinhibitors(i.e.,sitagliptin,vildagliptin,saxagliptin)haverecently beendeveloped.Thesedrugsdonotleadtoweightgain,arenotassociatedwithhypoglycemia,andcanbe administeredinpatientswithrenalinsufficiency.GLP1receptoragonists(i.e.,exenatideandliraglutide)alsoincrease physiologiclevelsofinsulinanddecreaseglucagon,resultinginlowerfastingandpostprandialglucose.Theyare associatedwithdelayedgastricemptying,increasedsatiety,decreasedfluidintake,andweightlossof45%without increasedhypoglycemia.Sideeffectsincludenauseaandvomiting.TheCVsafetyoftheseagentsarecurrentlybeing testedinlargescaleclinicaltrials.

AntiplateletTreatment
AspirinisremarkablyeffectiveinreducingCVmorbidityandmortalityinhighriskpatients(includingDM)withaprior historyofMIorstroke.Thus,aspirinisuniversallyindicatedasanappropriatetherapyinCHDpatientsforsecondary prevention.36Thebenefitofaspirintherapyinaprimarypreventioncohortiscontroversial,bothforpatientswithand withoutDM.BasedoncurrentevidenceandajointpositionstatementfromtheADAandAmericanHeartAssociation,37 aspirinhasamodestrelativeeffectonCVeventrates,intherangeofapproximately10%.Themagnitudeofbenefitis relatedtotheabsoluteriskofeventsinthepopulation.Themainadverseeffectsfromaspirintherapyarerelatedtoan increasedriskforgastrointestinalbleeding,whichapproaches15per1,000patientsperyear.Giventhatthislevelof bleedingriskisapproximatelyequaltotheexpectedbenefitinpatientsatlowCVDrisk,aspirintherapyisonly recommendedforhigherriskpatients.Specificrecommendationsareasfollows37: 1. Lowdoseaspirin(75162mg/dl)isreasonableinpatientswithDMandwithoutvascularhistorywhoareat increasedCVDrisk(i.e.,approximately1%peryear)ifthereisnotanincreasedriskforbleeding,duetoaprior historyofbleedingoruseofnonsteroidalantiinflammatorydrugsorwarfarin.Ingeneral,DMindividualswith>1 majorriskfactorandage>50formenor>60forwomen,wouldqualifyashighrisk. 2. AspirinisnotrecommendedforpatientswithDMwhoareatalowCVDrisk(i.e.,CHDrisk<0.5%peryear). 3. Lowdoseaspirinmightbeconsideredinpatientsatintermediaterisk,whichisdefinedas0.51%CHDriskper year. AnumberofriskcalculatorsareavailabletoestimateCHDrisk,includingtheUKPDSriskengine,whichcanbefoundon lineathttp://www.dtu.ox.ac.uk/riskengine/index.php.TheFraminghamriskscoreprovidesanotherriskcalculator.38

Hypertension
CoexistinghypertensioninDMisparticularlycommonandisassociatedwithhighrisk.Epidemiologicdatahave suggestedanincreasedhazardforCVeventswithasystolicbloodpressure>115mmHg.39Individualswithelevated bloodpressurearealso2.5timesmorelikelytodevelopDMwithin5years.40Thepresenceofhypertensionalsogreatly increasesthelikelihoodofprogressionofnephropathyandretinopathyinDMpatients.41TheUKPDStrialdemonstrated thatforeach10mmHgreductioninbloodpressure,therewasa15%reductioninDMrelatedmortality,an11% reductioninMI,anda13%reductioninmicrovascularcomplications,includingretinopathyornephropathy. Anumberofrandomizedcontrolledtrialsofhypertensivepatientshavedemonstratedimprovedoutcomesassociated withbloodpressurecontrol.Theseinclude:UKPDS,HOT(HypertensionOptimalTherapy),SHEP(SystolicHypertension intheElderlyProgram),SYSTEUR(SystolicHypertensioninEurope),HOPE(HeartOutcomesPreventionEvaluation), andLIFE(LosartanInterventionForEndpointreductioninhypertension).4146Thesetrialsincludedlargepopulations withDM.TheJointNationalCommittee(JNC)7recommendationssupportatargetedbloodpressureof<130/80mmHg inDMpatients.47TheADArecommendationsalsosupportthistarget.However,evidenceforthislowtargetislimited. TheACCORDtrialtargetedasystolicbloodpressure<120mmHgcomparedwithatargetof130140mmHg.There wasanonsignificantreductioninthecompositeoutcomeofMI,stroke,andCVdeath(HR,0.8895%CI,0.731.06),buta statisticallysignificantreductioninstrokeforthe<120mmHgcohort(HR,0.5995%CI,0.390.89). Bloodpressureshouldbemeasuredateveryofficevisit.Systolicbloodpressure130mmHgordiastolicpressure80 mmHgontwoseparatedaysisusedtoconfirmthediagnosisofhypertension.Ifsystolicpressureis140mmHgor diastolicpressureis90mmHg,patientsshouldreceivebothlifestyletherapyandpharmacologictreatment.Lifestyle interventionincludestheDASH(DietaryApproachestoStopHypertension)diet,withreducedsodiumintake,increased potassiumintake,increasedphysicalactivity,andmoderationofalcoholconsumption. AccordingtotheJNC7,acompellingcaseexistsfortheuseofmanyclassesofantihypertensiveagents,including diuretics,betablockers,angiotensinconvertingenzymeinhibitors(ACEIs),angiotensinreceptorblockers(ARBs),and calciumchannelblockers(CCBs)inpatientswithDM.Patientsmostoftenrequiremultidrugtreatmentregimens,often needingatleastthreeclassesofagents.MostpharmacologicstrategiesincludetheuseofeitherACEIsorARBs,with ARBssubstitutedforACEIsifnottolerated. TheADAcurrentlyrecommendsACEIsinDMpatients>55yearsoldandathighriskforCVD,andbothACEIsandARBs inT2DMpatientswithnephropathy.Thiazidediureticsarepreferredifglomerularfiltrationrate(GFR)>30ml/min/1.73m2 , whileloopdiureticsarepreferredifGFR<30ml/min/1.73mm2 .BetablockersarebeneficialinDMpatientsaspartofa multidrugregimen,buttheirefficacyasmonotherapyislessclear.Anexceptionwouldbeinpatientswithapriorhistoryof MI.Betablockerscandecreaseinsulinsensitivityandmasktheepinephrinemediatedsymptomsofhypoglycemia. Nevertheless,theyarenotcontraindicatedinDMpatients.48InCHFpatientsintheABCD(AppropriateBloodpressure ControlinDiabetes)trial,nitrendipinewasinferiortolisinoprilinreducingMACE.48

Dyslipidemia
LipoproteinabnormalitiesarecommoninDMindividuals.ThetypicalprofileofDMdyslipidemiaisoftenreferredtoas atherogenicdyslipidemia,whichincludeselevatedtriglycerides,lowHDL,andmodestlyelevatedLDLparticlesize.DM patientshavemoresmall,denseLDLparticles,whicharethoughttobemoreatherogenicthanotherLDLmoieties. Atherogenicdyslipidemiaisalsotypicallyseeninpatientswithcardiometabolicrisk,includingT2DM,familialcombined hyperlipidemia,familialhypoalphalipoproteinemia,andpolycysticovarysyndrome.49Patientswithcardiometabolicrisk oftenhavecentraladiposity,insulinresistance,dyslipoproteinemia,andhypertension. ManagementofdyslipidemiainpatientswithDMincludesthefollowingtreatmentgoals: Inadults,annualmeasurementoflipidsisappropriate.Lowriskindividuals<40yearsofagewithoutCVrisk factorsmaybeassessedevery2years. Inpatients>40yearsofagewithoutCVD,thetargetLDLis<100mg/dl. InhighriskpatientswithestablishedCVD,analternativeLDLtargetof<70mg/dlisreasonable.50 Lifestylemodificationshouldincludereducedintakeofsaturatedfatandcholesterol,weightlossifoverweight, increaseddietaryfiberintake,andincreasedphysicalactivity.Pharmacologicinterventionisindicatedwhen targetsarenotachievedwithlifestylechanges. AlthoughtheprimarytargetforDMdyslipidemiaisLDL,thereisasecondarytargetfornonHDL(i.e.,totalcholesterol minusHDL)whentriglyceridesare200499mg/dl.Thetargetis30mg/dlhigherthantheLDLgoal.Whentriglycerides are>500mg/dl,providersshouldinitiatetherapywithdietandeitherafibrateorniacin,priortoinitiatingotherLDL specifictherapies. EvidencetosupportloweringLDLinDMpatientsisprovidedbyseveralrandomizedcontrolledtrials,includingtheHPS (HeartProtectionStudy)andtheCARDS(CollaborativeAtorvastatinDiabetesStudy).Amongover20,000patientsenrolled inHPSwhowererandomizedto40mgdailysimvastatinorplacebo,5,963hadT2DM.51Over5yearsoftreatment,there wasa22%reductioninmajorvascularevents(i.e.,nonfatalMI,coronarydeath,stroke,orrevascularization)inDM patientsrandomizedtosimvastatincomparedwithplacebo(20.2%vs.25.1%,p<0.0001). CARDSenrolled2,800T2DMpatientswithoutpreviousCVDwhowererandomizedtoatorvastatin10mg/dayor placebo.52Theatorvastatintreatedarmwasassociatedwithanapproximate3040%reductioninLDLaswellasa37% reductioninprimarycompositeacutecoronarysyndrome,revascularization,orstroke(HR,0.6395%CI,0.480.83). TheefficacyofstatinsonreducingLDLandmajorvasculareventswasalsorecentlysummarizedinametaanalysisof 18,700patientswithDM(including92%withT2DM)enrolledin14largescalerandomizedcontrolledtrials.53Trialswere includediftheymetthefollowingcriteria:atleastoneoftheirprimaryobjectiveswastomodifylipidlevelsthroughstatin treatment,>1,000patientswereenrolled,anddurationoftreatmentwas>2years.Meandurationoftreatmentwas4.3 years. Themetaanalysisfoundthatforeach1mg/dldecreaseinLDL,statintherapywasassociatedwitha9%reductioninall causemortality(RR,0.9199%CI,0.821.01),includingCHDmortality(RR,0.8899%CI,0.751.03)andvascular mortality(RR,0.8799%CI,0.761.00).Therewasalsoastatisticallysignificant21%reductioninMACEforeach1mg/dl decreaseinLDL(RR,0.7999%CI,0.720.86),includingMIorcoronarydeath(RR,0.7899%CI,0.690.87),coronary revascularization(RR,0.7599%CI,0.640.88),andstroke(RR,0.7995%CI,0.670.93).Itisnoteworthythat63%ofall patientsincludedinthismetaanalysisdidnothaveahistoryofvasculardisease.

FutureDirections
Thereareanumberofongoingrandomizedclinicaltrialsdesignedtoevaluatethesafetyofnewerantidiabetictherapies. SincetheUSFDArequiresformalevaluationoftheCVsafetyofantidiabetictherapies,therewilllikelybeasharp increaseinthenumberoflargescaleCVoutcometrials.Forexample,therearefourongoingtrialswhicharetestingthe administrationofincretinmimeticagentsinpatientswithT2DM. TheTECOS(TrialtoEvaluateCardiovascularOutcomesaftertreatmentwithSitagliptin)includespatientswithT2DMand inadequateglycemiccontrolonmonoordualcombinationoralantihyperglycemictherapy.ThetrialisevaluatingtheCV efficacyandsafetyofsitagliptin.TECOSisalongterm,eventdriven,noninferioritystudyenrollingapproximately14,000 diabeticpatientsatriskforCVevents.Theprimaryobjectivesaretodeterminewhethersitagliptinaddedtousualcare reducesthecompositeCVendpointofCVdeath,nonfatalMI,nonfatalstroke,orunstablechestpainrequiring hospitalization.Patientrecruitmentcommencedin2008andresultsareexpectedin2014. TheEXAMINE(EXAMinationofCVoutcomes:aldogliptINversusstandardofcare)trialinpatientswithT2DMandacute coronarysyndromeisevaluatingalogliptinasanadjuncttodietandexercise.Thistrialwillenrollapproximately5,400 patients,withtheprimaryendpointbeingCVdeath,nonfatalMI,orstroke.Enrollmentbeganin2009andresultsare expectedin2014. TheLEADER(LiraglutideEffectandActioninDiabetes:EvaluationofcardiovascularoutcomeResults)trialisanevent driven,largescale,randomized,controlledtrialevaluatingtheCVsafetyofliraglutide.LEADERisenrollinghighrisk T2DMpatients.Recruitmentbeganin2010,andresultsareexpectedin2016. TheEXSCEL(EXnatideStudyofCardiovascularEventLowering)trialisexaminingtheCVsafetyofaonceweekly administrationofexenatideaddedtousualcareinpatientswithT2DM.TheprimarycompositeendpointisCVdeath, nonfatalMI,ornonfatalstroke.Approximately9,500T2DMpatientswillbeenrolledandfollowedforatleast4years. Recruitmentbeganin2010andstudycompletionisexpectedin2017. Additionaltargetsfortherapyincludesodiumglucosecotransporters(SGLT2)inhibitorssuchasdapagliflozin,which preventreabsorptionofglucoseinthekidney.Thekidneyplaysadeterministicroleinglucosehomeostasis.Specifically, glucosereabsorptionoccursintheproximalconvolutedtubules.Inanormalstate,<1%ofglucoseisexcretedinurine. GlucosetransportisaccomplishedbySGLTs,whichareafamilyofmembraneboundproteinsresponsiblefor transportinganumberofmoietiesacrossthebrushbordermembranesoftheproximalrenaltubules.SGLT2isahigh capacitytransporterexpressedmostlyinthekidney,andaccountsfor90%ofglucosereabsorption.SGLT2inhibitors blockthereabsorptionoffilteredglucose,leadingtoglycosuria.Thus,SGLT2inhibitorsarecandidatetargetstomanage hyperglycemiainthesettingofT2DM. DapagliflozinisanSLGT2inhibitor,likelywiththemostclinicaldataaccumulatedcurrently.Dapagliflozinhad demonstratedsustainedanddosedependentglucoseexcretionover24hours.Preliminarystudieshaveshownittobe safeandgenerallywelltolerated.Ininitialclinicalstudies,itwasassociatedwithanapproximate0.51.0%reductionin HbA1caswellasa12kglossinweightover12weeks.Overall,therateofhypoglycemiawaslow(<2%),anditwas associatedwitha26mmHgreductioninsystolicbloodpressureaswellasamilddiureticeffect.Nevertheless,thereis aconcernthatSGLT2inhibitorsmaybeassociatedwithanincreasedriskofurinarytractandgenitalinfections.54,55

KeyPoints
DMisgrowinginprevalenceandiscurrentlytheseventhleadingcauseofdeathintheUnitedStates. Nearly70%ofpatientswithdiabetesdieofCVcauses,andtheriskofanMIinadiabeticpatientwithoutexisting heartdiseaseisnearlyequaltothatofanondiabeticpatientwithexistingdisease. MetSynisaclusteringofthreeormoreriskfactorsassociatedwithanincreasedriskofdevelopingdiabetes. Generalpreventionstrategiesfordiabetesconsistoflifestylemanagement,including:caloric,carbohydrate,and fatreductionstoreachidealbodyweight,increasedphysicalactivity,andsmokingavoidance. HyperglycemiaisassociatedwithanexcessriskofCVevents.Whiletheassociationbetweenintensiveglucose controlandareductioninmicrovascularcomplicationshasbeenestablishedinrandomizedtrials,intensive glucosecontrolhasnotbeenconsistentlylinkedtoimprovedmacrovascularoutcomes. Lifestyleinterventionand/ormetforminareindicatedasthefirstlinetherapyinnewlydiagnosedpatientswith diabetes.AdditionalagentsincludeTZDs,sulfonylureas,DPPIVinhibitors,andGLP1agonistsandanalogs. LowdoseaspirincanbeconsideredindiabeticpatientsatelevatedCHDriskwhodonothaveahistoryof vascularevents. Thetargetbloodpressurefordiabeticpatientsissystolic<130mmHganddiastolic<80mmHg.Thiazide diuretics,ACEIs,betablockers,andCCBsareacceptabletherapies,dependingonindividualpatient characteristics. Managementofdyslipidemiaindiabeticpatientsincludesstatintherapyand/orlifestylemodificationtoachievean LDLcholesterollevel<100mg/dl,or<70mg/dlinpatientswithestablishedCVD.Othertherapiesmaybeinitiated inpatientswithexcessivelyhightriglyceridelevels.Theseincludedietarymodification,fibrates,and/orniacin.

References
1. SeshasaiSR,KaptogeS,ThompsonA,etal.Diabetesmellitus,fastingglucose,andriskofcausespecificdeath. NEnglJMed2011364:82941. 2. BellamyL,CasasJP,HingoraniAD,WilliamsD.Type2diabetesmellitusaftergestationaldiabetes:asystematic reviewandmetaanalysis.Lancet2009373:17739. 3. CDC.Nationaldiabetesfactsheet:nationalestimatesandgeneralinformationondiabetesandprediabetesin theUnitedStates,2011.Atlanta:U.S.DepartmentofHealthandHumanServices,CentersforDiseaseControl andPrevention,2011. 4. LieseAD,D'AgostinoRBJr,HammanRF,etal.TheburdenofdiabetesmellitusamongUSyouth:prevalence estimatesfromtheSEARCHforDiabetesinYouthStudy.Pediatrics2006118:15108. 5. AmericanDiabetesAssociation.EconomicCostsofDiabetesintheU.S.in2002.DiabetesCare200326:917 932. 6. GrundySM,CleemanJI,DanielsSR,etal.Diagnosisandmanagementofthemetabolicsyndrome:anAmerican HeartAssociation/NationalHeart,Lung,andBloodInstitutescientificstatement.Circulation2005112:273552. 7. FordES,GilesWH,DietzWH.PrevalenceofthemetabolicsyndromeamongUSadults:findingsfromthethird NationalHealthandNutritionExaminationSurvey.JAMA2002287:3569. 8. EckelRH,GrundySM,ZimmetPZ.Themetabolicsyndrome.Lancet2005365:141528. 9. HuG,QiaoQ,TuomilehtoJ,BalkauB,BorchJohnsenK,PyoralaK.Prevalenceofthemetabolicsyndromeandits relationtoallcauseandcardiovascularmortalityinnondiabeticEuropeanmenandwomen.ArchInternMed 2004164:106676. 10. NinomiyaJK,L'ItalienG,CriquiMH,WhyteJL,GamstA,ChenRS.Associationofthemetabolicsyndromewith historyofmyocardialinfarctionandstrokeintheThirdNationalHealthandNutritionExaminationSurvey. Circulation2004109:426. 11. NCEP.ThirdReportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelonDetection, Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII)finalreport.Circulation 2002106:3143421. 12. GastrointestinalSurgeryforSevereObesity.NIHConsensusDevelopmentConferenceStatement.Bethesda,MD: U.S.DepartmentofHealthandHumanServices,1991.Availableat: http://consensus.nih.gov/1991/1991gisurgeryobesity084html.htm.Accessed12/27/2011. 13. TuomilehtoJ,LindstromJ,ErikssonJG,etal.Preventionoftype2diabetesmellitusbychangesinlifestyleamong subjectswithimpairedglucosetolerance.NEnglJMed2001344:134350. 14. KnowlerWC,BarrettConnorE,FowlerSE,etal.Reductionintheincidenceoftype2diabeteswithlifestyle interventionormetformin.NEnglJMed2002346:393403. 15. ChiassonJL,JosseRG,GomisR,HanefeldM,KarasikA,LaaksoM.Acarboseforpreventionoftype2diabetes mellitus:theSTOPNIDDMrandomisedtrial.Lancet2002359:20727. 16. TheDiabetesControlandComplicationsTrial/EpidemiologyofDiabetesInterventionsandComplicationsStudy ResearchG.IntensiveDiabetesTreatmentandCardiovascularDiseaseinPatientswithType1Diabetes.NEngl JMed2005:264353. 17. Effectofintensivebloodglucosecontrolwithmetforminoncomplicationsinoverweightpatientswithtype2 diabetes(UKPDS34).UKProspectiveDiabetesStudy(UKPDS)Group.Lancet1998352:85465. 18. NathanDM,ClearyPA,BacklundJY,etal.Intensivediabetestreatmentandcardiovasculardiseaseinpatients withtype1diabetes.NEnglJMed2005353:264353. 19. HolmanRR,PaulSK,BethelMA,MatthewsDR,NeilHA.10yearfollowupofintensiveglucosecontrolintype2 diabetes.NEnglJMed2008359:157789. 20. PatelA,MacMahonS,ChalmersJ,etal.Intensivebloodglucosecontrolandvascularoutcomesinpatientswith type2diabetes.NEnglJMed2008358:256072. 21. GersteinHC,MillerME,ByingtonRP,etal.Effectsofintensiveglucoseloweringintype2diabetes.NEnglJMed 2008358:254559. 22. GersteinHC,MillerME,GenuthS,etal.Longtermeffectsofintensiveglucoseloweringoncardiovascular outcomes.NEnglJMed2011364:81828. 23. DuckworthW,AbrairaC,MoritzT,etal.Glucosecontrolandvascularcomplicationsinveteranswithtype2 diabetes.NEnglJMed2009360:12939. 24. RayKK,SeshasaiSR,WijesuriyaS,etal.Effectofintensivecontrolofglucoseoncardiovascularoutcomesand deathinpatientswithdiabetesmellitus:ametaanalysisofrandomisedcontrolledtrials.Lancet2009373:1765 72. 25. MarsoSP,KennedyKF,HouseJA,McGuireDK.Theeffectofintensiveglucosecontrolonallcauseand cardiovascularmortality,myocardialinfarctionandstrokeinpersonswithtype2diabetesmellitus:asystematic reviewandmetaanalysis.DiabVascDisRes20107:11930. 26. TurnbullFM,AbrairaC,AndersonRJ,etal.Intensiveglucosecontrolandmacrovascularoutcomesintype2 diabetes.Diabetologia200952:228898. 27. AmericanDiabetesAssociation.Standardsofmedicalcareindiabetes2011.DiabetesCare201134Suppl 1:S1161.

28. GoldbergRB,KendallDM,DeegMA,etal.Acomparisonoflipidandglycemiceffectsofpioglitazoneand rosiglitazoneinpatientswithtype2diabetesanddyslipidemia.DiabetesCare200528:154754. 29. DiamondGA,KaulS.Rosiglitazoneandcardiovascularrisk.NEnglJMed2007357:9389authorreply93940. 30. HomePD,PocockSJ,BeckNielsenH,etal.Rosiglitazoneevaluatedforcardiovascularoutcomesaninterim analysis.NEnglJMed2007357:2838. 31. NissenSE,WolskiK.Effectofrosiglitazoneontheriskofmyocardialinfarctionanddeathfromcardiovascular causes.NEnglJMed2007356:245771. 32. NissenSE,WolskiK.Rosiglitazonerevisited:anupdatedmetaanalysisofriskformyocardialinfarctionand cardiovascularmortality.ArchInternMed2010170:11911201. 33. SinghS,LokeYK,FurbergCD.Longtermriskofcardiovasculareventswithrosiglitazone:ametaanalysis.JAMA 2007298:118995. 34. DiamondGA,BaxL,KaulS.Uncertaineffectsofrosiglitazoneontheriskformyocardialinfarctionand cardiovasculardeath.AnnInternMed2007147:57881. 35. DruckerDJ,NauckMA.Theincretinsystem:glucagonlikepeptide1receptoragonistsanddipeptidylpeptidase4 inhibitorsintype2diabetes.Lancet2006368:1696705. 36. BaigentC,BlackwellL,CollinsR,etal.Aspirinintheprimaryandsecondarypreventionofvasculardisease: collaborativemetaanalysisofindividualparticipantdatafromrandomisedtrials.Lancet2009373:184960. 37. PignoneM,AlbertsMJ,ColwellJA,etal.Aspirinforprimarypreventionofcardiovasculareventsinpeoplewith diabetes:apositionstatementoftheAmericanDiabetesAssociation,ascientificstatementoftheAmericanHeart Association,andanexpertconsensusdocumentoftheAmericanCollegeofCardiologyFoundation.Circulation 2010121:2694701. 38. WilsonPW,D'AgostinoRB,LevyD,BelangerAM,SilbershatzH,KannelWB.Predictionofcoronaryheartdisease usingriskfactorcategories.Circulation199897:183747. 39. ChobanianAV,BakrisGL,BlackHR,etal.TheSeventhReportoftheJointNationalCommitteeonPrevention, Detection,Evaluation,andTreatmentofHighBloodPressure:theJNC7report.JAMA2003289:256072. 40. GressTW,NietoFJ,ShaharE,WoffordMR,BrancatiFL.Hypertensionandantihypertensivetherapyasriskfactors fortype2diabetesmellitus.AtherosclerosisRiskinCommunitiesStudy.NEnglJMed2000342:90512. 41. AdlerAI,StrattonIM,NeilHA,etal.Associationofsystolicbloodpressurewithmacrovascularandmicrovascular complicationsoftype2diabetes(UKPDS36):prospectiveobservationalstudy.BMJ2000321:4129. 42. HanssonL,ZanchettiA,CarruthersSG,etal.Effectsofintensivebloodpressureloweringandlowdoseaspirinin patientswithhypertension:principalresultsoftheHypertensionOptimalTreatment(HOT)randomisedtrial.HOT StudyGroup.Lancet1998351:175562. 43. FranseLV,PahorM,DiBariM,SomesGW,CushmanWC,ApplegateWB.Hypokalemiaassociatedwithdiuretic useandcardiovasculareventsintheSystolicHypertensionintheElderlyProgram.Hypertension200035:1025 30. 44. StaessenJA,FagardR,ThijsL,etal.Randomiseddoubleblindcomparisonofplaceboandactivetreatmentfor olderpatientswithisolatedsystolichypertension.TheSystolicHypertensioninEurope(SystEur)Trial Investigators.Lancet1997350:75764. 45. Effectsoframipriloncardiovascularandmicrovascularoutcomesinpeoplewithdiabetesmellitus:resultsofthe HOPEstudyandMICROHOPEsubstudy.HeartOutcomesPreventionEvaluationStudyInvestigators.Lancet 2000355:2539. 46. LindholmLH,IbsenH,DahlofB,etal.Cardiovascularmorbidityandmortalityinpatientswithdiabetesinthe LosartanInterventionForEndpointreductioninhypertensionstudy(LIFE):arandomisedtrialagainstatenolol. Lancet2002359:100410. 47. TheSeventhReportoftheJointNationalCommitteeonPrevention,Detection,Evaluation,andTreatmentofHigh BloodPressure.Bethesda,MD:NationalInstitutesofHealth,2004. 48. EstacioRO,JeffersBW,HiattWR,BiggerstaffSL,GiffordN,SchrierRW.Theeffectofnisoldipineascompared withenalapriloncardiovascularoutcomesinpatientswithnoninsulindependentdiabetesandhypertension.N EnglJMed1998338:64552. 49. CarrMC,BrunzellJD.Abdominalobesityanddyslipidemiainthemetabolicsyndrome:importanceoftype2 diabetesandfamilialcombinedhyperlipidemiaincoronaryarterydiseaserisk.JClinEndocrinolMetab 200489:26017. 50. GrundySM,CleemanJI,MerzCN,etal.ImplicationsofrecentclinicaltrialsfortheNationalCholesterolEducation ProgramAdultTreatmentPanelIIIGuidelines.JAmCollCardiol200444:72032. 51. CollinsR,ArmitageJ,ParishS,SleighP,PetoR.MRC/BHFHeartProtectionStudyofcholesterolloweringwith simvastatinin5963peoplewithdiabetes:arandomisedplacebocontrolledtrial.Lancet2003361:200516. 52. ColhounHM,BetteridgeDJ,DurringtonPN,etal.Primarypreventionofcardiovasculardiseasewithatorvastatinin type2diabetesintheCollaborativeAtorvastatinDiabetesStudy(CARDS):multicentrerandomisedplacebo controlledtrial.Lancet2004364:68596. 53. KearneyPM,BlackwellL,CollinsR,etal.Efficacyofcholesterolloweringtherapyin18,686peoplewithdiabetes in14randomisedtrialsofstatins:ametaanalysis.Lancet2008371:11725. 54. BaileyCJ,GrossJL,PietersA,BastienA,ListJF.Effectofdapagliflozininpatientswithtype2diabeteswhohave inadequateglycaemiccontrolwithmetformin:arandomised,doubleblind,placebocontrolledtrial.Lancet 2010375:222333. 55. NeumillerJJ,WhiteJR,Jr.,CampbellRK.Sodiumglucosecotransportinhibitors:progressandtherapeutic potentialintype2diabetesmellitus.Drugs201070:37785.

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4.6:MetabolicSyndrome
Author(s): NathanD.Wong,PhD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Recallthepathophysiology,keycomponents,anddefinitionsusedfordescribingthemetabolicsyndrome(MetS). 2. DescribetheguidelinesandapproachesforlifestylemanagementofMetS. 3. Discusstheguidelines,approaches,andtherapiesusedforclinicalmanagementofMetS,includingtreatmentof atherogenicdyslipidemia,elevatedbloodpressure,obesity,andelevatedglucose.

Pathophysiology
In1988,Reavenproposedthatinsulinresistancewascentraltothepathophysiology oftype2diabetesmellitus,hypertension,andcoronaryarterydisease.Insulinisa hormonethatfacilitatesglucoseuptakeintheadipocytes,hepatocytes,andskeletal muscle,andhelpstoregulatehepaticglucoseproductionandlipolysis(Figures1a, b).Theconditionofinsulinresistancewithassociatedmetabolicabnormalities associatedwithincreasedcardiovasculardisease(CVD)riskhasbeenreferredto byvariousnames,includingthemetabolicsyndrome(MetS).1 InsulinresistanceiscloselyrelatedtotheothercomponentsoftheMetS,namely abdominalobesity,dyslipidemia,glucoseintolerance,andelevatedbloodpressure. Moreover,insulinresistanceisassociatedwithabnormaluricacidmetabolism, hemostaticabnormalitiessuchaselevatedfibrinogenandplasminogenactivator inhibitor1levels,endothelialdysfunction,andreproductiveissuessuchas polycysticovarysyndrome.2,3 TheMetSoriginatesfromdysfunctionalenergybalance,characterizedfrom increasedtriglyceridesresultingfromfoodenergyintakeexceedingenergyoutput, whichoverwhelmsstorageavailableinsmallperipheraladipocytes.Thisresultsin increasedfreefattyacidsintheplasmaaffectingendocrineandparacrinefunctionin theadipocytes.Whileplasmafreefattyacidssuppressinsulinstimulatedglucose uptake,insulinresistanceleadstoinsuppressiblefattyacidrelease.Theresulting effectistheatherogeniclipoproteinphenotypeofelevatedtriglycerides,lowhigh densitylipoprotein(HDL),andsmalldenselowdensitylipoprotein(LDL)deriving primarilyfromanincreasedfluxoffreefattyacids.Also,elevatedbloodpressure resultsinpartviaangiotensinogensynthesizedbyadipocytesandfromeffectsof freefattyacidsoncentralorgansandbloodvessels.3

Figure1a

Figure1b

PathophysiologyoftheMetabolicSyndrome(InsulinResistance)(1of2) Figure1a Freefattyacids(FFAs)arereleasedinabundancefromanexpandedadiposetissuemass.Intheliver,FFAsproduceanincreasedproduction ofglucose,triglycerides,andsecretionofverylowdensitylipoproteins(VLDLs).Associatedlipid/lipoproteinabnormalitiesincludereductionsin highdensitylipoprotein(HDL)cholesterolandanincreaseddensityoflowdensitylipoproteins(LDLs).FFAsalsoreduceinsulinsensitivityin musclebyinhibitinginsulinmediatedglucoseuptake.Associateddefectsincludeareductioninglucosepartitioningtoglycogenandincreased lipidaccumulationintriglyceride.IncreasesincirculatingglucoseandtosomeextentFFA,increasepancreaticinsulinsecretion,resultingin hyperinsulinemia.Hyperinsulinemiamayresultinenhancedsodiumreabsorptionandincreasedsympatheticnervoussystemactivityand contributetothehypertension,asmightincreasedlevelsofcirculatingFFA. AdaptedwithpermissionfromEckelRH,GrundySM,ZimmettPZ.Themetabolicsyndrome.Lancet2005365:141528.

PathophysiologyoftheMetabolicSyndrome(InsulinResistance)(2of2) Figure1b SuperimposedandcontributorytotheinsulinresistanceproducedbyexcessiveFFAistheparacrineandendocrineeffectofthe proinflammatorystate.Producedbyavarietyofcellsinadiposetissueincludingadipocytesandmonocytederivedmacrophages,theenhanced secretionofinterleukin6(IL6)andtumornecrosisfactoralpha(TNF)amongothers,resultsinmoreinsulinresistanceandlipolysisofadipose tissuetriglyceridestorestocirculatingFFA.IL6andothercytokinesalsoareincreasedinthecirculationandmayenhancehepaticglucose production,theproductionofVLDLbytheliver,andinsulinresistanceinmuscle.CytokinesandFFAalsoincreasetheproductionoffibrinogen andplasminogenactivatorinhibitor1(PAI1)bytheliverthatcomplementstheoverproductionofPAI1byadiposetissue.Thisresultsina prothromboticstate.Reductionsintheproductionoftheantiinflammatoryandinsulinsensitizingcytokineadiponectinarealsoassociatedwith themetabolicsyndromeandmaycontributetothepathophysiologyofthesyndrome. AdaptedwithpermissionfromEckelRH,GrundySM,ZimmettPZ.Themetabolicsyndrome.Lancet2005365:141528.

DefinitionsofMetabolicSyndrome
TheMetScomprisesaconstellationofinterrelatedriskfactorsofmetabolicoriginthatpromotethedevelopmentof diabetesandatheroscleroticCVD.Themostwidelyrecognizedareatherogenicdyslipidemia,elevatedbloodpressure, andelevatedplasmaglucose.SeveraldefinitionshavebeenproposedtodefineMetS,whichdifferintheircriteriamost commonlycitedincludethoseproposedbytheNationalCholesterolEducationProgram(NCEP),4,5andtheInternational DiabetesFederation(IDF).6 The2005AmericanHeartAssociation(AHA)/NationalHeart,Lung,andBloodInstituteupdateoftheNCEPdefinition,5 definesthepresenceofMetSonthebasisofdemonstratingthreeormoreofthefollowingfiveabnormalities: 1. Abdominalobesity,asdeterminedbyawaistcircumference>88cminwomenor>102cminmen 2. Elevatedbloodpressurebasedonasystolicbloodpressureof130mmHgorgreater,adiastolicbloodpressure of85mmHgorgreater,orbeingonantihypertensivetreatment 3. LowHDLcholesterol(HDLC)definedas<40mg/dlinmenor<50mg/dlinwomen,ortakingmedicationtoraise levelsofHDLC 4. Elevatedfastingtriglyceridesdefinedas150mg/dlorgreater,ortakingmedicationtolowerlevelsofelevated triglycerides,ornonfastingtriglyceridesof400mg/dlorgreaterand 5. Impairedfastingglucoseof100mg/dlorgreater,ortakingmedicationtolowerglucoselevels.Alternatively,a nonfastingglucoseof140mg/dlorgreatercouldbeconsideredequivalenttothislevelforbeingdefinedasa criterionofMetS,with200mg/dlorgreaterdefiningdiabetes. TheIDFdefinitioniscloselyrelatedinusingthesamecriteriawiththesamecutpoints6 however,itrequiresthepresence ofabdominalobesity(asdefinedearlier)plustwooftheotherfactorsintheNCEPdefinition.Importantly,theIDF definitiondiffersfromtheNCEPdefinitionbyindicatinglowerwaistcircumferencecutpointstodefineabdominalobesity amongEuropeanCaucasians(80cmforwomenand94cmformen)andforcertainAsiangroupsandHispanics (80cmforwomenand90cmformen). Thevastmajority(>75%)ofpeoplewithMetS,evenintheabsenceofdiabetes,haveincreasedwaistcircumference, bloodpressure,andtriglycerides,anddepressedHDLClevelsofnote,however,isthat58%ofmenand63%ofwomen withMetSalsohaveLDLClevelsof130mg/dlorhigher7

PrevalenceandEpidemiology
DatafromUSadultsin19992002showaprevalenceofMetSof33.7%amongmenand35.4%amongwomen accordingtotheNCEPdefinition,withhigherestimatesof39.9%and38.1%,respectively,usingtheIDFdefinition.8 Thesefiguresaresubstantiallyhigherthanthatpreviouslyreportedintheprecedingdecade,whenprevalencerateswere wellunder30%.9,10 WidevariationsintheprevalenceofMetSareobservedacrossotherpartsoftheworld,anddependonthedefinition used.Forinstance,amongHongKongChinese,theprevalenceofMetSvariedfrom9.6%usingtheNCEPdefinitionto 13.4%usingtheWorldHealthOrganization(WHO)definition.11InalargeUnitedKingdompopulationbasedstudy,South AsianshadthehighestprevalenceofMetS(29%inmenand32%inwomenusingtheNCEPdefinition),andEuropean womenhadthelowest(14%),12andinalargestudyinvolving11Europeancohorts,prevalenceusingamodifiedWHO definitionwasslightlyhigherinmen(15.7%)thaninwomen(14.2%).13

MetabolicSyndromeandCardiovascularRisk
AmongUSadults,atwofoldgreaterriskofmortalityfromcoronaryheartdisease (CHD)andCVDinpersonswithMetSwasobservedinonestudy14eventhosewith MetSbutwithoutdiabetesandthosewithonlyoneortwoMetSriskfactorsareatan increasedriskofdeathfromCHDandCVD.Moreover,thosewithdiabetesinthe absenceofCVDhadasimilarriskoftotalmortalityasthosewithpreexistingCVD, hencesupportingtheconceptofdiabetesasaCVDriskequivalent.Thosewithboth diabetesandpreexistingCVDhavethehighestrisk(Figure2).Otherreportsalso documenttheprognosticimportanceoftheMetSamongmenintheWestof Scotlandstudy,15andinFinnishadults.16 Inametaanalysisofrisksforallcausemortality,CVD,anddiabetes,Fordetal.,17 notedthatamongstudiesthatusedtheexactNCEPdefinitionoftheMetS,relative risks(and95%confidenceintervals)associatedwiththeMetSwere1.27(0.901.78) forallcausemortality,1.65(1.381.99)forCVD,and2.99(1.964.57)fordiabetes. TheauthorsconcludedthatMetSmayattributeto67%ofallcausemortality,12 17%ofCVD,and3052%ofdiabetes.17 Finally,inalargemetaanalysisoflongitudinalstudies,whichincludedover170,000 individualsamong43cohorts,arelativeriskofcardiovasculareventsanddeathof 1.78(1.582.00)wasreported,withastrongereffectseeninwomencomparedwith men(relativerisk,2.63vs.1.98p=0.09)(Figure3).18 PersonswithdiabetesareconsideredtobeaCHDriskequivalent,accordingtothe NationalCholesterolEducationProgram(NCEP),5 warrantingaggressivetreatment guidelinessimilartothosewithknownCHD.Intheabsenceofpriormyocardial infarction,theyhaveasimilarriskoffutureCVmortalityaspersonswithaprior myocardialinfarctionwithoutdiabetes.Thepresenceofbothdiabetesandprior myocardialinfarctionisassociatedwithanevenhigherriskofCVmortality.19

Figure2

Figure3

CardiovascularDisease(CVD)andTotalMortalityinUSMenandWomenAges3074 Figure2 Cardiovasculardisease(CVD)andtotalmortalityinUSmenandwomenages3074:Age,gender,andriskfactoradjustedCoxregression, NationalHealthandNutritionExaminationSurvey(NHANES)IIfollowup(n=6,255),comparedtothosewithneithermetabolicsyndrome(MetS), diabetes,norCVD.MetS:p<0.05forcoronaryheartdisease(CHD)mortalityandp<0.01forCVDmortalitydiabetes,CVD,andCVDplus diabetes:p<0.001forCHD,CVD,andtotalmortality. DataadaptedwithpermissionfromMalikS,WongND,FranklinSS,etal.Impactofthemetabolicsyndromeonmortalityfromcoronaryheart disease,cardiovasculardisease,andallcausesinUnitedStatesadults.Circulation2004110:124550.

RelativeRiskand95%ConfidenceIntervalforMetabolicSyndromeandIncidentCardiovascularEventsandDeath Figure3 Studiesarelistedinchronologicalorderbyyearthattheircohortswerecreated(exceptforthelaststudylisted,whichincludesmultiple cohorts).Resultsareforavailableanalysesofincidentcardiovasculardiseaseanddeath,andmaydifferfromtheresultsofthetotalstudy populations.Boxesrepresenttherelativerisk(RR),andlinesrepresentthe95%confidenceinterval(CI)forstudies.Thediamondrepresentsthe pooledRR,anditswidthrepresentsits95%CI. AdaptedwithpermissionfromGamiAS,WittBJ,HowardDE,etal.Metabolicsyndromeandriskofincidentcardiovasculareventsanddeath:a systematicreviewandmetaanalysisoflongitudinalstudies.JAmCollCardiol200749:40314.

EvaluationandAssessmentofRisksintheMetabolicSyndrome

GivenawidespectrumofCHDriskassociatedwithMetS,intensifiedeffortsto screenandadequatelytreatpersonswiththeMetSareneeded.TheNCEPhas providedaclinicallyusefuldefinitionoftheMetS,5 whichhasbeenwidely disseminatedthroughthemedicalcommunityandhasbeensubsequently updated.4 AninitialevaluationofMetScanbedonebystandardlaboratorytests,orbyefficient pointofcareinstrumentsassessingtriglycerides,HDLC,andglucose,inaddition tobloodpressureandwaistcircumferencemeasurement.Asmostpersonswith MetShaveelevatedtriglycerides,adirectLDLCmeasurementisrecommended,as useoftheFriedewaldformulaforcalculatingLDLCwouldresultinLDLCbeing underestimatedinmanycasesduetoelevatedtriglycerides. Additionally,apropermeasurementofwaistcircumferenceandatleasttwo consistentmeasuresofbloodpressure(takingtheaverageofthetwo)should providetherequiredinformationtodiagnoseMetS.Importantly,themeasurementof glycatedhemoglobin(HbA1c)hasalsobeendesignatedinrecentAmericanCollege ofCardiologyFoundation(ACCF)/AHAasbeingreasonableforCVriskassessment inasymptomaticadultswithoutadiagnosisofdiabetes(ClassIIa,LevelofEvidence B).20 GiventhesignificantheterogeneityinestimatedriskofpersonswithMetS,initial evaluationofriskinpersonswithMetSandwithoutdiabetes,canutilizeFramingham riskscorestoestimatetotalCVDriskin10years(Table1).21Moreover,theuseof globalriskscoresforriskassessmentisanACCF/AHAClassI,LevelofEvidenceB recommendationforallasymptomaticadultswithoutahistoryofCHDtohelptarget preventiveinterventions.20Whilesome40%areactuallyatlowriskofCHD(<6%in 10years),fullyonethirdareathighriskbasedonpreexistingdiabetes,CVD,or >20%10yearriskofCHD.22Olderpersonsorthosewhoaresmokersorhave increasedtotalorLDLClevels,evenifonlyminimalelevationsofdefinedMetSrisk factorsarepresent,maybeatintermediateorhigherriskofCHD. Furthermore,thereisinterestastowhethertheadditionofnewerriskfactorssuch asCreactiveprotein(CRP),fibrinogen,andsmalldenseLDLwillfurtheraddto predictingriskinpersonswithMetS.Forinstance,theNursesHealthStudyhas shownthatamongthosewithMetS,ageadjustedincidenceratesoffutureCVD eventswere3.4and5.9per1,000personyearsforthosewithCRPlevelsof3and >3mg/L,withadditiveeffectsofhigherCRPlevelsalsoseenforthosewith45MetS riskfactors.23IthasalsobeenrecommendedthatCRPbeconsideredfor measurementinintermediateriskindividuals,20,24andinmenages50andoveror womenages60andoverwithoutCHD,butwhohaveanLDLC<130mg/dl,20which maycomprisemanypersonswithMetS. Thepresenceofsubclinicalatherosclerosissuchascarotidultrasoundintimal medialthickness,25anklebrachialindex(althoughalowanklebrachialindex<0.9 isdiagnosticofperipheralarterialdisease,aCHDriskequivalent),2627orcoronary arterycalcium(CAC),2830mayalsoidentifyindividualswithhigherCVriskbasedon theirdemonstratedindependentprognosticvalue(Figure4).Thismayhave importantimplicationsforpersonswithMetS(especiallyintheabsenceofdiabetes), giventheuncertaintyofriskassessmentonthebasisofglobalriskassessment alone. RecentACCF/AHAguidelinesrecommendconsideringatherosclerosisscreening (e.g.,byCACtesting)inthosewitha1020%10yearCHDrisk(ClassIIa,Levelof EvidenceB).20Theguidelinesstatethatthosefoundtohaveclinicallysignificant atherosclerosiscouldhavetheirrisklevelstratifiedupwards,(e.g.,reclassifyingan intermediateriskindividualashighrisk)thus,suchscreeningmayhave implicationsforrefiningriskassessmentinmanypersonswithMetS.Itis noteworthythattheserecommendationshavenowbeenextendedtothosewith diabeteswhoareage40yearsforCVriskstratification(ClassIIa,Levelof EvidenceB).20Afindingofsignificantcalcificationinsuchindividualscouldinfactbe apotentmotivatoronboththepartofthephysicianandpatienttomoreaggressively controlthemultipleCVDriskfactorsthatoftenpresentinpatientswithMetS.

Table1

Figure4

FraminghamRiskScore:Whatisthispatientsriskcardiovasculardisease? Table1 AdaptedwithpermissionfromDAgostinoRBSr,VasanRS,PencinaMJ,etal.Generalcardiovascularriskprofileforuseinprimarycare:the FraminghamHeartStudy.Circulation2008117:74353.

ComputedTomographyScanShowingSignificantCoronaryArteryCalcium(score>400) Figure4

ManagementoftheMetabolicSyndrome (1of2)
LifestyleManagement InitialmanagementoftheMetSshouldfocusonreversingtherootcausesof atherogenicdiet,sedentarylifestyle,andoverweightorobesity.31Weightcontrol,in particular,canbeneficiallymodifyallkeycardiometabolicriskfactors,including glucose,LDLC,HDLC,triglycerides,bloodpressure,insulinlevels,and inflammatorymeasuressuchashighsensitivityCRP. Inonestudy,subjectsassignedtoalowcarbohydratedietcomparedwithalowfat dietshowedgreaterweightlossandgreaterreductionsintriglycerides,alesser decreaseinHDLC,andimprovedinsulinsensitivity.32Comparisonofalow carbohydrate,highprotein,highfat(Atkins)approachwithaconventionallow calorie,highcarbohydrate,andlowfatdietshowedgreaterinitialweightlossonthe formerhowever,after12months,therewaslittledifferenceinweightloss.33 ThemosteffectivewaytomanagetheMetSappearstobeoveralllifestylechange programs.Forinstance,theDPP(DiabetesPreventionProgram)trialslifestyle interventionarm(involvinga7%weightlossandexerciseof150minutes/week) showeda58%reductioninnewdiabetesonsetcomparedtoplacebo(witheventhe metforminarmonlyshowinga31%reductioncomparedtoplacebo).34TheFinnish DiabetesPreventionStudyalsoshoweda58%reductioninnewdiabetesonsetas aresultoflifestyleinterventioninvolvingreductioninweight,saturatedfatintake,and increasesinfiberintakeandexercise.35 Lifestylemanagementguidelinesfocusonthemanagementofunderlyingrisk factorspredisposingtothedevelopmentofMetS,namelyoverweight/obesity, physicalinactivity,anddietarymodificationsthatareneeded(Table2).1 This includesrecommendationsformodestreductionsof5001,000caloriesperdayto providea710%reductioninbodyweightoverthefirstyear,withareductionofbody massindexto<25kg/m2 . Regularandcontinuousmoderateintensityphysicalactivityofatleast30minutes (preferably60minutes)atleast5daysperweek(anddailyifpossible)isalso recommended,althoughthegreatestbenefitoccursfromadifferencebetween someversusnophysicalactivity.Inparticular,thecombinationofweightreduction andincreasedphysicalactivitycansignificantlyreducetheincidenceofnewonset diabetesinpersonswithprediabetes. Furthermore,fortreatmentofMetS,dietaryrecommendationsconsistentwithAdult TreatmentPanel(ATP)IIIrecommendationsforalowintakeofsaturatedfats,trans fats,andcholesterolreducedconsumptionofsimplesugarsandincreased intakesoffruits,vegetables,andwholegrainsarereasonable,withanoverallintake ofsaturatedfatof<7%ofcalories,dietarycholesterolof<200mg/day,andtotalfat intakeof2535%ofcalories.5 Moreover,recentlyupdatedrecommendationsalso indicatesodiumrestrictionat<1500mg/day. ClinicalManagement Generalrecommendationsarealsogivenforthemanagementofclinicalrisk factors,includingatherogenicdyslipidemia,elevatedbloodpressure,elevated glucose,andaproinflammatorystate(Table2).1 Importantly,itcanbedemonstrated thatapproximately80%ofCHDeventscouldbepotentiallyavertedinpersonswith MetSifbloodpressure,LDLC,andHDLCwerecontrolledtooptimallevels(Figure 5).7 AtherogenicDyslipidemia BesidesthevastmajorityofpersonswithMetShavingelevatedtriglycerides(85%of menand73%ofwomen)aswellaslowHDLC(83%ofmenand87%ofwomen), many(58%ofmenand63%ofwomen)havesuboptimalLDLClevels.7 Importantly,
Table2

Figure5

thisLDLCinmanypersonswithMetSislikelytobeofthesmalldensepatternB phenotype,whichiswelldocumentedtobehighlyatherogenic.4,36,37Controlof LDLCremainstheprimarytargetoftherapy,1 andsubgroupanalysesofpatients withMetSfromseverallargescaletrialshaveshownthatimportantreductionsin CHDwithstatintherapysupporttheserecommendations.3840 Alsoofimportance,theACCORD(ActiontoControlCardiovascularRiskinDiabetes) trialinpersonswithtype2diabetesfailedtoshowanaddedbenefitoffenofibrate therapytoreduceCVDriskbeyondthatofastatinalone,41althoughtherewas benefitseenspecificallyinthesubgroupofpersonswithbothelevatedtriglycerides andlowHDLC.WhetherthesefindingswouldextendtopersonswithMetSwithout diabetesmellitus,however,isunclear. RecommendedgoallevelsforLDLCare<100mg/dlforhighriskpatients,<130 mg/dlformoderateandmoderatelyhighriskpatients,and<160mg/dlforlowerrisk patients)(Table2).4 ForthosepatientswithpreexistingCVD,recentguidelines suggestanoptionalgoalforLDLCof<70mg/dl.42Moreover,asecondary therapeutictargetrelevantformostpatientswithMetS(manywhowillhavefasting triglyceridesof200mg/dl)isnonHDLC,withthesetargetsbeing30mg/dlhigher thanLDLCtargets(Table2).4 AtertiarytargetislowHDLC,andwhilenospecific goalhasbeenrecommended,itwouldbereasonabletoconsidereffortstoraisethe HDLCabovethosecutpointsdefiningitasacriterionforMetS(40mg/dlinmenor 50mg/dlinwomen). Althoughlifestylemodalities(asdescribedearlier)aremandatorytoadequately addressdyslipidemiainMetS,itisrecognizedthatmanypersonswillrequire multiplepharmacologictherapiestoreachrecommendedgoalsforLDLC,with concomitantimprovementsinHDLCandtriglycerides.Themajorstatinsprescribed atmoderatetomaximaldosageswilllowerLDLCby40%orgreater,alongwith loweringtriglyceridesby25%ormoreandraisingHDLCby510%onaverage, basedonalargestudyconductedinpersonswithMetS.43 However,onceLDLCgoalisreachedandadditionalimprovementsintriglycerides and/orHDLCareneeded,fibrates(particularlyfenofibrate,whichcanbecombined safelywithstatins)orniacinshouldbeadded(orusedasmonotherapyiflowHDLC orelevatedtriglyceridesaretheprincipalproblemandLDLCisalreadyatgoal). EvidencefromseveraltrialssuggestsbenefitsintermsofreducedCVriskor atherosclerosisfromfibrates,niacin,orwhenthesearecombinedwithstatins.4448

TherapeuticGoalsandRecommendationsforClinicalManagementofMetabolicSyndrome Table2 CHD=coronaryheartdiseaseHDLC=highdensitylipoproteincholesterolHbA1c=glycatedhemoglobinLDLC=lowdensitylipoprotein cholesterol. AdaptedwithpermissionfromGrundySM,CleemanJI,DanielsSR,etal.Diagnosisandmanagementofthemetabolicsyndrome:anAmerican HeartAssociation/NationalHeart,Lung,andBloodInstituteScientificStatement.Circulation2005112:273552.

ProportionofCHDEventsPotentiallyPreventableFromOptimalControlofBP,LDLC,andHDLC Figure5 Optimalcontrolofbloodpressure(BPto<120mmHg/<80mmHg),lowdensitylipoproteincholesterol(LDLCto<100mg/dl),andhighdensity lipoproteincholesterol(HDLCto>60mg/dl)inmenandwomen. CHD=coronaryheartdisease. DataadaptedwithpermissionfromWongND,PioJR,FranklinSS,etal.Preventingcoronaryeventsbyoptimalcontrolofbloodpressureand lipidsinpatientswiththemetabolicsyndrome.AmJCardiol200391:14216.

ManagementoftheMetabolicSyndrome (2of2)
ElevatedBloodPressure HypertensionistheleadingMetSriskfactorpredisposingtoincreasedriskforCVmorbidityandmortality,theassociation ofelevatedbloodpressuretoMetSbeingstronglylinkedthroughthecausativepathwayofobesity.Hyperactivityofthe sympatheticnervoussystemandreninangiotensinaldosteronesystemisassociatedwithincreasedbloodpressure, insulinresistance,andendothelialdysfunction,whicharealloftenfoundinpersonswithMetS.49Ithasbeen demonstratedthatelevatedbloodpressureispresentin84%ofmenand77%ofwomenwithMetSintheabsenceof diabetes.7 Thegoalforantihypertensivetherapyinthosewithoutovertdiabetesorchronickidneydiseaseis<140/90mmHg,andif theseconditionsarepresent,<130/80mmHghowever,inpersonswithtype2diabetes,theACCORDtrialdidnotshow overallCVeventstobesignificantlyreducedfrommoreversuslessintensivecontrolofbloodpressure,exceptforstroke prevention.50Despiteelevatedbloodpressureof130139mmHgsystolicor8589mmHgdiastolicfittingthedefinition ofbeingacriterionforMetS,thesepatientswouldonlyqualifyforlifestylemodificationperJointNationalCommittee7 (JNC7)recommendations51however,EuropeanSocietyofHypertensionguidelineswouldsupplementlifestyle modificationwithantihypertensivedrugtherapyforthesepersonswhenatleastthreeofthefollowingCVriskfactorsare present:male>55yearsofageorfemale>65yearsofage,dyslipidemia,smoking,familyhistoryofprematureCVD,left ventricularhypertrophy,andmicroalbuminuria.52 Certainly,mildelevationsofbloodpressurecanbecontrolledwithlifestylemodifications,especiallyweightcontrol, increasedphysicalactivity,alcoholmoderation,sodiumreduction,andincreasedconsumptionoffreshfruitsand vegetables,inaccordancewiththeDietaryApproachestoStopHypertension(DASH)diet.53Inthosewithovert hypertension,pharmacologictherapywilloftenberequiredtoreachgoallevelsofbloodpressure,andwhilesome investigatorshavesupportedtheuseofangiotensinconvertingenzyme(ACE)inhibitors(orangiotensinreceptor blockers[ARBs]inACEintolerantpatients)giventheirdocumentedrenoprotectiveroleinpersonswithdiabetesorkidney disease,noclinicaltrialsspecificallyconductedinpersonswithMetStosupportsuchanapproachexists. Giventhedifficultyofcontrollinghypertension,oftenrequiringtwoorthreemedicationsforitscontrol,theJNC7 recommendsinitiationwithtwodrugs(oratwodrugcombination)forthosewithstage2hypertension(systolicblood pressureof160mmHgorhigherordiastolicbloodpressureof100mmHgorhigher)thosewithdiabetesorchronic kidneydisease(orotherhighriskMetSpatients)wouldrequiresuchpolypharmacyatlowerlevels(e.g.,150mmHg systolicorhigher)toachievethelowerrecommendedgoalsforthesepatients. ElevatedGlucose ElevatedfastingglucoseinpersonswithMetSisdefinedas100mg/dl,andincludesbothimpairedfastingglucoseand diabetes.Theroleoflifestylemanagement,particularlyweightreductionand/orincreasedphysicalactivityindelayingthe onsetoftype2diabetesinthosewithimpairedfastingglucose,iswellestablishedfromresultsoftheDPPtrial,34and theFinnishDiabetesPreventionStudy.35Forpersonswithestablishedtype2diabetesmellitus,pharmacologictherapy isneededtoreachagoallevelofHbA1cof<7%toreducetheriskofmicrovascularcomplications.4 Sucharegimenmay alsopreventmacrovascularcomplications,althoughdataarecurrentlylimited. TheUKPDS(UnitedKingdomProspectiveDiabetesStudy)showedaborderlinesignificant(p=0.052)16%reductionin CVeventsasaresultofintensiveglycemiccontrol,resultinginamedianHbA1clevelof7.0%,comparedto7.9%inthe conventionallytreatedarm,54althoughasubgroupofoverweightpatientsrandomizedtometformindidshowsignificant reductionsinmicrovascularcomplicationsandmyocardialinfarction.55 Morerecently,theACCORDandADVANCE(ActioninDiabetesandVascularDisease:PreteraxandDiamicronModified ReleaseControlledEvaluation)clinicaltrials,however,haveprovidedmixedresultsregardingtheefficacyofintensive glycemiccontrol(comparedtoamoremoderateregimen)toreduceCVeventshowever,theresultsweresuggestiveofa benefitinthosewithoutknownmacrovasculardiseaseatbaseline.56,57 ForpersonswithMetSbutwithoutdiabetes,dataarelimitedregardingtherapeuticbenefitsofantiglycemicmedications. IntheDPPtrial,whilemetforminuseinimpairedglucosetolerantpatientswasassociatedwitha31%reductionofnew diabetesonsetcomparedtoplacebo,thisbenefitwasnotasgreatasthe58%reductionseeninthoseassignedto aggressivelifestylemanagementalone.34 MostrecentlyandperhapsofgreatestinterestaretheresultsfromtheDREAM(DiabetesReductionAssessmentWith RamiprilandRosiglitazoneMedication)study,wherethethiazolidinedionerosiglitazonewasassociatedwithasignificant

(p<0.001)60%reductionintheincidenceofnewdiabetesordeathcomparedtoplaceboovera3yearfollowupperiod however,overallCVeventsweresimilar,andtherewasahigherincidenceofheartfailure(0.5%vs.0.1%,p=0.01)inthe rosiglitazonetreatedsubjects.58 AsubstantialreductioninriskofdevelopingnewdiabeteswasalsoshowninasimilartrialACTNOW(ActosNowforthe PreventionofDiabetes)involvingpioglitazone.59Itisunknownwhetherthereductioninnewonsetdiabeteswilltranslate intoreducedmacrovasculareventratesinthefuture.Atpresent,despitethesepromisingdata,neithermetforminnor thiazolidinedionesarerecommendedsolelyforthepurposeofpreventingdiabetesbecausetheircosteffectiveness, overallbenefits,andlongtermsafetyovernonpharmacologicapproacheshavenotbeendocumented.4 Prothrombotic/ProinflammatoryStates Increasedlevelsoffibrinogen,plasminogenactivatorinhibitor1,andothercoagulationfactorsareseeninpersonswith MetS.Whileaspirintherapyistypicallyrecommendedinhighriskpersons,includingthosewithdiabetesorpreexisting CVD,lowdoseaspirinisaconsiderationforpersonswhoareatmoderatelyhighrisk(e.g.,1020%riskofaCHDevent in10years),whichwillincludemany,butnotallpersonswithMetS.4 Aproinflammatorystateexhibitedbyelevatedcytokines(e.g.,tumornecrosisfactoralphaandinterleukin6)andacute phasereactants(e.g.,CRP,fibrinogen)isfrequentlyseeninpersonswithMetS.4 TheAHA/CentersforDiseaseControl andPreventionhasrecommendedmeasurementofhighsensitivityCRPasareasonabletesttoidentifya proinflammatorystateinintermediateriskindividuals.23Alevelof>3mg/Lcanbeusedtodefineahighriskstate, supportingtheneedforlifestylechanges,particularlyweightreduction,whichhasbeenshowntoreduceCRPlevels.60 Althoughnodrugsareknowntospecificallyreducelevelsofinflammationotherthanaspirin,drugsusedtotreatother riskfactorssuchasstatins,nicotinicacid,fibrates,ACEinhibitors,andthiazolidinedioneshavebeenshowntoreduce levelsofCRPhowever,therearecurrentlynoguidelinesindicatingtheuseofanymedicationsspecificallytoreducea proinflammatorystateapartfromtheirapprovedindicationsforcontrollingotherriskfactors.4

Conclusion
TheMetSisassociatedwithanincreasedriskoffuturediabetesandCVD.WhilepersonswithdiabetesareCHDrisk equivalentsandwarrantaggressiveclinicalmanagement,awidespectrumofglobalriskispresentinpersonswith MetS,necessitatingcarefulassessmentofCVrisk.WhileinitialglobalriskassessmentutilizingFraminghamorother riskalgorithmsisappropriate,considerationofnovelriskmarkersandscreeningforsubclinicalatherosclerosismay improveriskstratificationandidentifythoseatgreatestriskforfutureCVDeventsandmortality. BothprimarycareandsubspecialtyphysiciansshouldassessforthepresenceofMetSineachpatient.Identificationof MetSwillalsogetphysiciansaccustomedtosimultaneoustreatmentofmultipleriskfactors(particularlyabdominal obesity,dyslipidemia,andelevatedbloodpressure),insteadofthetraditionalmodeloftreatmentofriskfactorsin isolation.Mostimportantly,intensifiedeffortsatlifestyletherapies,includingeffectivedietaryandphysicalactivity interventionsguidedbytrainedindividuals,arecrucialifasignificantimpactistobemadeonMetSanditsfuture complications.Inclusionofothermembersofthehealthcareteam,suchasregistereddietitiansandexercise physiologists,toprovidetheneededtimetohelpeducatepatientsonhealthylifestylesandtheiradherence,iscriticalto achievesuccessinmanagementofMetS.

KeyPoints
TheMetSisaclusteringofriskfactorsassociatedwithinsulinresistanceknowntopromoteorincreasetherisk fordevelopmentofdiabetesandCVD. Inconjunctionwithincreasesinobesityworldwide,theprevalenceofMetScontinuestoincreaseapproximately onethirdoftheadultpopulationindevelopedcountriescanbecharacterizedwithMetSbydifferentdefinitions. MetS,evenintheabsenceofdiabetes,isassociatedwithanincreasedriskofCVDandtotalmortality.Thosewith diabetesareconsideredaCVriskequivalent,andareatgreaterriskofCVDandmortality. EfficientandrapiddeterminationofMetSrequiresanassessmentofbloodglucose,triglycerides,andHDLC, whichcanbeperformedbyacliniclaboratoryorpointofcareinstrument,aswellaswaistcircumferenceand bloodpressure.AdditionalassessmentofLDLCandcigarettesmokingwillgiveamorecompleteevaluationof globalcardiometabolicrisk.Finally,optionalscreeningforsubclinicalatherosclerosiscanfurthercomplementCV riskassessment. TheAHAandNationalHeart,Lung,andBloodInstitutehavereleasedguidelinesfortheclinicalmanagementof MetS,whichfocusonlifestylemanagementforabdominalobesityandphysicalinactivity,andclinical managementofatherogenicdyslipidemia,elevatedbloodpressure,elevatedglucose,andprothromboticstate. Amultidisciplinaryteamofhealthcareproviders,includingphysicians,nurses/nursepractitioners,dietitians,and exercisespecialists,iscrucialforachievingsuccessinthemanagementofMetS.

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4.7:CardiovascularDiseasePrevention:ConsiderationsforWomen
Author(s): MarthaGulati,MD,MS,FACC C.NoelBaireyMerz,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. 2. 3. 4. Describetheimpactofcardiovasculardisease(CVD)onwomen. ExplainhowtouseriskassessmenttoolstoestimateCVriskinwomen. ListthemajorriskfactorsforCVDinwomenandidentifythosethatareuniquetowomen. SummarizecurrentguidelinesrelatedtowomenregardingCVDprevention.

Introduction
CVDistheleadingcauseofdeathforwomenintheUnitedStates.1 CVDprevalence andmortalityishigherinwomenthaninmen.1 MorewomenhavediedofCVDthan ofcancer,chroniclowerrespiratorydisease,Alzheimerdisease,andaccidents combined.1 Thedeathrateinfemalesfromcoronaryheartdisease(CHD)wason theriseafter1979,whentherewasagreatdeclineinmortalityduringthesametime periodinmen.Onlyinthislastdecade(since2000)hastherebeenadeclinein mortalityfromCHDinwomen,toarateof95.7per100,000femalesin2007,athird ofwhatitwasin1980.2,3 TheFraminghamHeartStudydemonstratedalateronsetofCVDinwomenthan men,withinitialmanifestationofCVDoccurring10yearslaterinwomencompared withmen,andmyocardialinfarction(MI)asmuchas20yearslater.4 Despitethe lowerprevalenceofCVDinyoungerwomen,theconsequencesofprematureCHD arerelativelyworseinwomen,withatwofoldincreaseinmortalityafteracuteMIin womenundertheageof50yearscomparedwithmenofthesameage(Figure1).5 TheenormityoftheproblemofCVDinwomenunderscorestheneedtoidentifyand preventthedevelopmentofriskfactorsforCVDinwomen,andtoconsiderthoserisk factorsthatareuniquetowomen.

Figure1

GenderDifferencesinDeathRatesDuringHospitalizationforMyocardialInfarction Figure1 AdaptedwithpermissionfromVaccarinoV,ParsonsL,EveryNR,BarronHV,KrumholzHM.Sexbaseddifferencesinearlymortalityafter myocardialinfarction.NationalRegistryofMyocardialInfarction2Participants.NEnglJMed1999341:21725.

AwarenessofCardiovascularDiseaseinWomen
AbarriertothepreventionofCVDinwomenislackofawarenessofthediseaseinwomenandthemedicalcommunity. Overtime,ithasbeenshownthatawarenessinwomenofCVDastheleadingcauseofdeathinwomenhasincreased from1997to2009,butithasremainedstablesince2006,andisdisproportionatelylowerinracialandethnicminorities.6 Inasurveyperformedin2004,fewerthanoneinfivephysiciansrecognizedthatmorewomenthanmendieeachyear fromCVD.7 AwarenessandsymptomrecognitionimpactsmortalityfromCHDinwomen.DatafromCRUSADE(CanRapidRisk StratificationofUnstableAnginaPatientsSuppressAdverseOutcomeswithEarlyImplementation)andtheNCDR ACTIONRegistryGWTG(NationalCardiovascularDataRegistryAcuteCoronaryTreatmentandInterventionsOutcomes NetworkGetWiththeGuidelines)demonstratednoreductionintimefromsymptomonsettohospitalpresentationfor womenwithanMIsincenationalawarenesscampaignsinwomenwereinitiated.Inaddition,womenages4060years hada3.46%longertimetopresentationthanmen.8

RiskStratification
The2010AmericanCollegeofCardiologyFoundation(ACCF)/AmericanHeart Association(AHA)GuidelineforAssessmentofCVRiskinAsymptomaticAdults recommendsassessingaglobalriskscore(suchastheFraminghamriskscore) thatusesmultipletraditionalCVriskfactorsforallasymptomaticadultswithouta clinicalhistoryofCHDasaClassIindication.9 VariationsoftheFraminghamriskscoreexist,withoneversionincludingdiabetesin theriskscorecalculation,andthelaterversioninNationalCholesterolEducation ProgramAdultTreatmentPanel(NCEPATP)IIIconsidersdiabetesaCHD equivalent.Endpointsvaryaswell.DatafromtheNationalHealthandNutrition ExaminationSurvey(NHANES)showedthataFraminghamtyperiskmodelwas usefulinwomenforpredictingCVevents,withaCstatisticof0.829.10However,the focuson10yearriskestimatesmakesriskscoringlessusefulinwomen.11 TheAHAEffectivenessBasedGuidelinesforthePreventionofCVDinWomen2011 updaterecommendsstratifyingwomenintothreecategories:1)highrisk,2)atrisk, and3)optimalrisk,andplacesemphasisonthelifetimeriskofCVDinwomen.12 Highriskstatusisdefinedashavingoneormorehighriskstates,whichinclude theclinicalpresenceofCHD,cerebrovasculardisease,peripheralarterialdisease, abdominalaorticaneurysm,endstageorchronickidneydisease,diabetesmellitus, or10yearpredictedCVDriskof10%,whichisasignificantlylowerthresholdfor definitionofhighriskthanthepreviouscutoffof20%,usedinthepriorguidelines andtheNCEPATPIIIguidelines.12 Atriskstatusisdefinedashavingoneormoreofthefollowingriskfactors: cigarettesmoking,systolicbloodpressure120mmHg,diastolicbloodpressure 80mmHg,ortreatedhypertension,totalcholesterol200mg/dl,highdensity lipoproteincholesterol(HDLC)<50mg/dl,ortreatedfordyslipidemia,obesity (particularlycentraladiposity),poordiet,physicalinactivity,familyhistoryof prematureCVDoccurringinfirstdegreerelativesinmen<55yearsofageorin women<65yearsofage,metabolicsyndrome,evidenceofadvancedsubclinical atherosclerosis(e.g.,coronarycalcification,carotidplaque,orthickenedintima mediathickness),poorexercisecapacityontreadmilltestand/orabnormalheart raterecoveryafterstoppingexercise,systemicautoimmunecollagenvascular disease(e.g.,lupusorrheumatoidarthritis),historyofpreeclampsia,gestational diabetes,orpregnancyinducedhypertension.12 Optimalriskisdefinedassomeonewithoutanyoftheprecedingriskfactors present,withidealCVhealthandbehaviors.Thisincludesatotalcholesterolunder 200mg/dl,bloodpressure<120/80mmHg,fastingbloodglucose<100mg/dl,body massindex(BMI)<25kg/m2 ,nonsmoker,meetingphysicalactivitygoals,and havingahealthydiet(Table1).12 Otherriskscoresexist.TheReynoldsRiskScorecalculatesriskinwomenand men.ItincludeshighsensitivityCreactiveprotein(hsCRP)andfamilyhistoryas riskfactors,andconsiderscerebrovasculareventsasanoutcome.13TheEuropean SCORE(SystematicCoronaryRiskEvaluation)hasbeendeveloped,andincludes ageasameasureofexposuretimetoriskratherthanasariskfactor,and consideredgeographicvariabilitywithinEuropeancountriesasthecalibration metric.14

Table1

ClassificationofCVDRiskinWomen Table1 CHD=coronaryheartdiseaseCVD=cardiovasculardiseaseDASH=DietaryApproachestoStopHypertensionDBP=diastolicblood pressureHDLC=highdensitylipoproteincholesterolIMT=intimamediathicknessSBP=systolicbloodpressure. AdaptedwithpermissionfromMoscaL,BenjaminEJ,BerraK,etal.Effectivenessbasedguidelinesforthepreventionofcardiovasculardisease inwomen2011update:aguidelinefromtheAmericanHeartAssociation.Circulation2011123:124362.

EstablishedRiskFactorsforCardiovascularDisease (1of2)
Age AgeisapowerfulpredictorofCVD,andspecificallyCHD.TheprevalenceofCVD increaseswithageinbothmenandwomen.1 CHDeventslagatleast10yearsin womencomparedtomen.4 IncontrasttothelinearincreaseinCHDinmenasthey age,thereisamoreexponentialincreaseinCHDinwomenaftertheageof60,15 withoneinthreewomenhavingevidenceofCHDaftertheageof65years,in contrastwithoneineightinwomenages4564(Figure2).16TheNCEPATPIII considerstheageof55yearsorabovetobeariskfactorforwomen,comparedto 45yearsformen.Despitethis,thehighestsexdifferenceinCHDmortalityis observedinrelativelyyoungmiddleagedwomen,whereacuteMImortalityistwice thatofagematchedmen,comparedtonosexdifferenceamongelderlywomenand men.5 FamilyHistory AhistoryofCHDinafirstdegreerelativeimpartsriskonanindividual.17TheNCEP ATPIIIandtheAHAguidelinesforthepreventionofCVDinwomendefinesfamily historyofprematureCHDasafirstdegreerelativewithCHDbeforetheageof65 yearsforwomenandage55yearsformen.12,18PrematureCHDinfirstdegree femalerelativesisarelativelymorepotentfamilyhistoryriskfactorcomparedto malerelatives.19The2010ACCF/AHAGuidelineforAssessmentofCVRiskin AsymptomaticAdultsrecommendsthatfamilyhistoryofatherothromboticCVD shouldbeobtainedforCVassessmentinallasymptomaticadults.9 Hypertension Theprevalenceofhypertensionoverallishigherinwomencomparedtomen,but variesbyage.BasedontheNHANESdata,beforetheageof45,morementhan womenhavehypertension.20Fromage4564,theprevalenceofhypertensionin menandwomenwithhypertensionissimilar,butatage65andabove,thereisa higherprevalenceofhypertensioninwomencomparedwithmen.Forwomentaking oralcontraceptives,hypertensionis23timesmorecommonthaninwomennot takingthem.21 TheNHANESsurveyfrom19992004demonstratedthathypertensivewomenwere morelikelytobetreatedthanmen,buttheyarelesslikelytoachievebloodpressure control.22Inadditiontoahigherprevalenceofhypertensioninolderwomen,blood pressurecontrolisalsopoorerinthatagegroup.IntheWHI(WomensHealth Initiative)observationalstudy,only29%ofhypertensivewomenages7079had bloodpressuresunder140/90mmHgcomparedwith41%and37%ofthoseages 5059and6069,respectively.23 Thepresenceofhypertensionisassociatedwithanincreasedriskofthe developmentofcongestiveheartfailure,butthisriskappearstobegreaterin women.FromtheFraminghamHeartStudyandFraminghamOffspringStudy,the riskofdevelopingheartfailureinthosewithhypertensioncomparedwith normotensivesubjectswasabouttwofoldgreaterinmenandthreefoldgreaterin women.24 Womenwhopresentwithstrokesaremorelikelytohaveahistoryofhypertension thanmen.25Thisisespeciallyimportantbecausethelifetimeriskofstrokeis greaterinwomencomparedwithmen,relatedtotheirgreaterlifeexpectancyandthe factthatstrokeratesincreasesubstantiallywithage.26,27 Diabetes DiabetesissuchasignificantriskfactorforCVDthatitisconsideredaCHDrisk equivalent.18ThepresenceofdiabetesisarelativelygreaterriskfactorforCHDin
Figure2

womencomparedwithmen,increasingawomansriskofCHDbythreeto sevenfoldwithonlyatwotothreefoldincreaseindiabeticmen.28Inaddition,the riskoffatalCHDinadiabeticwomanisincreased3.5timesinanondiabetic woman,whichishigherthanseenindiabeticmenwhencomparedwithnondiabetic men(relativeriskoffatalCHDistwicethatofanondiabeticman).28 TheAmericanDiabetesAssociationsuggeststhatdiabetesscreeningshouldbe consideredforwomenandmenovertheageof45years,andthenrepeatedevery3 yearsiftheresultsarenormal.29Forwomenwithahistoryofgestationaldiabetes, screeningfordiabetesshouldoccur612weekspostpartum,andthenevery12 yearsthereafter.30

IncidenceofHeartDiseaseinWomenbyAge Figure2 AdaptedwithpermissionfromWengerNK.Coronaryheartdisease:anolderwoman'smajorhealthrisk.BMJ1997315:108590.

EstablishedRiskFactorsforCardiovascularDisease (2of2)

Dyslipidemia Dyslipidemiaiscommoninwomen,withmorethanhalfofAmericanwomenhavingatotalcholesterol>200mg/dland 36%withalowdensitylipoproteincholesterol(LDLC)>130mg/dl.WomenarelesslikelytohaveanHDL<40mg/dl (13%ofwomencomparedto23%ofAmericansoverall).31Notablyinwomen,adversechangesinthelipidprofile accompanymenopauseandincludeincreasedlevelsoftotalcholesterol,LDLC,andtriglyceridesanddecreasedlevels ofHDLC,32,33althoughitremainsunclearhowmuchriskfactorworseningisrelatedtoaging,asopposedto menopauserelatedhormonalchanges.34 TheATPIIIguidelinesnameLDLCastheprimarytargetoflipidloweringtherapytoreduceriskofCVD.35Furthermore, the2010ACCF/AHAGuidelineforAssessmentofCVRiskinAsymptomaticAdultsdoesnotrecommendmeasurementof lipidparameters,includinglipoproteins,apolipoproteins,particlesize,anddensity,beyondastandardfastinglipidprofile forCVriskassessmentinasymptomaticadults.9 However,calculationofnonHDLC,thedifferencebetweentotal cholesterolandHDLC,isrecommended,andtreatmentguidelinesfortheconsiderationofpharmacotherapyand therapeutictargetsfornonHDLCcholesterolare30mg/dlhigherthanthetherapeutictargetforLDLC.9 Incontrast,the LipoproteinManagementinPatientswithCardiometabolicRiskConsensusstatementfromtheAmericanDiabetes AssociationandtheACCFin2008recommendsthatthemajorityofdyslipoproteinemicpatientswithcardiometabolicrisk factorsbetreatedwithastatin,andthatstatintherapybeguidedwithmeasurementofapolipoproteinBinadditionto LDLCandnonHDLCassessments.36 HDLCisapredictorofCVDinbothmenandwomen,37butmayberelativelymorepredictiveinwomen.3841Inthe Framinghamstudy,meninthelowestquartileforHDLC(HDL<36mg/dl)hada70%greaterriskofMIcomparedwith thoseinthehighestHDLCquartile(HDL>53mg/dl).However,thisriskwasevenstrongerforwomenwithlowHDLC. WomeninthelowestHDLCquartile(HDL<46mg/dl)had67timestherateofcoronaryeventscomparedwiththosein thehighestHDLCquartile(HDL>67mg/dl),evenafteradjustmentforotherriskfactors.41LowlevelsofHDLChave alsobeenshowntobeassociatedwithmoreprogressionofangiographicallysignificantcoronarydiseaseinwomen thaninmen.42HDLClevelsinwomenaveragearound10mg/dlhigherthaninmen,throughouttheirlives.41Thisis reflectedintheEffectivenessBasedGuidelinesforthePreventionofCVDinWomen2011updateguidelinesandtheATP IIIguidelines,asdesiredHDLCisrecommendedtobe50mg/dlinwomen,asopposedto40mg/dlinmen.12,43,44 Smoking In2009,23.1%ofmenand18.3%ofwomenreportedtobaccouse,puttingthematincreasedriskofCVD.45Cigarette smokingmaybemoredetrimentalinwomenthanmenonaverage,femalesmokersdie14.5yearsearlierthanfemale nonsmokers,andmalesmokersdie13.2yearsearlierthanmalenonsmokers.46Cessationofsmokingsubstantially reducesriskmortalityriskamongformersmokersdecreasesnearlytothatofneversmokersin1014yearsafter cessation.47 TheuseoforalcontraceptivesandsmokingimpartsanevengreaterriskofMIthansmokingalone.Theriskofsmoking 25ormorecigarettesadayincreaseswomensriskby12fold,butsmoking25ormorecigarettesadayandtakingoral contraceptionincreasesonesriskby32fold.48 PhysicalActivity/PhysicalFitness PhysicalinactivityisacommonriskfactorforCHD,butsedentarybehaviorismorecommoninwomencomparedwith men(34.5%vs.30.3%).45BetweenNHANESin19881994andNHANESin20012006,theproportionofwomenwho engagedin12ormoreboutsofphysicalactivitypermonthfellfrom49%to43%.49Physicalinactivityisariskfactorfor CVD,givenitsassociationwithhigherbloodpressure,worsecholesterol,poorerglucosemetabolism,andpoorer mentalhealth.Inactivityalsocontributestoobesity. PhysicalinactivityisanindependentriskfactorforacuteMI,50andintheNursesHealthStudy,itwasfoundthatwomen whowalked3045minutesthreetimesaweekreducedtheirriskofMIby50%,independentofages.51Inameta analysisofstudiesofphysicalactivityinwomen,therelativeriskofnewCHDdecreasedacrossincreasinglevelsof activity,witha43%lowerriskofnewCHDinwomeninthehighestphysicalactivitygroupcomparedtotheleastactive women.52 Exercisecapacity,alsoknownasphysicalfitness,hasbeenshowntobeastrongindependentpredictorofallcause mortalityinasymptomaticwomen.53,54IntheSt.JamesWomenTakeHeartProject,asymptomaticwomenwhowere unabletoachieve5metabolicequivalents(METs)onaBruceprotocolhadathreefoldincreasedriskofdeathcompared withwomenwhoachieved>8METs.53Furthermore,theriskofdeathamongasymptomaticandsymptomaticwomen whoseexercisecapacitywas<85%ofthepredictedvalueforagewasatleasttwicethatofwomenwhoseexercise capacitywasatleast85%oftheiragepredictedvalue.55IntheEffectivenessBasedGuidelinesforthePreventionofCVD inWomen2011update,physicalinactivityorpoorphysicalfitnessiscriteriaforplacingawomanintheatriskgroup.12

EmergingRiskFactors (1of2)
MetabolicSyndrome NHANESdatafrom20032006indicatethat32.6%ofwomenmetthecriteriaformetabolicsyndrome,56andthe presenceofmetabolicsyndromeisassociatedwithincreasedriskofthedevelopmentofdiabetes.57Inaddition,those withthemetabolicsyndromeareatanincreasedriskofdevelopingCVD,andthisassociationisstrongestinwomen, witharelativeriskofCHDof2.63,comparedtoarelativeriskof1.98inmen(comparedtotheirsamegender counterpartswithoutthemetabolicsyndrome).58 Obesity ObesityisepidemicintheUnitedStates,withthe20072008NHANESestimationofobesityinwomenat36%.59The risingincidenceofdiabetesiscloselyassociatedwithobesity.DatafromtheFraminghamHeartStudydemonstratea doublingintheincidenceofdiabetesoverthepast30years,mostdramaticallyinthe1990sandprimarilyamong individualswithaBMI>30kg/m2 .60 IntheNursesHealthStudy,obesitywasthemostpowerfulpredictorofdiabetes.WomenwithaBMI>35kg/m2 hada relativeriskfordiabetesalmost40foldgreaterthanwomenwithaBMI<23kg/m2 .61 PatternofobesityappearstoberelatedtoCVD.Elevatedwaistcircumferenceabove35inches,indicativeofvisceral obesity,isrelatedtoelevatedCVDrisk,whereaselevatedwithBMIaloneisnot.62Obesityhasalsobeenassociatedwith anincreasedmortalityfromCVD,wheretheNHANES2004datademonstrateda13%increasedriskinCVdeaths comparedwiththosewithanormalBMI.63 Obesityisalsoassociatedwithadecreaseinlifeexpectancyinwomen,asdemonstratedintheFraminghamHeart Study,wherea40yearoldnonsmokingwomanwouldlose7.1yearsoflifeexpectancyasaresultofobesity.64Despite thesedata,obesityisnotconsideredanindependentriskfactorforCVD,asmuch/alloftheriskisrelatedtotraditional riskfactors,whichareworsenedwithobesity. Furthermore,obesitymaysimplybeamarkerforlowphysicalactivityandfitnesslevels.Priorworkinwomenwhereboth obesityandphysicalfitnessweremeasuredsuggeststhatobesewomenwhoarephysicallyfitarenotatelevatedrisk, andconversely,leanwomenwhoarenotphysicallyfithaveelevatedrisk.65 HighSensitivityCReactiveProtein WhileitisunclearifhsCRPisanindependentriskfactorforCVD,itmayimproveriskdetectioninwomen.6668Inthe WomensHealthStudy,itwasdemonstratedthataglobalriskpredicationmodelthatincludedhsCRPimprovedCVrisk predictioninwomen.66Furthermore,ithasbeendemonstratedthathsCRPisastrongerpredictorofCVeventsin womenthanLDLC.68 Forwomenwiththemetabolicsyndrome,hsCRPmayaddprognosticinformationregardingfuturecardiacrisk.Inone studyofapparentlyhealthywomen,thosewomenwiththemetabolicsyndromeandabaselinehsCRPlevel>3.0mg/L hadalmosttwicetheriskoffutureCVeventsthanthosewiththemetabolicsyndromeandanhsCRP<3.0mg/L.69 MeasuringhsCRPisnotrecommendedinroutineriskassessmentofwomen,butratherasanoptioninthosepersons intheintermediateriskrange,basedontheFraminghamriskscore.70ThebenefitsofassessinghsCRPorany treatmentbasedonthisstrategyremainuncertain. AutoimmuneDisease Systemicinflammationinautoimmunediseasemayaccelerateatherosclerosis.71Rheumatoidarthritisandsystemic lupuserythematosus(SLE)havebeenassociatedwithasignificantlyincreasedrelativeriskforCVD.71 AnanalysisusingdatafromtheCaliforniaHospitalDischargeDatabasefoundthatyoungwomenbetweentheagesof 18and44withSLEare2.27timesmorelikelythantheiragematchedpeerswithoutSLEtobehospitalizedbecauseof acuteMI,3.80timesmorelikelytobehospitalizedbecauseofcongestiveheartfailure,and2.05timesmorelikelytobe hospitalizedbecauseofcerebrovascularaccident.72 Traditionalriskfactorssuchassmoking,familyhistoryofprematuredisease,hypertension,andelevatedcholesteroldo notcompletelyaccountfortheincreasedriskofCHDinpatientswithSLE.Forexample,Manzietal.determinedthat womenintheFraminghamOffspringStudyages3544withSLEwere50timesmorelikelytohaveanacuteMIthan

womenofthesameage.73IntheEffectivenessBasedGuidelinesforthePreventionofCVDinWomen2011update, systemicautoimmunecollagenvasculardiseaseisnowlistedasacriterionfortheatriskriskstatus.12 PolycysticOvarySyndrome Uniquetowomen,polycysticovariansyndrome(PCOS)isassociatedwiththedevelopmentofmanyofthefeaturesof metabolicsyndromeaswellasinsulinresistance.ArecentmetaanalysisfoundthatwomenwithPCOShavean increasedprevalenceofimpairedglucosetolerance,themetabolicsyndrome,anddiabetescomparedtowomenwithout PCOS.74 WhileitisunclearifPCOSisanindependentriskfactorforprematureCVDinwomen,recentdatasuggestelevatedrisk independentofestablishedriskfactorsinolderpostmenopausalwomen.75Furthermore,intheNationalHeart,Lung, andBloodInstitute(NHLBI)sponsoredWISE(WomensIschemiaSyndromeEvaluation)studyofpostmenopausal womenwithPCOS,cumulative5yearCVDeventfreesurvivalwas79%forwomenwithPCOScomparedto89%for womenwithoutPCOS.75

EmergingRiskFactors (2of2)
FunctionalHypothalamicAmenorrhea Itisestimatedthatupto10%ofpremenopausalwomenhavedocumentedovariandysfunction,withalargerproportion havingsubclinicalhormonaldysfunctionthatmayresultinanincreasedriskofCVD.Functionalhypothalamic amenorrhea(FHA)isacauseofapremenopausalovariandysfunctionandoccurswhengonadotropinreleasing hormoneincreases,therebyincreasingluteinizinghormoneinapulsefrequencycausingamenorrheaand hypoestrogenemia.FHAisinducedbypsychologicalstressorsormetabolicinsultsuchascaloricrestrictionorexcessive exercise. Inalargecohortstudy,womenwithmenstrualirregularitieshada50%increasedriskofnonfatalandfatalCHD comparedtowomenwithregularmenstrualcycling.AdditionaldataindicatethatFHAisassociatedwithpremature coronaryatherosclerosisinwomenundergoingcoronaryangiography,76andthatuseoforalcontraceptivetherapymay beprotection.77WhilethesefindingssuggestthatamenorrheaandcyclingirregularitymaybeariskfactorforCVDin women,furtherworkisneeded. PreEclampsiaandPregnancyAssociatedHypertension Forwomenwhoexperiencepreeclampsia,theyhavea3.6to6.1foldgreaterriskofdevelopinghypertension,anda3.1 to3.7foldhigherriskofdevelopingdiabetes,dependingonwhetherthepreeclampsiawasmildorsevere.78Pre eclampsiaisalsoariskfactorforfutureischemicstroke.79 Arecentmetaanalysisfoundthatwomenwithahistoryofpreeclampsiahaveapproximatelydoubletheriskfor subsequentischemicheartdisease,stroke,andvenousthromboemboliceventsoverthe510yearsfollowingthe pregnancy.80TheEffectivenessBasedGuidelinesforthePreventionofCVDinWomen2011updatelisthistoryofpre eclampsiaorpregnancyinducedhypertensionascriteriafortheatriskstatus.12 GestationalDiabetes Uniquetowomenistheriskfactorofgestationaldiabetes.Ahistoryofgestationaldiabetesdoublestheriskofdiabetes inthe4monthspostpartumandremainsalifelongriskfactorfordiabetes.30Fastingglucoselevelsof>121mg/dlduring pregnancyincreasetheriskfordiabetesintheearlypuerperiumby21fold.81TheEffectivenessBasedGuidelinesforthe PreventionofCVDinWomen2011updateincorporatedahistoryofgestationaldiabetesasanatriskcriterion,requiring attentiontoCVriskfactorsandtheimplementationoftherapeuticlifestylechangesinthesewomenthroughouttheir life.12 BreastCancerTherapy Recentadvancementsinbreastcancertreatmenthaveledtoimprovedsurvival,butelevatedriskofCVD.82Evidence suggeststhatbreastcancertherapiesareassociatedwithvaryingdegreesofdirectCVinjuryinconjunctionwith significantindirectlifestylechangesthatalsoreduceCVreserve.82 Whileitisuncertainwhetherbreastcanceroverall,orspecifictherapiesforbreastcancerperse,willemergeasrisk factorsforCVD,thisisanincreasinglyimportantissueinthemanagementofwomensurvivingbreastcancer.Further workisneededtogleantherelativeandabsoluteriskforCVphysicianswhowillincreasinglybecalledupontoevaluate andtreatthesewomen.

OtherIssues
ReproductiveHormones OralContraceptiveTherapy TheAmericanCollegeofObstetriciansandGynecologists(ACOG)andtheWorldHealthOrganization(WHO)have publishedguidelinesonmedicaleligibilityforcontraceptiveuse.83,84Formostwomen,whoarehealthyandfreeofCVD andCVriskfactors,theuseofcombinationestrogenprogestinoralcontraceptivesisassociatedwithlowrelativeand absoluterisksofCVD.85Womenwhoaresmokersovertheageof35,womenwithuncontrolledhypertension,and womenwithahistoryofischemicheartdiseasehaveanunacceptablelevelofriskassociatedwithoral contraceptives.85,86 PostmenopausalHormoneTherapy AmajorityofCVDoccursaftermenopauseinolderwomen,whichisassociatedwithanincreasedburdenofriskfactors forCVD.32Forthisreason,itwasthoughtthatpostmenopausehormonetherapyshouldreducetheriskofCVD,and initialobservationaldatasupportedthishypothesis.Nonetheless,randomizedtrialssuchasHERS(Heartand Estrogen/ProgestinReplacementStudyIandII),WHI,andRUTH(RaloxifeneUseforTheHeart)didnotfindhormone therapyorselectiveestrogenreceptormodulators(SERMs)topreventCVD,intermsofbothprimaryandsecondary prevention.8790 TheAHAEffectivenessBasedGuidelinesforthePreventionofCVDinWomen2011updatestatesthathormone replacementtherapyandSERMSshouldnotbeusedfortheprimaryorsecondarypreventionofCVDandareaClassIII, LevelofEvidenceA,intervention.12

UndertreatmentofWomen
Womenhavebeenshowntoreceiverelativelyfewerpreventiverecommendations,suchaslipidloweringtherapy,aspirin, andlifestyleadvice,thansimilarlyscoredFraminghamriskmen.7,91Whilehypertensivewomenaremorelikelytobe treatedthanmen,theyarelesslikelytohavebloodpressureatgoal.92WomenarelesslikelytobetreatedtogoalLDL C,93withthelargestgenderdisparityingoalLDLCamongstfemalediabetics.94

KeyPoints
CVDistheleadingcauseofmortalityinwomen,andCVDprevalenceandmortalityishigherinwomenthanmen. Framinghamtyperiskmodelsareusefulinwomenforpredictingshortterm(10year)andpopulationrisklonger termriskandindividualriskassessmentforwomenrequireadditionalinformationoralternativestrategies. ThereareanumberofriskfactorsforCVDthatareuniquetowomen. PostmenopausalhormonetherapyshouldnotbeusedforthepreventionofCVD. Womenaremorelikelytobeundertreatedandreceivefewerpreventiverecommendations,suchaslipidlowering therapy,aspirin,andlifestyleadvice,thandomenwithsimilarFraminghamriskscores.

References
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4.8:ExerciseRehabilitationandExerciseforPrevention
Author(s): BarryA.Franklin,PhD,FAHA

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Describetheimpactofexposuretoorthostaticorgravitationalstressonfunctionalcapacityfollowinganacutecoronary eventorrevascularizationprocedure. 2. Definetheminimumorthresholdintensityforimprovingcardiorespiratoryfitnessincardiacpatients,withspecific referencetothepercentageofoxygenuptakereserveorasapercentageofthehighestheartrateachievedduringpeakor symptomlimitedexercisetesting. 3. Explain"theruleof2and3milesperhour"whenprescribingtreadmillexerciseworkloads(metabolicequivalents [METs])forpatients. 4. Summarizetherationaleforupperbodyandresistanceexercisetrainingincoronarypatients,withspecificreferenceto theperformanceofactivitiesofdailyliving. 5. Reviewtherelationshipbetweencardiorespiratoryfitness,expressedasMETs,andallcauseandcardiovascular(CV) mortalityinpatientswithestablishedCVdisease(CVD).

Introduction
Anestimated80millionAmericans(nearlyoneinthree)haveCVDinfact,coronary heartdisease(CHD)andstrokearecurrentlythenumber1andnumber4causesof mortality,respectively.AccordingtotheAmericanHeartAssociation,CHDcaused approximatelyoneofeverysixdeathsintheUnitedStatesin2006.Moreover,1.3 millioncoronaryangioplastyproceduresand448,000coronaryarterybypassgraft surgerieswereperformedthatyear,atacostofover$100billion.In2010,an estimated785,000Americansexperiencedanewcardiacevent,andapproximately 470,000hadarepeatacutemyocardialinfarction(AMI).Accordingly,forliterally millionsofpreviouslyaffectedadultsintheUnitedStates,interventionsthathave beenshowntoreducetheriskofrecurrentCVevents,collectivelyreferredtoas secondaryprevention,includeexercisebasedcardiacrehabilitation. PreventionofatheroscleroticCVDcanbedividedintothreetypes:1)primordial (preventionofriskfactors),2)primary(treatmentofriskfactorsandtheirsequelae [subclinicaldisease]),and3)secondary(preventionofrecurrentCVevents)(Figure 1).1 Thismodulereviewstheroleofstructuredexercise,increasedlifestylephysical activity,orboth,inthesecondarypreventionofCHD,withspecificreferencetoearly convalescenceandexercisebasedrehabilitationafterAMI,outpatientexercise programming,cardioprotectiveadaptationstoexercisetraining,cardiorespiratory fitnessasapredictorofmortality,safetyofexercisebasedcardiacrehabilitation, exertionrelatedCVevents,andcounselingstrategiestoenhanceexercise compliance.

Figure1

RiskFactorFrameworkandtheProgressionofCardiovascularDiseaseWithTypesofPreventionInterventions Figure1 Illustratedareprimordial,primary,andsecondaryprevention,whichhaveenvironmentalmodulators,includinghealthcareaccessthebuilt environmentpublicpolicyinitiativesandlocationswhereinterventionscanbemade(e.g.,personal,family,school,workplace).Cardiovascular healthmarkers/interventionsincludetheAmericanHeartAssociationsLifesSimple7(smokingstatus,bodymassindex,physicalactivity,healthy dietscore,totalcholesterol,bloodpressure,fastingplasmaglucose),pharmacotherapies(e.g.,aspirin,betablockers,statins,angiotensin convertingenzymeinhibitors)whenindicated,andcoronaryrevascularization,whenappropriate. CHF=congestiveheartfailureMI=myocardialinfarctionPAD=peripheralarterialdisease. ReproducedwithpermissionfromFranklinBA,CushmanM.Recentadvancesinpreventivecardiologyandlifestylemedicine:athemedseries. Circulation2011123:227483.

EarlyConvalescenceandExerciseBasedRehabilitationAfter AcuteMyocardialInfarction
Prolongedbedrestasadvocatedbeforethe1950sisnolongerrecommendedin thecareofuncomplicatedpatientswithAMI.Extendedbedresthasbeenshownto resultinphysiologicdeconditioning,restingtachycardia,andasignificantdecrease inaerobiccapacityormaximaloxygenconsumption(VO2 max).2 Other consequencesincludemuscleatrophy,weakness,constipation,urinaryretention, thrombophlebitis,pulmonaryembolism,hypostaticpneumonia,orthostatic intolerance,anddepression. ArmchairTreatment Aclassicreportfrom1952involving81inpatientswithAMIwhoweresubjectedto "armchairtreatment"furtherpromptedliberalizationofactivityrestrictionsoonafter anacutecoronaryevent.3 Therewerenocomplicationsattributedtotheintervention, andthemortalityrateofpatientstreatedwithchairrestwaslowerthanthatofa controlgroupwhohadreceivedconventionaltherapy(e.g.,bedrest).Thistrialas wellasnumerousotherschangedthemanagementofuncomplicatedAMI,andearly mobilizationwasregardedasasafepracticeassociatedwithnumerous physiological,psychological,andeconomicbenefits. ValueofOrthostaticorGravitationalStress Becauselackoforthostaticstressislargelyresponsibleformanyofthedeleterious effectsofprolongedbedrestafterAMI,interventionsdesignedtosimulate gravitationalstress,suchasintermittentsittingorstanding,areincreasinglyused duringhospitalizationandearlyconvalescence.Nearlythreedecadesago, researchersmeasuredVO2 maxinhealthysubjectsbeforeandafter14daysofbed restusingdailytreatmentswithareversegradientgarmentthatsimulatedthe effectsofstanding.Aerobiccapacitydecreasedonly6%insubjectswhoreceived venouspoolingtreatments,comparedwitha15%decreaseinnontreated(control) subjects(Table1).4 Thesedatahaveimportantimplicationsforinpatientsandearly posthospitaldischargeactivityrecommendationsafteranacutecoronaryeventor revascularizationprocedure,especiallycoronaryarterybypasssurgery.5 Accordingly,simpleexposuretoorthostaticorgravitationalstresscanobviatemuch ofthedeteriorationinfunctionalcapacitythatnormallyfollowsanacutecoronary eventorintervention.Electrocardiographically(ECG)monitoredlowleveltreadmillor cycleergometerexerciseforuncomplicatedpatients,soonaftertheevent,may providemoreprecisequantificationoftheirexercisetoleranceandidentifyexertion relatedsignsorsymptomsofresidualmyocardialischemia,threateningventricular arrhythmias,orboth,potentiallysuggestingadditionalmyocardiuminjeopardy and/orelectricalinstabilityandtheneedforadditionaldiagnosticstudiesor interventions. SpontaneousImprovementinMaximalOxygenConsumptionAfterAcute MyocardialInfarction Asignificant23metabolicequivalent(MET1MET=3.5mlO2 /kg/min)increasein aerobiccapacityoftenoccursbetween3and11weeksafterclinicallyuncomplicated AMI,eveninpatientswhoundergonoformalexercisebasedcardiac rehabilitation.6,7Thisispresumablybecauseselfcareandotheroutofhospital activitiesperformedbypatientssoonafterhospitaldischargefrequentlyleadto sustainedincreasesinoxygenuptakethatcanexceedtheminimalor"threshold" intensityfortrainingwhich,formostdeconditionedpatientswithCHD,approximates 45%oftheoxygenuptakereserve.Nevertheless,improvementinaerobiccapacity canbefurtheraugmentedbymedicallydirectedgroup(phaseII)orhomebased exerciserehabilitationprogramssoonafteranacutecoronaryevent.6 PhaseIICardiacRehabilitation:ImpactonMortalityandMedicalManagement Recently,researchersexaminedtherelationshipbetweenthenumberofECG

Table1

monitoredexercisesessionsattendedandsubsequentCVeventsin30,161 Medicarebeneficiarieswhohadcardiacrehabilitation.8 Aftercorrectingforbaseline differences,patientswhoattendedmoresessions,uptoatotalof36,demonstrated adosedependentreductioninmortalityandrecurrentMI. Theauthor'sexperiencesuggeststhatashorttermECGmonitoredphaseIIcardiac exerciseprogramaugmentsthedetectionofsignificantexertionrelatedarrhythmias, increasespatienteducationandselfconfidence,andperhapsmoreimportantly, permitsvalidationoftheexerciseprescriptionandverificationofthepatient'sability toimplementtheexerciseprogramsafelyandeffectively.

MeanChangesinMaximalOxygenUptake(VO2max)BeforeandAfterBedRest Table1 AdaptedwithpermissionfromConvertinoVA,SandlerH,WebbP,AnnisJF.Inducedvenouspoolingandcardiorespiratoryresponsesto exerciseafterbedrest.JApplPhysiol198252:13438.

OutpatientExercisePrescription:TrainabilityModulators (1of2)
Structuredexercisetrainingsessionsshouldincludeapreliminaryaerobicwarmup (approximately10minutes),acontinuousoraccumulatedconditioningphase(30 minutesormultiple10to15minutemoderatetovigorousintensityexercisebouts), andacooldown(510minutes),followedbystretchingactivities. Thewarmupservesasaperiodofadaptationbyincreasingbloodflowand enhancingtheefficiencyofworkingmuscle.Moreover,apreliminaryaerobicwarm upservestodecreasethesusceptibilitytoinjuryandtheoccurrenceofcardiac abnormalitiesthatmaybeprovokedbysuddenstrenuousactivity.9 Theseinclude symptomsorsignsofmyocardialischemia(e.g.,exertionalangina,significantST segmentdepression)and/orelectricalinstability(ventricularectopicactivity).The idealwarmupforanyenduranceactivityisthesameactivity,butatalowerintensity. Hence,individualswhousebriskwalkingduringtheendurancephaseshould concludethewarmupperiodwithamoderatewalkingpace.Similarly,cycle ergometryat150300kgm/minservesasanidealwarmupforindividualswhotrain at450600kgm/min. Thecooldownprovidesagradualrecoveryfromtheintensityofthestressofthe endurancephase.Exercisesofamusclestretchingormusclelengtheningnature arerecommended.Awalkingcooldownenhancesvenousreturnduringrecovery, decreasingthelikelihoodofhypotensionandrelatedadversesequelae(e.g.,post exerciselightheadedness).Italsofacilitatesthedissipationofbodyheat,promotes morerapidremovaloflacticacidthanstationaryrecovery,andamelioratesthe potentialdeleteriouseffectsofthepostexerciseriseinplasmacatecholamines.10 Themosteffectiveexercisesfortheenduranceorconditioningphaseinclude walking,jogging,running,stationarycycleergometry,outdoorcycling,swimming, skippingrope,rowing,andcombinedarmlegergometry.Theminimumorthreshold intensityforimprovingcardiorespiratoryfitness(VO2 max)incardiacpatients approximates45%oftheoxygenuptakereserve,whichcorrespondsto approximately70%ofthehighestheartrateachievedduringpeakorsymptom limitedexercisetesting.11Overtime,theexerciseintensityshouldbeincreasedto 5080%oftheoxygenuptakereserve(ormaximalheartratereserve)tofurther increaseaerobicfitness.Nevertheless,becausesymptomaticorsilentmyocardial ischemiamaybehighlyarrhythmogenic,12theprescribedheartraterangefor enduranceexerciseshouldbesetsafelybelow(10bpm)theischemicECGor anginalthreshold.13 Thereareseveraladjunctivemethodologiestoregulatetheexerciseintensity, includingtheBorgRatingofPerceivedExertion(RPE)scale.TheBorgcategoryand categoryratioscalesconsistof15and12grades,respectively,from6to20and from0to10+(Table2).14Exerciseratedas1215(620scale),between"somewhat hard"and"hard,"or46(010scale),between"somewhatstrongandverystrong,"is generallyconsideredappropriateforcardiorespiratoryconditioning. Improvementinaerobiccapacitywithexercisetraininggenerallyshowsapositive correlationtotheconditioningfrequency,intensity,andduration.Theincreasein VO2 maxamonghealthyindividualsgenerallyshowsaninverserelationshipwith age,habitualphysicalactivity,andbaselinecardiorespiratoryfitness.15Thus,young tomiddleagedsedentaryindividuals(withlowbaselineVO2 max)tendtoshowthe greatestpercentageincreaseinVO2 maxwithexercisetraining.However,incardiac patients,therelationshipismorecomplexchangesinaerobiccapacitymaynot showaninverserelationshipwithinitialVO2 max.Somepatientswithareduced exercisecapacityarelimitedbecausetheyaredeconditionedandthushavegreat potentialtoimprovecardiorespiratoryfitness,whereasothersarelimitedbyleft ventricular(LV)dysfunctionandhavelesspotentialforimprovement. Ithasbeenpreviouslysuggestedthatcardiacpatientsonbetablockadedonot improvegreatlyonexercisetrainingregimens.Althoughasustainedincreasein

Table2

Table3

heartratehastraditionallybeensuggestedasaprerequisitetoachievingan exercisetrainingresponse,patientsonbetablockerscanstillachievetheincrease inmetabolicratenecessaryforfavorableadaptationandimprovement.16,17Thus, patientswithCHDwhoaretreatedwithbetablockerscanderivetheexpected enhancementofcardiorespiratoryfitnessduringexercisetraining,regardlessofthe typeofbetablockerthatisprescribed.15 LimitationsoftheMETConceptforActivityPrescription Themetaboliccostsofmanyhousehold,recreational/training(Table3),and occupationalactivitieshavebeendefinedintermsofoxygenuptake.Consequently, activityprescriptionmaybemadeintermsofMETs.18Thisinvolves recommendationofactivitiesthataresufficientlybelowthemaximalMETlevel achievedduringpeakorsymptomlimitedexercisetesting.Theconceptissimple, easytounderstand,andissometimesusedasatrainingandactivityprescription guide.19 Thereare,however,severalinherentlimitationsinusingestimatedMETsinactivity prescription.Theaerobicrequirementsofselectedphysicalactivitiesrepresent averageenergyexpenditurelevels,andthesemayvaryconsiderablyamong individualsofdifferentage,bodyhabitus,andfitnessandskilllevels.Moreover,it cannotbeassumedthatoccupationalandrecreationalactivitiesdemandingoxygen consumptionequaltothatachievedduringexercisetestingproducessimilarcardiac demands.Additionalfactorsatworkincludethestressesofemotions,excitement, cognition,andenvironment,aswellastheactivationofmusclegroupsnotused duringtheexercisetests. Finally,theoxygencostslistedformanycommonoccupationalanddomestic activitieswerederivedfromcontinuoussteadystatework,whereasactivitiesofdaily lifearepredominantlyintermittent.Iftheactivityisperformedusingaworkrest approach,thetaskcanoftenbeaccomplishedatoxygenconsumptionlevelswell belowthoseestimatedforit.Thus,usingtheMETmethodforprescribingactivitymay considerablyunderestimatethepatient'scapacityforphysicalwork. Insummary,theMETconcepthaslimitedapplicabilityintherecommendationof activitiesforcoronarypatients.Heartrateresponseandratingofperceivedexertion (Table2)14immediatelyafterphysicaleffortusuallyprovideamoreobjective assessmentofcardiacandsomaticdemandsthanmetabolicequivalenttables.

RatingofPerceivedExertion Table2 ReproducedwithpermissionfromBorgGA.Psychophysicalbasesofperceivedexertion.MedSciSportsExerc198214:37781.

ApproximateMetabolicCostofVariousRecreationalandTrainingActivities Table3 METs=metabolicequivalents AdaptedwithpermissionfromFoxSM3rd,NaughtonJP,GormanPA.Physicalactivityandcardiovascularhealth.3.Theexerciseprescription: frequencyandtypeofactivity.ModConceptsCardiovascDis197241:2530.

OutpatientExercisePrescription:TrainabilityModulators (2of2)
TheRuleof2and3MilesperHour Becausemostelderly,deconditioned,overweight/obese,and/orcardiacpatientsprefertowalkatmoderateintensities,it ishelpfultorecognizethatwalkingonlevelgroundat2and3mphspeedsapproximate2and3METs,respectively. Moreover,ata2mphwalkingspeed,each3.5%increaseintreadmillgradeaddsapproximately1METtothegross energycost.Patientswhodesiretowalkata2mphpace,butrequirea5METworkloadfortrainingwouldbeadvisedto add10.5%gradetothisspeed.Forpatientswhocannegotiatethefasterwalkingspeed(3mph),recognizethateach 2.5%increaseintreadmillgradeadds1additionalMETtothegrossenergyexpenditure.Accordingly,aworkloadof3.0 mph,7.5%grade,wouldapproximateanaerobicrequirementof6METs.Usingthispracticalrulecanbehelpfulto cliniciansinprescribingtreadmillexerciseworkloadsfortheirpatients,withouttheneedforconsultingtables, nomograms,orforthatmatter,metabolicformulasorcalculations.15 UpperBodyTraining Lowerextremitytrainingdoesnotnecessarilyconfertrainingbenefittotheupperextremitiesandviceversa.Itistherefore importanttorecognizethepotentialbenefitofbothtypesoftraining.Many"reallife"activitiesrequirearmworktoagreater extentthanlegwork.Consequently,cardiacpatientswhorelyontheirupperextremitiesforoccupationalorrecreational activitiesshouldbeadvisedtotrainthearmsaswellasthelegs,withtheexpectationofimprovedcardiorespiratoryand hemodynamicresponsestobothformsofeffort.20 Althoughupperextremityexerciseforcardiacpatientshasbeentraditionallyproscribed,numerousstudieshavenow demonstratedthesafetyandeffectivenessofarmexercisetraininginpatientswithCHD.21Moreover,itappearsthatthe armsrespondtoaerobicexerciseconditioninginasimilarquantitativeandqualitativemannerasthelegs,showing comparablerelativedecreasesinsubmaximalratepressureproductandincreasesinpeakpoweroutputand cardiorespiratoryfitness,expressedasMETs.22GuidelinesforarmexerciseprescriptionareshowninTable4,and shouldincluderecommendationsregardingthreevariables:theappropriateexerciseheartrate,theworkloadorpower outputthatwillelicitasafeandeffectivemetabolicloadfortraining,andthepropertrainingequipmentormodalities.21 ResistanceTraining Cardiacpatientsoftenlackthephysicalstrengthand/orselfconfidencetoperformcommonactivitiesofdailyliving. Resistancetrainingcanprovideaneffectivemethodforimprovingmuscularstrengthandendurance,preventingand managingavarietyofchronicmedicalconditions,favorablymodifyingselectedcoronaryriskfactors,andenhancing psychosocialwellbeing.23Weighttraininghasalsobeenshowntoattenuatetheratepressureproductwhenanygiven loadislifted,whichmayreducecardiacdemandsduringdailyactivitiessuchascarryinggroceriesorliftingmoderateto heavyobjects.24Moreover,thereareintriguingdatatosuggestthatstrengthtrainingcanincreasemuscularendurance capacitywithoutanaccompanyingincreaseinVO2 max.25Recentstudieshavealsoshownthatmuscularstrengthis inverselyassociatedwithallcausemortalityandthepresenceofmetabolicsyndrome,independentofcardiorespiratory fitnesslevels.26,27 Althoughthetraditionalweighttrainingprescriptionhasinvolvedperformingeachexercisethreetimes(e.g.,threesetsof 1015repetitionsperset),itappearsthatonesetprovidessimilarimprovementsinmuscularstrengthandendurance,at leastforthenoviceexerciser.Consequently,singlesetprogramsperformedatleasttwotimesaweekare recommendedratherthanmultisetprograms,becausetheyarehighlyeffective,lesstimeconsuming,andlesslikelyto causemusculoskeletalinjuryorsoreness.23Suchregimensshouldinclude810differentexercisesataloadthat permits815repetitionsperset. LifestylePhysicalActivity Despitethe"aerobicexerciserevolution"andthemuchheraldedSurgeonGeneral'sreport,28structuredexercise programshavebeenonlymarginallyeffectiveforgettingpeopletobemorephysicallyactive.Althoughthebenefitsof regularexercisearewelldocumented,recentphysicalactivityprevalencedataareparticularlytroubling.Alargeproportion ofadultsfailtoachievetherecommendedmoderatetovigorouslevelsofphysicalactivity(i.e.,moderateintensityaerobic [endurance]physicalactivityforaminimumof30minuteson5dayseachweekorvigorousintensityaerobicphysical activityforaminimumof20minuteson3dayseachweek).29Forexample,walkingisthemostpopularphysicalactivity identifiedbyadults,but<7%ofthosewhoseprimaryexerciseiswalkingaredoingsoattherecommendedfrequency, intensity,orduration.30 Randomizedclinicaltrialshavenowshownthatanalternativeapproachtostructuredexercise(i.e.,increasedlifestyle physicalactivity)hassimilareffectsoncardiorespiratoryfitness,bodycomposition,andcoronaryriskfactorsasa

structuredexerciseprogram.31,32Thesefindingshaveimportantimplicationsforpublichealth,suggestingaviable alternativetosedentarypeoplewhoarenotreadytocomplywithaformalexerciseprogram.Accordingly,physiciansand alliedhealthprofessionalsshouldcounselpatientstointegratemultipleshortboutsofphysicalactivityintotheirdaily lives. Pedometerscanbehelpfulinthisregard,ascanprogramsthatusethem(e.g.,AmericaontheMove33)toenhance awarenessofphysicalactivitybyprogressivelyincreasingdailysteptotals.Accordingtoonesystematicreview, pedometerusersinvariedexerciseinterventionssignificantlyincreasedtheirphysicalactivitybyanaverageof2,491 stepsperdaymorethantheircontrolcounterparts.34

CardioprotectiveAdaptationstoExerciseTraining
RegularexerciseparticipationcandecreasetheriskofinitialandrecurrentCV events,presumablyfrommultiplemechanisms,includingantiatherosclerotic,anti ischemic,antiarrhythmic,antithrombotic,andpsychologicaleffects(Table5).15 Chronicaerobicexercisecanresultinmoderatelossesinbodyweightand moderatetolargelossesinbodyfat.Enduranceexercisecanpromotedecreasesin bloodpressure(particularlyinhypertensives),totalbloodcholesterol,serum triglycerides,andlowdensitylipoproteincholesterol,andincreasesintheaerobic capacityand"antiatherogenic"highdensitylipoproteincholesterolsubfraction. Exercisealsohasfavorableeffectsonglucoseandinsulinhomeostasis, inflammatorymarkers(e.g.,Creactiveprotein),coagulability,fibrinolysis,and coronaryendothelialfunction. Because>40%oftheCVriskreductionassociatedwithexercisecannotbe explainedbychangesinconventionalriskfactors,acardioprotective"vascular conditioning"effecthasbeenproposed,includingenhancednitricoxidevasodilator function,improvedvascularreactivity,alteredvascularstructure,orcombinations thereof.35Decreasedvulnerabilitytothreateningventriculararrhythmiasand increasedresistancetoventricularfibrillationhavealsobeenpostulatedtoreflect exerciserelatedadaptationsinautonomiccontrol,includingreducedsympathetic driveandincreasedvagaltone.Moreover,ischemicpreconditioningbeforecoronary occlusion,atleastinanimalmodels,hasbeenshowntoreducesubsequentinfarct sizeand/orthepotentialformalignantventriculararrhythmias.36,37

Table5

PotentialCardioprotectiveEffectsofRegularPhysicalActivity Table5 CACs=cultured/circulatingangiogeniccellsEPCs=endothelialprogenitorcellsHDL=highdensitylipoproteinHR=heartrateLDL=low densitylipoproteinO2=oxygen.

CardiorespiratoryFitnessasaPredictorofMortality
NumerousstudiesinpatientswithsuspectedorknownCHDhavenowidentifiedalowlevelofcardiorespiratoryfitness, expressedasMETs,asanindependentriskfactorforallcauseandCVmortality.3849Anexercisecapacity<5METs generallyindicatesahighermortalitygroup,whereasanexercisecapacity>9METsidentifiesacohortwithafavorable longtermprognosis,regardlessoftheunderlyingextentofcoronarydisease.4448UsingtheconventionalBruce treadmillprotocol,thesefitnesslevelscorrespondtofailuretocompleteStageI(1.7mph,10%grade)andtheattainment ofStageIII(3.4mph,14%grade)orgreater,respectively.Moreover,each1METincreaseinexercisecapacityappearsto conferan835%reductioninmortality.50Theimportanceofexercisecapacityintheriskstratificationofcoronarypatients hashistoricallyreceivedinadequateattentionbecauseofthetendencyforclinicianstofocusonsigns/symptomsof myocardialischemia,electricalinstability,orboth,aswellasotherclinicalmarkersofprognosis(e.g.,LVejectionfraction [LVEF]). Nevertheless,usingthewelldescribedprimaryangioplastyinAMI(PAMI2)database,investigatorsrecentlyreportedthat exercisecapacitymoreaccuratelypredicts2and5yearmortalitythandoesLVEFinpatientswithSTelevationMIwho wereemergentlytreatedwithpercutaneousintervention.51Accordingly,physiciansandalliedhealthprofessionals shouldencourageunfitmenandwomenwithCHDtoimprovetheirexercisecapacitiesbystartingandmaintaininga regularexerciseprogram,soastomovethemoutoftheleastfit,"highrisk"cohort(bottom20%<5METs).52Onthe otherhand,ifafitnesslevel>9METstrulyexertsacardioprotectiveeffect,ithasenormousimplicationsforcost containmentandmedicalcare.

SafetyofExerciseBasedCardiacRehabilitation
AlthoughtheincidenceofCVcomplicationsduringexerciseisconsiderablygreateramongcardiacpatientsthanamong presumablyhealthyadults,itisstillrelativelylow.AccordingtoonewidelycitedsurveyofCVeventsduringoutpatient cardiacexercisetherapy,theincidenceofcomplicationswasonecardiacarrestper111,996patienthours,oneMIper 293,990patienthours,andonefatalityper783,972patienthoursofexercise.53However,thesedataantedatethecurrent useofriskstratificationprocedures,emergentcoronaryrevascularization,newercardioprotectivepharmacotherapies, ablationtechniques,ventricularassistdevices,andantitachycardiapacemakersandimplantablecardioverter defibrillators.Thus,thesecomplicationratesmaynotnecessarilybeextrapolatedtocontemporarycardiacpatients. MorerecentstudiessuggestonemajorCVcomplicationineveryapproximately58,000participanthoursofoutpatient cardiacexercisetherapynofatalitieswerereported.5456Atthisrate,atypicalrehabilitationprogramwith100patients exercising3hoursperweekcouldexpectoneCVeventevery3.7years(assumingperfectattendanceandno business/holidayclosings).Itshouldbeemphasized,however,thattheabsenceoffataleventsassociatedwithexercise basedcardiacrehabilitationappliesonlytomedicallysupervisedprogramsequippedwithadefibrillatorandappropriate emergencydrugs.Numerousreportsindicatethatthevastmajorityofwitnessed,exertionrelatedcardiacarrests occurringundersuchconditionsaresuccessfullyresuscitated.5356

ExertionRelatedCardiovascularEvents
VigorousphysicalexertionmayprecipitateAMIorcardiacarrestinselectedpersonswithknownoroccultCHD.57By increasingcardiacdemandsandsimultaneouslyshorteningdiastoleandcoronaryperfusiontime,exercisemayevokea transientoxygendeficiencyatthesubendocardiallevel,whichisexacerbatedbyabruptcessationofexercise,arterial vasodilatation,orboth.Becausecardiacdemandsremainhighimmediatelyafterexercise,suddenpostexercise decreasesinbloodpressureandcoronaryperfusionmayincreasethelikelihoodofamyocardialO2 supply/demand imbalance. Ischemiacanalterdepolarization,repolarization,andconductionvelocity,triggeringthreateningventriculararrhythmias that,inextremecases,maybeharbingersofventriculartachycardiaorfibrillation.Symptomaticorsilentmyocardial ischemia,sodiumpotassiumimbalance,increasedcatecholamineexcretion,andcirculatingfreefattyacidscanalso heightenelectricalinstability. TheincidenceofCVeventsduringverylighttomoderateintensityactivitiesisextremelylowandsimilartothatexpected atrest.However,vigorousphysicalexertion(i.e.,6METs),especiallywhenitissudden,unaccustomed,orinvolving shortburstsofhighintensityexercise,appearstotransientlyincreasetheriskofAMIandcardiacarrestinsusceptible individuals.57Theaerobicrequirementsandcardiacdemandsoftheseactivitiesmaybeinfluencedbyteammembers, opponentexpertise,individualskillandfitnesslevels,andsuperimposedenvironmentalstressors,includingaltitude, cold,heat,andhumidity,orcombinationsthereof.Moreover,theexcitementofcompetitionmayincreasesympathetic activityandlowerthethresholdtoventricularfibrillation.Recreationalanddomesticactivitiesthatareassociatedwithan increasedincidenceofCVeventsincludecompetitiverunning,racquetsports,deerhunting,andsnowremoval.58 AlthoughtherelativeriskofAMIandsuddencardiacdeathappearstoincreasetransientlyduringstrenuousphysical exertioncomparedwiththeriskatothertimes,theabsoluteriskissmall.ExerciserelatedCVeventsaremorelikelyto occuramonghabituallysedentaryindividualswithknownoroccultCVDwhowereperformingunaccustomedvigorous physicalactivity.Ontheotherhand,theneteffectofregularphysicalactivityand/orincreasedcardiorespiratoryfitnessis anattenuatedriskofexertionrelatedCVeventsandaloweroverallmortalityfromCVD. RecommendationstopotentiallyreducetheriskofexertionrelatedCVeventsinclude:1)counselhabituallysedentary patientstoavoidunaccustomed,vigorousphysicalactivity(e.g.,racquetsports,waterskiing,heavylifting,shoveling snow)2)advocateappropriatewarmupandcooldownprocedures3)promoteeducationofwarningsigns/symptoms (e.g.,chestpainorpressure,lightheadedness,heartpalpitations/arrhythmiasunusualshortnessofbreath)4) emphasizestrictadherencetoprescribedtrainingpulserates5)usecontinuousorinstantaneousmonitoringin selectedcoronarypatients6)minimizecompetition7)modifyrecreationalgamestodecreasetheenergycostandheart rateresponsetoplay(e.g.,doublesasopposedtosinglestennis)and8)reduceexerciseintensitiesinhot/humid weather.58

StrategiestoEnhanceExerciseCompliance
Althoughmanypatientscanbemotivatedtoinitiateanexerciseprogram, maintainingthecommitmentcanbechallenging.Unfortunately,negativevariables oftenoutweighthepositivevariablescontributingtosustainedinterestand enthusiasm,includinglimitedsupervision/coaching,timeinconvenience, musculoskeletalproblems,exerciseboredom,costissues,lackofprogress awareness,intercurrentillnessorinjury,andworkorfamilyrelatedconflicts. Collectively,thesedeterrentsoftenleadtoadeclineinadherenceandexercise dropouts. Thelikelihoodthatpatientswillorwillnotengageinalongtermstructuredexercise programisgovernedinlargepartbytheirexpectationsorpredictionsoftheeffects andconsequencesofthatbehaviorinrelationtotheirgoalsandobjectives.The StagesofChangeModel(i.e.,precontemplation,contemplation,determination, action,maintenance,relapse)canhelpidentifypatientswhoarepositivelyinterested inor,ontheotherhand,absolutelyunwillingtomakeanexercisecommitment.59 Fortheformersubset,motivationalinterviewingcanbeusedtohelpencouragea behavioraltransformation. Counterproductiveargumentsshouldbeavoidedatthistimeandhealthcare providersshouldstrivetoencouragepatientstohearthemselvesexpresswhythey wantto(orshould)exercise.60Overcominginertia(i.e.,thepatient'ssedentary lifestyle)isamajorbarriertosuccess.Itisalsooneoftheeasiestobstaclesto overcome.Wesimplyneedtogetpatientstoact(e.g.,"athousandmilejourney startswithonesmallstep").Anyactiontheytake,nomatterhowtrivial,mayserveas thecatalysttopermanentlifestylechange. Thefervoroftheprimaryphysicians'recommendationappearstobethesinglemost powerfulpredictorofcardiacrehabilitationparticipation.61Accordingly,increased effortsmustbedirectedatbettereducatingthisgroup(andtheircardiologist contemporaries)regardingthebenefitsofexercisebasedcardiacrehabilitation. Severalresearchbasedcounselingandmotivationalstrategiesmayenhance patientinterestandfacilitateinitiationofandcompliancewithastructuredexercise program,increasedlifestyleactivity,orboth(Table6).

Table6

StrategiestoEnhanceExerciseCompliance Table6

Conclusion
Thechallengeforphysiciansandotherhealthcareprovidersistoreferincreasingnumbersofcoronarypatientstohome, club,ormedicallysupervisedexerciserehabilitationprogramssothatmanymoreindividualsmayrealizethe cardioprotectiveandgeneralhealthbenefitsthatregularphysicalactivitycanprovide.Nevertheless,todriveutilization, referralsmustbecomplementedbyincreasingeffortsatenrollmentandregularparticipation.62Exerciseismedicine, andforthevastmajorityofcoronarypatientswhoarenotregularlyphysicallyactive,theprescriptionremainsunfilled.

FutureDirections
TheAmericanHeartAssociation/AmericanCollegeofCardiologyFoundation(AHA/ACCF)Guidelineson SecondaryPreventionandRiskReductionTherapyforPatientsWithCoronaryandOtherAtheroscleroticand VascularDiseasewereupdatedinlate2011.63TheupdateoftheACCF/AHAGuidelinesfortheManagementof STElevationMyocardialInfarctionisscheduledforpublicationin2012.64Bothguidelinesaddresstheroleof physicalactivity/structuredexerciseandcardiorespiratoryfitnessinreducingtheriskofrecurrentCVevents. Contemporarytranstelephonicandnewermethodsofmonitoringandsurveillancecanextendexercisebased cardiacrehabilitationservicestoothermoreconvenientsettings.Avarietyofthesetechniquesmaybeused betweenpatientsmanagedathomeandrehabilitationstaff,includingregulartelephonecontact,mailoremail (e.g.,completionofactivitylogs),useofpedometersand/orambulatoryactivitytrackingdevices,videorecording, Internet,andtranstelephonicECGmonitoring.65

KeyPoints
Exercisebasedcardiacrehabilitationincludesresearchbasedoutcomes(e.g.,regularphysicalactivity,improved cardiorespiratoryfitness)thathavebeenshowntoreducetheriskofrecurrentCVevents. Simpleexposuretoorthostaticorgravitationalstress,suchasintermittentsittingorstandingduring hospitalizationandearlyhomeconvalescence,canobviatemuchofthedeteriorationinfunctionalcapacitythat normallyfollowsanacutecoronaryeventorintervention. Theminimumorthresholdintensityforimprovingcardiorespiratoryfitnessincardiacpatientsapproximates45% oftheoxygenuptakereserve,whichcorrespondstoapproximately70%ofthehighestheartrateachievedduring peakorsymptomlimitedexercisetesting. Walkingonlevelgroundat2and3milesperhour(mph)approximates2and3METs,respectively.Ata2mph walkingspeed,each3.5%increaseintreadmillgradeaddsapproximately1METtothegrossenergycost.For patientswhocannegotiatea3mphwalkingspeed,recognizethateach2.5%increaseintreadmillgradeadds1 additionalMETtothegrossenergyexpenditure. Structuredexerciseshouldbecomplementedbyupperbodytraining,resistancetraining,andincreasedlifestyle physicalactivity(e.g.,parkingthecarfartherawayfromstoreswhenshopping,avoidingelevators/escalators,walk breaksatwork).Usingapedometercanbehelpfulintrackingdailysteptotals. Amongcoronarypatients,each1METincreaseinexercisecapacityisassociatedwithan835%reductionin mortality.Thereportedreductionsinmortalityarecomparabletoorgreaterthanthoseobservedformany cardioprotectivemedications(e.g.,aspirin,statins,betablockers). TheabsoluteriskofexerciserelatedCVeventsduringoutpatientcardiacexercisetherapyisextremelylow. Recentstudiessuggest1majorCVcomplicationinevery58,000participanthoursofoutpatientcardiacexercise therapynofatalitieswerereported. RecreationalanddomesticactivitiesthatareassociatedwithanincreasedincidenceofCVeventsinsusceptible individualsincludecompetitiverunning,racquetsports,deerhunting,andsnowremoval. Thefervorofthephysicians'recommendationappearstobethesinglemostpowerfulpredictorofexercisebased cardiacrehabilitationparticipation.

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32. AndersenRE,WaddenTA,BartlettSJ,etal.Effectsoflifestyleactivityvsstructuredaerobicexerciseinobese women:arandomizedtrial.JAMA1999281:33540. 33. USDepartmentofHealthandHumanServices.2008PhysicalActivityGuidelinesforAmericans.Availableat: http://www.health.gov/paguidelines/pdf/paguide.pdf.Accessed01/14/2012. 34. BravataDM,SmithSpanglerC,SundaramV,etal.Usingpedometerstoincreasephysicalactivityandimprove health:asystematicreview.JAMA2007298:2296304. 35. GreenDJ,ODriscollG,JoynerMJ,CableNT.Exerciseandcardiovascularriskreduction:timetoupdatethe rationaleforexercise?JApplPhysiol2008105:7668. 36. BillmanGE,SchwartzPJ,StoneHL,etal.Theeffectsofdailyexerciseonsusceptibilitytosuddencardiacdeath. Circulation198469:11829. 37. HullSS,VanoliE,AdamsonPB,etal.Exercisetrainingconfersanticipatoryprotectionfromsuddendeathduring acutemyocardialischemia.Circulation199489:54852. 38. BlairSN,KohlHW3rd,PaffenbargerRSJr,etal.Physicalfitnessandallcausemortality.Aprospectivestudyof healthymenandwomen.JAMA1989262:2395401. 39. BlairSN,KampertJB,KohlHW3rd,etal.Influencesofcardiorespiratoryfitnessandotherprecursorson cardiovasculardiseaseandallcausemortalityinmenandwomen.JAMA1996276:20510. 40. WeiM,GibbonsLW,KampertJB,etal.Lowcardiorespiratoryfitnessandphysicalinactivityaspredictorsof mortalityinmenwithtype2diabetes.AnnInternMed2000132:60511. 41. WeiM,KampertJB,BarlowCE,etal.Relationshipbetweenlowcardiorespiratoryfitnessandmortalityinnormal weight,overweight,andobesemen.JAMA1999282:154753. 42. ChurchTS,KampertJB,GibbonsLW,etal.Usefulnessofcardiorespiratoryfitnessasapredictorofallcauseand cardiovasculardiseasemortalityinmenwithsystemichypertension.AmJCardiol200188:6516. 43. LaukkanenJA,LakkaTA,RauramaaR,etal.Cardiovascularfitnessasapredictorofmortalityinmen.ArchIntern Med2001161:82531. 44. MyersJ,PrakashM,FroelicherV,etal.Exercisecapacityandmortalityamongmenreferredforexercisetesting.N EnglJMed2002346:793801. 45. VanheesL,FagardR,ThijsL,etal.Prognosticsignificanceofpeakexercisecapacityinpatientswithcoronary arterydisease.JAmCollCardiol199423:35863. 46. KavanaghT,MertensDJ,HammLF,etal.Predictionoflongtermprognosisin12,169menreferredforcardiac rehabilitation.Circulation2002106:66671. 47. KavanaghT,MertensDJ,HammLF,etal.Peakoxygenintakeandcardiacmortalityinwomenreferredforcardiac rehabilitation.JAmCollCardiol200342:213943. 48. GulatiM,PandeyDK,ArnsdorfMF,etal.Exercisecapacityandtheriskofdeathinwomen.TheSt.JamesWomen TakeHeartProject.Circulation2003108:15549. 49. LyerlyGW,XuemeiS,LavieCJ,etal.Therelationshipbetweencardiorespiratoryfitnessandallcausemortalityin womenwithimpairedfastingglucoseornondiagnoseddiabetes.MayoClinProc200984:7806. 50. MyersJ,HerbertW,RibislP,FranklinB.Isnewsciencedrivingpracticeimprovementsandbetterpatient outcomes?Applicationsforcardiacrehabilitation.ClinInvestMed200831:E4007. 51. DutcherJR,KahnJ,GrinesC,FranklinB.Comparisonofleftventricularejectionfractionandexercisecapacityas predictorsoftwoandfiveyearmortalityfollowingacutemyocardialinfarction.AmJCardiol200799:43641. 52. FranklinBA,McCulloughPA.Cardiorespiratoryfitness:anindependentandadditivemarkerofriskstratification andhealthoutcomes.MayoClinProc200984:7769. 53. VanCampSP,PetersonRA.Cardiovascularcomplicationsofoutpatientcardiacrehabilitationprograms.JAMA 1986256:11603. 54. VongvanichP,PaulLabradorMJ,MerzCNB.Safetyofmedicallysupervisedexerciseinacardiacrehabilitation center.AmJCardiol199677:13835. 55. FranklinBA,BonzheimK,GordonS,TimmisGC.Safetyofmedicallysupervisedoutpatientcardiacrehabilitation exercisetherapy:a16yearfollowup.Chest1998114:9026. 56. PavyB,IliouMC,MeurinP,etal.Safetyofexercisetrainingforcardiacpatients.ResultsoftheFrenchregistryof complicationsduringcardiacrehabilitation.ArchInternMed2006166:232934. 57. ThompsonPD,FranklinBA,BaladyGJ,etal.Exerciseandacutecardiovascularevents:placingtherisksinto perspective.AScientificStatementfromtheAmericanHeartAssociationCouncilonNutrition,PhysicalActivity,and MetabolismandtheCouncilonClinicalCardiology.Circulation2007115:235868. 58. FranklinBA.Cardiovasculareventsassociatedwithexercise.Theriskprotectionparadox.JCardiopulmRehab 200525:18995. 59. ProchaskaJO,DiClementeC.Transtheoreticaltherapy,towardamoreintegrativemodelofchange.Psychother TheoryResPract198219:27688. 60. FranklinBA,VanheckeTE.Counselingpatientstomakecardioprotectivelifestylechanges:strategiesforsuccess. PrevCardiol20082:503. 61. AdesPA,WaldmannML,McCannWJ,etal.Predictorsofcardiacrehabilitationparticipationinoldercoronary patients.ArchInternMed1992152:10335. 62. BoydenT,RubenfireM,FranklinB.Willincreasingreferraltocardiacrehabilitationimproveparticipation?Prev Cardiol201013:198202. 63. SmithSCJr,BenjaminEJ,BonowRO,etal.AHA/ACCFsecondarypreventionandriskreductiontherapyfor patientswithcoronaryandotheratheroscleroticvasculardisease:2011update:aguidelinefromtheAmerican HeartAssociationandAmericanCollegeofCardiologyFoundation.EndorsedbytheWorldHeartFederationand

thePreventiveCardiovascularNursesAssociation.JAmCollCardiol201158:243246. 64. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarctionexecutivesummary:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(WritingCommitteetorevisethe1999guidelinesforthe managementofpatientswithacutemyocardialinfarction).JAmCollCardiol200444:671719. 65. BaladyGJ,AdesPA,BittnerVA,etal.Referral,enrollment,anddeliveryofcardiacrehabilitation/secondary preventionprogramsatclinicalcentersandbeyond:apresidentialadvisoryfromtheAmericanHeartAssociation. Circulation2011124:295160.

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Thisportionoftheactivityisnotconducivetoprinting.Pleasevisittheonlineversionofthisproducttoseethisitem.

Chapter4Exam
Visittheonlineversionoftheproducttoseethecorrectanswerandcommentary. 1. Whichofthefollowingarelimitationsofthetraditional10yearCHDFRS? A. Underestimationofcardiovascularriskattributabletoage. B. Overestimationofriskinyoungerpatients. C. Overweightingoffamilyhistory. D. Underestimationofriskamongwomen. E. Incorporationofexpensivetesting.

2. WhichstatementisTRUEregardingcardiovascularriskassessment? A. Randomizedclinicaltrialshavedemonstratedabenefitinclinicaloutcomes ofusingglobalclinicalriskscorescomparedtoriskfactorcounting. B. Randomizedclinicaltrialshavedemonstratedabenefitinclinicaloutcomes ofusinghsCRPcomparedtothetraditionalFRS. C. Randomizedclinicaltrialshavedemonstratedabenefitinclinicaloutcomes ofdefininghigh,intermediate,andlowrisk10yearCHDriskfactorsas>20%, 1020%,and<10%,respectively. D. Randomizedclinicaltrialshavedemonstratedthebenefitinclinical outcomesofdesignatingabdominalaorticaneurysmasaCHDequivalent warrantingaggressivesecondarypreventionefforts. E. Prospectivecohortstudieshavedemonstratedtheincrementalprognostic utilityofCACscanningaboveandbeyondclinicalriskscores.

3. WhichofthefollowingstatementsisTRUEregardingtherecentlyproposedlifetime riskscoreforcardiovascularriskassessment? A. Itwasderivedfromamultiethniccohort. B. Itimprovesriskcommunicationtoyoungerindividuals. C. ItusesarestrictiveclinicalendpointfocusingonCHD. D. Itmaybecalculatedviaonlinecalculatorsandtables.

4. MeasurementofCRPforcardiovascularriskrefinementismostappropriatein whichofthefollowing?

A. A54yearoldwomanwithdiabetesmellitusandanLDLCof118mg/dl. B. A50yearoldobesemanwithhypertension,recurrentgoutyflares,andan LDLCof105mg/dl. C. A60yearoldwomanwithhypertension,afamilyhistoryofprematureCHD, rheumatoidarthritis,andanLDLCof108mg/dl. D. A46yearoldmanwithnotraditionalriskfactorsandanLDLCof102mg/dl. E. A56yearoldmanwithhypertension,anHDLCof33mg/dl,andanLDLC of118mg/dl.

5.TNisa55yearoldwomanwhoisreferredtoyouforlipidmanagement.Sheis beingtreatedforhypertension,buthasnohistoryofdiabetesmellitus.Shehada stenttotheleftanteriordescendingarteryplaced3yearsagoforanginalsymptoms andapositivestresstest.Sincethattime,shehashadnofurtheranginasymptoms. Sheisoverweight,buttriestowalkonaregularbasis.Shehasbeenonpravachol sinceherstentplacement. HerBMIis33kg/m2 andwaistcircumferenceis35inches.Herbloodpressureis 125/84mmHgandheartrateis52bpm. Herlipidprofile:Totalcholesterol190mg/dl,LDLC80mg/dl,HDLC40mg/dl,and triglycerides350mg/dl. Inadditiontolifestylemodifications,whichofthefollowingistheappropriatenext stepforthispatient? A. Increasethepravacholdose. B. Startafibrate. C. Nochangeinmedications. D. Addplantstanols/sterols.

6.YournextpatientwasdischargedfromthehospitalafteranonSTsegment elevationMI2monthsago.Heisa55yearoldmanwithahistoryofhypertension anddiabetesmellitus.Herecentlyquitsmoking2monthsago.Hefeelswelland hashadnoepisodesofangina.Thepatientiscurrentlytaking20mgofsimvastatin. Hisbloodpressureis115/84mmHgandheartrateis54bpm.HisBMIis27kg/m2 . Hislipidprofile:Totalcholesterol270mg/dl,LDLC120mg/dl,HDLC40mg/dl,and triglycerides550mg/dl. Whichofthefollowingshouldbetheprimarytargetfortherapyatthistime? A. LDLC. B. HDLC. C. Triglycerides. D. NonHDLC.

7.Yournextpatientisanobesemale,55yearsofage,withoutpriorhistoryofheart disease.Hehasrecentlyundergoneanultrasoundexamofhisabdomen,which demonstratedmildaorticenlargement.Hestoppedsmokingseveralyearsagoand leadsasedentarylifestyle.Hishypertensioniscurrentlywellcontrolled.Hehasno historyofdiabetesmellitus. Onexam,hisbloodpressureis120/80mmHgandheartrateis58bpm.HisBMIis 27kg/m2 .Hislungsareclearheartsoundsarenormalwithnogallops,murmurs, orrubs.Peripheralpulsesareequaland2+throughout.Noperipheraledemais noted. Hislipidprofile:Totalcholesterol240mg/dl,LDLC155mg/dl,HDLC35mg/dl,and triglycerides250mg/dl. Inadditiontolifestylemodification,initialtherapyforthispatientshouldbewhichof thefollowing? A. StatinandfibrateforanLDLC<130mg/dlandtriglycerides<150mg/dl. B. Lifestylemodificationonly. C. StatinforanLDLC<100mg/dl. D. StatinforanLDLC<130mg/dl.

8.A64yearoldwomanwithstentplacementinherleftanteriordescending coronaryartery6monthspriorpresentsforfollowup.Shehashypertension, diabetes,andcoronaryarterydisease.Shedeniesanyanginalsymptomsand walksonthetreadmillfor30minutesdaily. WhichofthefollowingisrecommendedtopotentiallyimproveherCVriskfactorsor CVrisks? A. Consuming1g/dayoflongchainomega3fattyacids. B. VitaminCandEsupplements. C. FolicacidandotherBvitaminssupplements. D. Reducinghersodiumintaketo<2300mg/day.

9.Herphysicalexamrevealsaweightof180lbs,BMIof32kg/m2 ,waist circumferenceof37inches,andBP128/76mmHgonantihypertensivemedication. Laboratorystudiesrevealatotalcholesterolof149mg/dl,LDLCof65mg/dl,HDLC of46mg/dl,triglyceridesof190mg/dl,andaglycatedhemoglobinof7.5%.Shehas madeseveralattemptstoloseweightoverthepastyear,buthasbeen unsuccessful. Whichofthefollowingisanappropriaterecommendationforweightlossinthis patient? A. Bariatricsurgeryisanappropriateoptionandcanimproveherdiabetes management.

B. PhenteraminecanbeconsideredgivenherBMI>30kg/m2 andcomorbid conditions. C. Sheshouldincreaseherexercisetoagoalof60minutesaday. D. Anappropriateinitialgoalis20lbweightlossoverthenext3months.

10.A46yearoldmanwithastrongfamilyhistoryofcoronaryarterydisease,butno othersignificantpastmedicalhistory,presentsforageneralevaluation.Hisweight is210lbs,BMI31kg/m2 ,waistcircumference40inches,andBP135/84mmHg. Laboratorystudiesrevealatotalcholesterolof189mg/dl,LDLCof110mg/dl,HDL Cof38mg/dl,triglyceridesof205mg/dl,andafastingglucoseof107mg/dl.Heisa nonsmokerandonlyexercisessporadically. Whichofthefollowingisthemostappropriaterecommendationforhim? A. Heshouldfocusonconsumingalowfatdiet,givenhisdyslipidemia. B. HeshouldfollowtheDASHdiet,givenhisborderlinebloodpressurevalues. C. Heshoulddrink23alcoholicbeveragesadaytolowerhisCVrisks. D. Heshouldconsumeoilyfishatleast2timesaweek.

11.A51yearoldmanwithhypertensionandhyperlipidemiaisbeingseeninfollow upforsmokingcessation.Heiscurrentlyonlisinopril20mgdaily,amilodipine10 mgdaily,andvarenicline1mgtwicedaily.Hehasbeenhavingtroublesleeping,has poorappetite,andhaslostinterestingolfing,whichhedoeseveryweekend. Whichofthefollowingstepsismostappropriateinhiscare? A. Stopvarenicline. B. Arrangeforfollowupin1week. C. Refertocounseling. D. Startnicotinegum. E. Startbupropion.

12. Whichofthefollowingoccurswithsmokingcessation? A. IncreasedCRP. B. DecreasedLDLC. C. IncreasedHDLC. D. Increasedplatelets.

13.A59yearoldmanisbeingdischargedafterarecentinferiorMI.Hewas counseledaboutquittingsmokingandwasstartedonbupropiontherapy.Your nurseisscheduledtocallhimnextweektofollowup. Whichofthefollowingwillmostlikelyimprovehislongtermabstinence? A. Exerciseprescription. B. Followupin6weeks. C. Nicotineinhaler. D. Referraltoquitline.

14. AllofthefollowingarevalidtreatmentgoalsforpatientswithT2DM,EXCEPT: A. ThetargetHbA1cis<7%. B. ThetargetLDLcholesterollevelinthesettingofpriorMIis<70mg/dl. C. Thetargetsystolicanddiastolicbloodpressureis<130/80mmHg. D. AlladultsshouldbeshouldbeonaspirintherapyforthepreventionofCV complications.

15. WhichofthefollowingstatementsabouttheMetSynisFALSE? A. Itsprevalenceincreaseswithage. B. Insulinresistanceisacentralcomponentofitspathophysiology. C. ItisassociatedwithincreasedriskforMIbutnotfordevelopmentofT2DM. D. Itstreatmentisfocusedonmodificationofriskfactorssuchasdyslipidemia andhypertension.

16. WhichofthefollowingstatementsaboutpioglitazoneisFALSE? A. ItisamongtheclassofdrugsknownasTZDs,whichbindtoandactivatethe nuclearreceptorknownasperoxisomeproliferatoractivatedreceptor(PPAR). B. Risksassociatedwithuseincludeincreasedfluidretentionandcongestive heartfailure. C. Inearly2011theUSFDAissuedawarningstatingthatitisassociatedwith increasedriskofMI. D. Othereffectsincludereducedbloodpressure,markersofinflammation,

carotidintimamedialthickness,andbonemineralization.

17. WhichofthefollowingarenotgenerallyconsideredafeatureoftheMetS? A. Elevatedtriglycerides. B. ElevatedLDLC. C. Elevatedbloodpressure. D. Impairedfastingglucose. E. BandC.

18. WhichofthefollowingisNOTtrueregardingtheMetS? A. MostpersonswithMetSareathighriskofCHD(basedon10yearrisk>20% orhavingpreexistingCHD). B. MostpersonswithMetShaveabdominalobesity. C. MostpersonswithMetShavesuboptimallevelsofbloodpressure(120/80 mmHg). D. PersonswithMetShaveagenerallylowerriskofCHDeventsthando personswithdiabetes. E. AandD.

19. StatintherapycangenerallyberecommendedinpersonswithMetSifwhichofthe followingis/areTRUE? A. TheyalsohavediabetesorCHD. B. TheyfallwithintheNCEPguidelinesforinitiatingtherapybasedonrisklevel andLDLC. C. RegardlessofLDLCbecauseofthesmalldensepatternLDLCgenerally associatedwiththeirhightriglyceridesandlowHDLC. D. AandB. E. BandC.

20.

WhichisthefollowingisFALSEwithrespecttomanagementofCVrisksintheMetS patient? A. BloodpressurecontrolcanofteninvolvetheuseofACEinhibitorsandARBs. B. Managementofprediabetesshouldincludetheuseofthiazolidinediones, whichhavebeenshowntobeeffectiveinpreventingdiabetes. C. AspirinmaybeconsideredforpreventioninthosepersonswithMetSwho areatintermediateriskofCHD. D. ThegeneraltargetforHbA1cis<7%inpersonswithMetSwhoalsohave diabetes,althoughalessstringenttargetmaybeappropriateforthosewithlong standingorpoorlycontrolleddiabetesorwhoalsohavemacrovasculardisease. E. BandC.

21. BasedonthefindingsoftheDPPtrial,onecangenerallyconcludewhichofthe following? A. Alifestylebasedregimenthatincludesweightreductionandphysicalactivity tothedegreespecifiedinthestudycaneffectivelypreventtheonsetofnew diabetesinpersonswithprediabetes B. Metformintherapywasnoteffectiveinthepreventionofdiabetes. C. Metformintherapyshouldbeprescribedasanadjuncttodietandexercisein allpersonswhohaveprediabetes. D. CVeventscanbepreventedfromacombinationofmetforminandlifestyle therapyinpersonswithprediabetes. E. BothAandD.

22.A41yearoldG1P1femaleisseenintheoutpatientclinic.Shewasinitiallyseen byacardiologist3monthsprior,whileinthehospital,whenthediagnosisofpre eclampsiawasmade.Duringthelast2monthsofherpregnancy,shewas persistentlyhypertensiveandwasstartedonmetoprololXL12.5mgdaily.Atthe timeofherdelivery,shedevelopedpreeclampsia,butherdeliveryofherchildwas withoutcomplications,andwithin7daysofdelivery,herbloodpressurereturnedto normalandherobstetricianstoppedhermedications.Sheisnow3months postpartumandcontinuestobeoffallantihypertensivemedicationsandherblood pressureatthisvisitis122/75mmHg. WhichofthefollowingisaTRUEstatement? A. Morementhanwomenhavehypertensioninthoseovertheageof65years. B. Preeclampsiaincreasestheriskoffuturehypertension,stroke,and diabetesdevelopment. C. Womenovertheageof65withhypertensionaremorelikelytohavetheir bloodpressurecontrolledwhencomparedwithyoungerwomenormenofany age. D. Preeclampsiaincreasestheriskoffuturedevelopmentofhypertensionand stroke,butnotdiabetes.

23.A50yearoldG2P2femalewithahistoryofobesity,hypothyroidism,and gestationaldiabetespresentsforassessmentofcardiacrisk.Hermotherhasa historyofhypertensionandstrokeatage70.Herfatherhasdiabetes.Herbrothers haveobesity.Herchildrenareingoodhealth.ThepatientworksasanITconsultant anddoesnotexerciseregularly.Shehasneversmoked. Onphysicalexam,herheartrateis85bpmandbloodpressureis125/80mmHg.In general,sheisobese.Hercardiovascularexamdemonstratesregularrateand rhythm,normalS1 andS2 ,andnomurmurs,rubs,orgallops.Shehasnoedema. Selectedtestingisasfollows:Hertotalcholesterolis180mg/dl.HerHDLCis52 mg/dl. WhichofthefollowingisrecommendedasameasuretopreventCHD? A. Obtainanassessmentofglycemiaataminimumofevery2years. B. Placethepatientonadailyaspirin. C. ObtainanhsCRPlevel. D. Obtainanassessmentofthyroidfunctionevery24years. E. Placethepatientonfolicacid.

24. UsingtheBorgcategoryscale(620)forperceivedexertion,theintensitythatis generallysafeyetappropriateforcardiorespiratoryconditioningshouldapproximate whichofthefollowing? A. 9(verylight). B. 11(fairlylight). C. 13(somewhathard). D. 17(veryhard). E. 19(very,veryhard).

25. Apatientwithcoronarydiseasehasa5METcapacity,andpreferstoexerciseonthe treadmillatacomfortablewalkingspeed,whichhesetsat2mph.Hiscardiologist wantshimexercisingat60%ofhisexercisecapacity,whichisapproximately3 METs.Whichofthefollowingistheprescribedpercenttreadmillgradetoachieve thisaerobicrequirement? A. 1%. B. 2%. C. 2.5%.

D. 3%. E. 3.5%.

26. Allotherfactorsbeingequal,patientswithcoronarydiseaseenrolledinastructured exerciseprogramaremostlikelytoachievethegreatestrelativereductioninCVrisk whentheyincreasetheirexercisecapacityfromthebaselineMETvalueshown,to thefinal(higher)value? A. 46METs. B. 68METs. C. 79METs. D. 1113METs. E. 1214METs.

PleasevisittheonlineversiontoengageinthisExam. 1.ThecorrectanswerisD.ThetraditionalFRSunderestimatescardiovascularriskinwomen. ChoiceAisincorrect.Ageisthepredominantcontributortorisk.ChoiceBisincorrect.Riskin youngerpatientsisunderestimated.ChoiceCisincorrect.Familyhistoryisnotincludedinthe riskequation.ChoiceEisincorrect.OneoftheadvantagesoftheFRSisthelowcostofthe inputsneededforitscalculation. 2.ThecorrectanswerisE.Whileevidencesupportsmatchingintensityoftherapytodegreeof risk,norandomizedcontrolledtrialsprovidingoutcomedatasupportanyoftheapproaches describedinthisquestion.Prospectivecohortstudies,however,dosuggestimproved discriminationandreclassificationusingCACscoringinadditiontotraditionalriskscores. 3.ThecorrectanswerisB.Oneoftheprincipaladvantagesofthelifetimeriskscoreis improvedriskcommunicationofrisktoyoungerpatients.ChoiceAisincorrect.Thelifetimerisk scoredevelopedbyDr.LloydJoneswasderivedfromthelargelyCaucasianFraminghamcohort. ChoiceCisincorrect.Theequationcalculatesriskforthecompositecardiovascularendpointof cardiovasculardeath,MI,coronaryinsufficiency,anginapectoris,atherothromboticstroke,and intermittentclaudication.ChoiceDisincorrect.Todate,therearenoavailabletoolstofacilitate calculationoflifetimeriskscores. 4.ThecorrectanswerisE.ChoiceAisathighriskandadditionaltestingisnotwarranted. ChoicesBandCrepresentchronicinflammatorydiseasesthatcomplicateinterpretationofCRP, whichisanonspecificinflammatorymarker.ChoiceDisalowriskpatient,andadditionaltesting isnotwarranted.AnswerEistheonlyasymptomaticintermediateriskpatientforwhomCRPis appropriate. 5.ThecorrectanswerisB.HerLDLisacceptable,percurrentguidelines.However,the patient'snonHDLiselevatedat150mg/dl.HergoalnonHDLis<130mg/dl.Additionofafibrate oranitrate,togetherwithlifestylemodification,wouldassistherinachievinghernonHDLgoal. References
1. GrundySM,CleemanJI,MerzCN,etal.,onbehalfoftheNationalHeart,Lung,andBloodInstitute AmericanCollegeofCardiologyFoundationAmericanHeartAssociation.Implicationsofrecent clinicaltrialsfortheNationalCholesterolEducationProgramAdultTreatmentPanelIIIguidelines. Circulation2004110:22739.

2. ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.Executive SummaryoftheThirdReportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelon Detection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII). JAMA2001285:248697.

6.ThecorrectanswerisC.Thetriglyceridesareover500mg/dltherefore,theprimarygoalof therapyistolowerthetriglycerides.Oncethetriglyceridesareundercontrol,theLDLshouldbe lowered. References


1. GrundySM,CleemanJI,MerzCN,etal.,onbehalfoftheNationalHeart,Lung,andBloodInstitute AmericanCollegeofCardiologyFoundationAmericanHeartAssociation.Implicationsofrecent clinicaltrialsfortheNationalCholesterolEducationProgramAdultTreatmentPanelIIIguidelines. Circulation2004110:22739. 2. ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.Executive SummaryoftheThirdReportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelon Detection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII). JAMA2001285:248697.

7.ThecorrectanswerisC.Thispatienthasanabdominalaneurysm,whichisaCHD equivalent.Therefore,hisprimarytargetisanLDL<100mg/dl,withanoptiontolowertheLDLto <70mg/dl. References


1. GrundySM,CleemanJI,MerzCN,etal.,onbehalfoftheNationalHeart,Lung,andBloodInstitute AmericanCollegeofCardiologyFoundationAmericanHeartAssociation.Implicationsofrecent clinicaltrialsfortheNationalCholesterolEducationProgramAdultTreatmentPanelIIIguidelines. Circulation2004110:22739. 2. ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.Executive SummaryoftheThirdReportoftheNationalCholesterolEducationProgram(NCEP)ExpertPanelon Detection,Evaluation,andTreatmentofHighBloodCholesterolinAdults(AdultTreatmentPanelIII). JAMA2001285:248697.

8.ThecorrectanswerisA.Onegramperdayoflongchainomega3fattyacids(EPAandDHA) isrecommendedtolowerCVrisksinthosewithCHD.Threetofourgramsadaymaybeneeded tolowertriglycerides.VitaminCandEsupplementshavenotbeenshowninrandomizedtrialsto lowerCVrisks,althoughdietaryantioxidantconsumptionintheformoffruitsandvegetablesare encouraged. Severalrandomizedstudieshavefailedtoshowabenefitoffolicacidsupplementationdespite loweringofhomocysteinelevels.Thosewithhypertensionorthoseatriskofhypertension(e.g., AfricanAmericans,individuals>50years,thosewithdiabetesorchronickidneydisease)should consume<1500mg/dayofsodium. 9.ThecorrectanswerisC.Bariatricsurgeryiscurrentlyarecommendedoptionforthosewitha BMI>40kg/m2oraBMI>35kg/m2 andseriouscomorbidconditionsincludinghypertension, diabetes,sleepapnea,andcoronaryarterydisease.Phenteramineissympathomimeticagent approvedfortheshorttermtreatmentofobesity(<12weeks),butiscontraindicatedinthosewith CVD.Physicalactivitygoalsof60minutesadaymayberequiredforweightloss,andespecially forweightmaintenanceafterweightloss.AccordingtotheNHLBIPracticalGuide,theinitialgoal forweightlossis10%ofbodyweightover6months,oraround18lbsin6months(ratherthan3 months)forthispatient. 10.ThecorrectanswerisD.TheAHArecommendsoilyfishconsumptionatleast2timesa weekforalladults,but1g/dayofEPAandDHAforthosewithCHD.Whilealowfatdietmay lowerhisLDLClevels,thepatientalsohasmetabolicsyndromewithimpairedfastingglucose, borderlinebloodpressures,andhightriglyceridesandlowHDLC.Therefore,replacementoffat withsimplecarbohydratescouldworsensomeoftheseotherparameters.Thus,aglobal approachincludingincreasedconsumptionofoilyfish,vegetables,fruits,andwholegrain,in additiontoloweringsaturatedfatandcholesterolintake,isrecommended. TheDASHdietismosteffectiveforBPloweringinthosewithhypertension,andtherecent OptimalMacronutrientIntakeTrialtoPreventHeartDisease(OmniHeart)study,1 showedthata

DASHtypedietbutwithreducedcarbohydrates,andgreateramountsofplantbasedproteinor monounsaturatedfats,hadmorefavorableeffectsonBPandlipids.Formenwhoconsume alcohol,2orfeweralcoholicbeveragesperdayarerecommended,andalcoholconsumption canfurtherincreasetriglycerides. References AppelLJ,SacksFM,CareyVJ,etal.Effectsofprotein,monounsaturatedfat,andcarbohydrate intakeonbloodpressureandserumlipids:resultsoftheOmniHeartrandomizedtrial.JAMA 2005294:245564. 11.ThecorrectanswerisA.Thispatientisexhibitingsignsandsymptomsofdepression includingdifficultysleeping,changeineatinghabits,andanhedonia.Thisisaknownsideeffect ofvarenicline.Followupandappropriatereferralsshouldbemadeforhisdepression,butthe mostimportantfirststepistodiscontinuethevarenicline. 12.ThecorrectanswerisC.OneofthebenefitsofsmokingcessationistheincreaseofHDL C.ThereisnochangeinLDLClevels.Theplateletnumberdoesnotchange,buttheyareless activatedandthrombogenicwithsmokingcessation.CRPlevelsdecreasewithsmoking cessation. 13.ThecorrectanswerisB.Arrangingforfollowupiscriticalinimprovingthepatient'slong termabstinencefromtobacco.Thehighestabstinenceratesposthospitalizationareseenin patientsseen>1monthaftertheirevent.Nicotineshouldbeusedincautioninthefirst2weeks afterMI.Referraltocardiacrehabilitationwillimprovethislikelihoodoflongtermabstinence,as willreferraltoaquitline. 14.ThecorrectanswerisD. 15.ThecorrectanswerisC. 16.ThecorrectanswerisC. 17.ThecorrectanswerisB. 18.ThecorrectanswerisA. 19.ThecorrectanswerisD. 20.ThecorrectanswerisB. 21.ThecorrectanswerisA. 22.ThecorrectanswerisB.Preeclampsiaincreasestheriskofdevelopinghypertension, stroke,anddiabetes.13Ithasbeenshownthatwomenwhohavehadpreeclampsiahavea3.6 to6.1foldgreaterriskofdevelopinghypertension,anda3.1to3.7foldhigherriskofdeveloping diabetes.1 Ahistoryofpreeclampsiadoublestheriskofsubsequentischemicstrokeandheart diseaseoverthefollowing510yearsafterthepregnancy.2,3 BasedontheNHANESdata,therearemorewomenthanmenwithhypertensionovertheageof 65.4 ThisisparticularlytrueforAfricanAmericanwomen,whohavethehighestrateof hypertension.4 Itisalsoofnotethatwomenovertheageof65arelesslikelytohavetheirblood pressuretreatedtogoal.5 References
1. LykkeJA,LanghoffRoosJ,SibaiBM,FunaiEF,TricheEW,PaidasMJ.Hypertensivepregnancy disordersandsubsequentcardiovascularmorbidityandtype2diabetesmellitusinthemother. Hypertension200953:94451. 2. BrownDW,DuekerN,JamiesonDJ,etal.Preeclampsiaandtheriskofischemicstrokeamongyoung women:resultsfromtheStrokePreventioninYoungWomenStudy.Stroke200637:10559.

3. BellamyL,CasasJP,HingoraniAD,WilliamsDJ.Preeclampsiaandriskofcardiovasculardisease andcancerinlaterlife:systematicreviewandmetaanalysis.BMJ2007335:974. 4. RogerVL,GoAS,LloydJonesDM,etal.,onbehalfoftheAmericanHeartAssociationStatistics CommitteeandStrokeStatisticsSubcommittee.Heartdiseaseandstrokestatistics2011update:a reportfromtheAmericanHeartAssociation.Circulation2011123:e18e209. 5. GuQ,BurtVL,PauloseRamR,DillonCF.Genderdifferencesinhypertensiontreatment,drug utilizationpatterns,andbloodpressurecontrolamongUSadultswithhypertension:datafromthe NationalHealthandNutritionExaminationSurvey19992004.AmJHypertens200821:78998.

23.ThecorrectanswerisA.Inwomenwithahistoryofgestationaldiabetes,theAmerican DiabetesAssociationandAmericanCollegeofObstetriciansandGynecologistsrecommend obtaininganassessmentofglycemia612weekspostpartum.Ifthesearenormal,glycemia shouldbeassessedataminimumofevery2years.1,27 Thispatientfallsintotheatriskcategory,givenherhistoryofobesity,physicalinactivity,and gestationaldiabetes. Fortheatriskorhealthywoman,aspirinmaybeusefulinwomen>65yearsofageifbenefitfor ischemicstrokeandMIpreventionislikelytooutweightheriskofgastrointestinalbleedingand hemorrhagicstroke,andmaybereasonableforwomen<65yearsofageforischemicstroke prevention.2 TheEffectivenessBasedGuidelinesforthePreventionofCardiovascularDiseaseinWomendo notendorseroutinescreeningwithhsCRP.2 PreventiveguidelinesdonotrecommendtheassessmentofthyroidfunctionforCHDprevention. Folicacidshouldnotbeusedfortheprimaryorsecondarypreventionofcardiovasculardisease. References
1. SimmonsD,McElduffA,McIntyreHD,ElrishiM.GestationalDiabetesMellitus:NICEfortheU.S.?A comparisonoftheAmericanDiabetesAssociationandtheAmericanCollegeofObstetriciansand GynecologistsguidelineswiththeU.K.NationalInstituteforHealthandClinicalExcellenceguidelines. DiabetesCare201033:347. 2. MoscaL,BenjaminEJ,BerraK,etal.Effectivenessbasedguidelinesforthepreventionof cardiovasculardiseaseinwomen2011update:aguidelinefromtheAmericanHeartAssociation. Circulation2011123:124362.

24.ThecorrectanswerisC.Researchhasshownthatexerciserated1215(620scale), betweensomewhathardandhard,isgenerallyconsideredappropriateforcardiorespiratory conditioning,approximating5075%oftheVO2 max.Thus,13(somewhathard)wouldrepresent anappropriateintensityforexercisetraining. 25.ThecorrectanswerisE.Accordingtotheruleof2and3mph,ata2mphwalkingspeed, each3.5%increaseintreadmillgradeaddsapproximately1MET. 26.ThecorrectanswerisA.Thecohortofpatientswhoseemtoderivethegreatestbenefit fromanexerciseprogram,arethosewhomoveoutoftheleastfit,highrisksubset(bottom 20%<5METs).Ontheotherhand,thosewithanexercisecapacity>9METsarealreadyinthe lowestriskcategory.