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1、HeartFailure:AnUnderappreciatedComplicationofDiabetes.AConsensusReportoftheAmericanDiabetesAssociationHeartfailure(HF)hasbeenrecognizedasacommoncomplicationofdiabetes,withaprevalenceofupto22%inindividualswithdiabetesandincreasingincidencerates.DataalsosuggestthatHFmaydevelopinindividualswithdiabetes
2、evenintheabsenceofhypertension,coronaryheartdisease,orvalvularheartdiseaseand,assuch,representsamajorcardiovascularcomplicationinthisvulnerablepopulation;HFmayalsobethefirstpresentationofcardiovasculardiseaseinmanyindividualswithdiabetes.Giventhatduringthepastdecade,theprevalenceofdiabetes(particula
3、rlytype2diabetes)hasrisenby30%globally(withprevalenceexpectedtoincreasefurther),theburdenofHFonthehealthcaresystemwillcontinuetorise.ThescopeofthisAmericanDiabetesAssociationconsensusreportwithdesignatedrepresentationfromtheAmericanCollegeofCardiologyistoprovideclearguidancetopractitionersonthebesta
4、pproachesforscreeninganddiagnosingHFinindividualswithdiabetesorprediabetes,withthegoaltoensureaccesstooptimal,evidence-basedmanagementforallandtomitigatetherisksofseriouscomplications,leveragingpriorpolicystatementsbytheAmericanCollegeofCardiologyandAmericanHeartAssociation.BriefOverviewofScopeandNe
5、edTraditionally,thepreventionandmanagementofchroniccomplicationsinindividualswithtype1(T1D)andtype2(T2D)diabeteshavebeenfocusedonnephropathy,retinopathy,neuropathy,andatheroscleroticcardiovasculardisease(ASCVD)(includingischemicheartdisease,stroke,andperipheralvasculardisease)(1).However,heartfailur
6、e(HF)hasbeenrecognizedasacommoncomplicationofdiabetes,withaprevalenceofupto22%inindividualswithdiabetesandincreasingincidencerates(2-4).Thisrecognitionstemsinpartfromtrialsfocusedoncardiovascularsafetyofnewerdrugstotreatdiabetes.DataalsosuggestHFmaydevelopinindividualswithdiabetesevenintheabsenceofh
7、ypertension,coronaryheartdisease,orvalvularheartdiseaseand,assuch,representsamajorcardiovascularcomplicationinthisvulnerablepopulation(5).Giventhatduringthepastdecade,theprevalenceofdiabetes(particularlyT2D)hasrisenby30%globally(6)(withprevalenceexpectedtoincreasefurther),theburdenofHFonthehealthcar
8、esystemwillcontinuetorise.ThescopeofthisAmericanDiabetesAssociation(ADA)consensusreportwithdesignatedrepresentationfromtheAmericanCollegeofCardiology(ACC)istoprovideclearguidanceandtorecommendbestapproachestogeneralinternists,primarycareproviders,andendocrinologistsforHFscreening,diagnosis,andmanage
9、mentinindividualswithT1D,T2D,orprediabetestomitigatetherisksofseriouscomplications,leveragingpriorpolicystatementsbytheACC(7)andAmericanHeartAssociation(AHA)(2).ThisconsensusreportwasdevelopedbythewritinggroupconvenedbyADAwithrepresentationfromACCthroughaseriesofconferencecalls,emails,andindependent
10、workfromMarch2021throughMarch2022.HFEpidemiologyPrevalenceandIncidenceofHFAmongIndividualsWithDiabetesTheepidemiologicassociationbetweenHFanddiabetesiswellrecognized(SUPPlementarvTabIe1)(2,3).Resultsofseverallongitudinalobservationalstudiesofpopulation-basedcohortswithdiabetesandprediabetes,includin
11、gFraminghamHeartStudy(8),FirstNationalHealthandNutritionExaminationSurvey(NHANESI)EpidemiologicFollow-upStudy(9),ReykjavikStudy(10),andtheScottishdiabetesmellitusregister(3),haveshownatwo-tofourfoldincreasedriskofHFamongmenandwomenwithdiabetesorprediabetescomparedwiththosewithout(8,10).Additionally,
12、HFwasthemostcommonfirstpresentationofcardiovasculardiseaseinindividualswithT2Dwhenevaluatedincontemporarycohortsincludingmillionsofpeoplewithlinkedprimarycare,hospitaladmission,diseaseregistry,anddeathcertificaterecordsinEngland.T2DwasanindependentriskfactorforincidentHFandincreasedHF-associatedmorb
13、idityandmortalityduringamedian5.5-yearfollow-upperiod(2,3).ThesedataarefurthersupportedbyrecentevidencefromtheUKProspectiveDiabetesStudy(UKPDS),withincidenceratesofupto11.9per1,000patient-yearsover10yearsoffollow-up(H).TheincidenceandprevalenceofHFarealsoincreasedamongpatientswithT1D,ashighlightedby
14、findingsfromtheScottishdiabetesmellitusregister(3),whiletheSwedishNationalDiabetesRegistry(12)alsoreportedatwotofivetimeshighercrudeincidencerateofHFhospitalizationandmortalityformenandwomenwithT1Dcomparedwiththosewithoutdiabetes(3,13)andhigherprevalenceofdiastolicdysfunction(14).Inarecentsystematic
15、reviewincluding12millionglobalparticipants,investigatorsfoundthatHFmaybeevenmoreprevalentamongmenandwomenwithT1DthanamongthosewithT2D(4).ThedeleteriousrelationshipbetweendiabetesandHFpersistsafteradjustmentforageandrelevantcomorbidities(15).Whilealongerdurationofdiabetesisclearlylinkedtohigherriskfo
16、rincidentHF,theassociationbetweendiabetesandHFisobservedeveninindividualswithrecent-onsetdiabetesoryoungerage(14,16).GlycemiccontrolandinsulinresistancearestronglyassociatedwithriskforincidentHF,suggestingacontinuousrelationshipbetweenanybloodglucoseabnormalityandHFriskandHFprognosis(10,11,17)(SUPPI
17、ememarVTabIe1).PrevalenceandIncidenceofDiabetesAmongPeopleWithHFTherelationshipbetweendiabetesandHFhasauniquebidirectionalassociation.Forexample,insulinresistanceisprevalentin60%ofindividualswithHF(18)andnew-onsetdiabetesiscommonamongthosewithHF,asshowninseverallargecohorts(19,20,21)(SUPPIementarVTa
18、bIe2).GivenheightenedriskfordiabetesinthosewithHF,itisnotsurprisingthatdataindicateahighprevalenceofdysglycemiainthispopulation,withprevalencerangingfrom20%incommunity-basedcohorts(22)to34%inpharmacologicalinterventiontrialsforsystolicHF(23-27),andupto47%inacutedecompensatedHF(28-30).Race-relateddif
19、ferenceshavealsoemergedintheprevalenceofdiabetesinindividualswithHF.Severalstudieshavefoundtheprevalenceofdiabetestobe47-56%forBlack,Hispanic,andNativeAmericanindividualswithHFQI-33).Similarly,amongindividualswithimpairedmyocardialdiastolicrelaxation,diabetesismorecommoninBlack(40.5%)andHispanic(40.
20、9%)individualscomparedwithWhitecounterparts(27.2%)(33).Moreover,intheAsianSuddenCardiacDeathinHeartFailure(ASIAN-HF)registry,41.3%ofindividualsfrom11AsianregionssufferingfromHFwerealsoaffectedbydiabetes(34).Clearerdataareneededregardingrace-relatedimpactsonhealthandriskfortheintersectionofdiabetesan
21、dHF.FewstudieshavedirectlycomparedtheprevalenceandincidenceratesofdiabetesinpeoplewithHFandreducedejectionfraction(HFrEF)versusthosewithpreservedejectionfraction(HFpEF).However,inastudyofhospitalizedindividualswithHF,prevalenceofdiabeteswas40%amongbothHFrEFandHFpEFpatients(35).Morespecificdataregard
22、ingdistributionofdiabetesburdenamongthosewithHFrEFandHFpEFareneeded.KeyPointsBothT1DandT2DincreasetheriskofdevelopingHFacrosstheentirerangeofglucoselevels,butHFmaybemoreprevalentinpeoplewithT1DcomparedwithT2D.ThereisincreasedincidencerateofHFamongpeoplewithdiabetesevenafteradjustmentforageandcomorbi
23、dities.HFmaybethefirstpresentingcardiovascularcomplicationinindividualswithdiabetes.RiskFactorsTheriskfactorsforHFinbothT2DandT1Dincludediabetesduration,poorglycemiccontrol,uncontrolledhypertension,hyperlipidemia,higherBMI,microalbuminuria,renaldysfunction,ischemicheartdisease,andperipheralarterydis
24、ease(2,12,13).Currenttrendssuggestcontrolofmodifiableriskfactorsispoorinthosewithdiabetes(36),emphasizingtheimportanceofcarefulreviewofeachduringclinicalvisits.AnoverviewoftheirimpactonHFispresentedinSUPPIementarVMatnriaLPathophysiologyThepathophysiologyofHFinindividualswithdiabetesiscomplexandrefle
25、ctstheinteractionsofmultipleriskfactorsactinginconcertwithdysregulatedSUbceIIuIarpathwaysthatextendbeyondtheconsequencesofdiabetes-associatedhyperglycemia,allleadingtofunctionalandstructuralchangesinthediabeticheart,asillustratedinSUPPlernemarVFia1.uDiabeticcardiomyopathy,definedasventriculardysfunc
26、tionintheabsenceofcoronaryarterydisease(CAD)andhypertension(37),isanincreasinglyrecognizedentity.SeveralpotentialmechanismscontributingtothedevelopmentofHFindiabetesincluderenin-angiotensin-aldosteronesystem(RAAS)activation,mitochondrialdysfunction,oxidativestress,inflammation,changesinintracellular
27、calciumhomeostasis,increasedformationofadvancedglycationendproducts,andmyocardialenergysubstratealterationsincludingincreasedfreefattyacidutilization,decreasedglucoseutilization,andincreasedoxygenconsumption,resultingindecreasedcardiacefficiency(2,15,37-40)(SUPPIementarVFia1).Despitetheincreasedrate
28、soffattyacidutilization,triglyceridesandotherlipidmetabolites(e.g.,ceramides,diacylglycerol,etc.)accumulateinthemyocardiumofindividualswithdiabetes(15,41).Thesederangementsinmyocardiallipidandglucosemetabolismareincreasinglyrecognizedasanearlyeventinthedeteriorationofdiabetes-relatedcardiacfunction(
29、).Ultimately,theseresultinmaladaptivefibrosis,microvascularrarefaction,Iipotoxicity,anddecreasednitricoxideavailability,leadingtofurthercardiovasculardysfunction.WhilethepredominantmechanismsforHFrEFareconsideredtobedirectmyocardialinjuryduetoassociatedCADorhypertension,aunifyingtheoryofthepathophys
30、iologyofHFpEFsuggestsacentralroleforendothelialandmicrovasculardysfunction(42).Wepointthereadertoreviewarticles(15,43)andscientificstatements(2)thatdescribethesemechanismsindetail.WhileindividualswithT1DexhibitselectstructuralfeaturescharacteristicofanearlyHFpEFphenotypereflectiveofincreasedleftvent
31、riclestiffness(38),therearealsonotableHFsimilaritiesbetweenT1DandT2D.Sharedmechanismsincludecardiovascularautonomicneuropathy(38,44),specificallyassociatedwithimpairedleftventriclediastolicrelaxationinbothpeoplewithT2D(45)andpeoplewithT1D(40),andcoronarymicrovasculardysfunction(46-48)withtheassociat
32、edfunctionaland/orstructuralabnormalitiesofthecoronarymicrovasculature(47,49)resultinginmyocardialperfusionimpairment(39,40).SexdifferencesinendothelialandmicrovascularfunctionmayalsoplaypivotalpathogenicrolesintheetiologyofHFinwomenwithdiabetes(50).Accumulatingevidenceshowsthatwomenwithdiabetesexhi
33、bitgreaterendothelial(51),coronarymicrovascular(52),anddiastolic(48)abnormalitiescomparedwithmenwithdiabetes.UnderlyingmechanismsfortheincreasedriskofHFinwomenwithdiabetesarenotentirelyclear,butsexhormones,adifferentspectrumofcardiovascularriskfactors,and/ordifferencesinprescriptionpatternsbetweenme
34、nandwomenmayplayarole(53).FurtherresearchisneededtoclarifytheexactmechanismscontributingtothisexcessHFriskinwomenwithdiabetes(particularlyT1D)andidentifyappropriatesex-specificpreventionandtreatmentstrategies.KeyPointsIndividualswithdiabetesmaydevelopudiabeticcardiomyopathy,definedasleftventriculars
35、ystolicordiastolicdysfunctionintheabsenceofothercauses(suchasCADorhypertension),withexcessriskinwomen.BothHFpEFandHFrEFmaybepresentindiabetes.ThepathophysiologyofHFinindividualswithdiabetesreflectscomplexinteractionsbetweennumerouspathwayswithdeleteriouseffectsonmyocardialremodelingandmusclefunction
36、.HF:DiagnosisandClinicalStagesHFrepresentsacontinuumofcardiacstructuralabnormalityanddysfunctionandassociatedcardiovascularrisk.UsefulmeansbywhichtoclassifythevariousstagesofHFhavebeenarticulatedbytheACC/AHA/HFSA(HeartFailureSocietyofAmerica)HFguidelines(54)andrecentlyaffirmedbytheUniversalDefinitio
37、nandClassificationofHeartFailuretaskforce(55).DetectionofpeopleathighriskforHF(stageA)orthosewithstageBHF(withoutsymptomsbutwitheitherstructural/functionalcardiacabnormalitiesorelevatedbiomarkersnatriureticpeptidesortroponin)wouldpermitearlierimplementationofeffectivestrategiestopreventordelaythepro
38、gressiontoadvancedHFinindividualswithdiabetes,suchasoptimizinguseofRAASinhibitorsand-blockersorearlierinitiationofothertherapieswithmorerecentlyprovenabilitytopreventprogressionofHFsuchassodiumglucosecotransporter2(SGLT2)inhibitors(SGLT2i).However,theimplementationofavailablestrategiestodetectasympt
39、omaticHFhasbeensuboptimal,highlightingopportunitiesformorewidespreadawarenessofthesubjectandneedformoreassiduousapplicationofbeneficialtherapiesinsuchindividuals.Althoughechocardiographymightidentifysignsofmaladaptiveleftventricularremodeling,itsroutineusehasnotbeenconsideredcost-effectiveandthushas
40、notbeensystematicallyrecommendedforasymptomaticindividuals,includingthosewithdiabetes.Ontheotherhand,theadditionofrelativelyinexpensivebiomarkertestingaspartofthestandardofcaremayhelptorefineHFriskpredictioninindividualswithdiabetes(Table1).Table1BiornarkerSandC)PtirnalCiJtoffSforincidentHFindiabete
41、sCohortThousand&1Study(58)PooledcohortfromAtherosclerosisRiskinCommunities(ARIC),DallasHeartStudy(DHS),andMulti-EthnicStudyofAtherosclerosis(MESA)(56)EXAMINE(57)StVincenfsScreeningtoPreventHeartFailure(STOP-HF)(59)NT-PrOBNPSeleCtedPreVemionOfCardiaCeveNtsiraPoPUIaTiOnOfdiabeticPatientSWithoUtACohort
42、historyofCardiacdisease(PONTIAC)(60)CanagliflozinCardiovascularAssessmentStudy(CANVAS)(131,211)AllHRandORvaluesareshownwith95%Cl.HHF,hospitalizationforHF;HR,hazardratio;hs-cTN,high-sensitivitycardiactroponin;LV,leftventricular;OR,oddsratio.MACE:hospitaladmissionsforacutecoronarysyndrome,HF,stroke,an
43、dcardiacrevascularizationanddeath.StageA:IndividualsatRiskforHFThepresenceofestablisheddiabetesindicatesthatanindividualisatriskforHF,andthesepatientsshouldbeconsideredinthestageAcategoryandatheightenedriskforprogressiontolaterstagesofHF.Inthisstage,theachievedcontrolofglycemiaandotherriskfactorsmay
44、modify(orinsteadamplify)riskforclinicalHF.TheseriskfactorsarediscussedaboveinHfepidemiologyandinSUPPIementarVMaterialandshouldbeconsideredwhenevaluatinganindividualwithdiabetes.KeyPointsAnyonewithadiagnosisofdiabetesandtheriskfactorsshowninFiQ.1isinthestageAcategoryofHF.StageB:Pre-HF/EarlyDetectionA
45、CC/AHA(2,55)stageBHFislinkedtoincreasedrisksofcardiovascularandall-causemortality,aswellasprogressiontomoreadvancedstagesofovertHF(2,54)(Fig,1),andmaybereferredtoasupre-HF.nManyindividualswithdiabetescanbeclassifiedinstageB(54).Figure1STACEAMZfar.STAGCBMRKtl4Ur4rSTAGEC/D Oe*lt HrrtrmM“rMZ MD CAD Sei
46、 WOH Ortbopnra FarMyMMlMKtUnMl JyIeM WeftMligMe Weigbl Rc LVy*Molkactic0 LVdAMtllc4)fMtio LVhypertrophy Chbe IocrtAMdfiUia(PrrMBreaMViewIargeDownIoadslideStepwiseapproachforscreeninganddiagnosisacrossHFstages.CXR,chestX-ray;HFpEF,heartfailurewithpreservedejectionfraction;HFrEF,heartfailurewithreduce
47、dejectionfraction;hs-cTN,high-sensitivitycardiactroponin;JVD,jugularveindistension;LV,leftventricle.Inrecognitionoftheimportanceofbiomarkerstosupportthedetectionofcardiacdysfunctionatanearlystage,thedefinitionofstageBintherecentUniversalDefinitionandClassificationofHeartFailurewasrevisedtoincludeasy
48、mptomaticindividualswithatleastoneofthefollowing:1)evidenceofstructuralheartdisease,2)abnormalcardiacfunction,or3)elevatednatriureticpeptidelevelsorelevatedcardiactroponinlevels(55).Thisapproachiscompatiblewiththe2017ACC/AHAHFFocusedUpdate,whichissuedaclassIlarecommendationforuseofnatriureticpeptide
49、measurementtoidentifyHFatanearlystage(2).SubclinicalStructuralHeartDiseaseSubclinicalchangesthatmaybepresentinstageBincludeventricularsystolicordiastolicdysfunction,LVhypertrophy,chamberenlargement,valvulardisease,and/orevidenceofincreasedfillingpressures.BiomarkersforDetectionofStageBHFSpecifictoindividualswithdia
