HeartFailure上海交通大學醫學院附屬仁濟醫院心內科張清副教授HeartFailure_ZhangQingHeartfailure

isthepathophysiologicalstateinwhichtheheartisunabletopumpsufficientbloodtosatisfythemetabolicdemandsofthebodywithenoughpreload.TheProgressiveDevelopment

ofCardiovascularDiseaseEndstageHeartDiseaseCongestiveHeartFailureVentricularDilationRemodelingArrhythmia&LossofMuscleMyocardialInfarctionMyocardialIschemiaCADAtherosclerosisEndothelialDysfunctionRiskFactorsCoronaryThrombosisForprogressivedurationCongestiveheartfailureisclassifiedintoacuteandchronicheartfailureCongestiveheartfailureisclassifiedintoleftside,rightsideandbiventricularheartfailureForanatomicaltypeChronicheartfailureHeartFailure_ZhangQingCauses

Fundamentalcauses:impairmentofmyocardium,suchasAMI,cardiomyopathy,myocarditisoverloadingoftheheart,suchashypertension,aorticstenosis,mitralstenosis,emphysema,aorticinsufficiency,mitralinsufficiency,VSD,PDA,ASD.diminishedLVcompliance,suchasventricularhypertrophy

Precipitatingfactors

infection,especiallypulmonaryinfection,fever

physical,environmental,oremotionalstressincreasedsodiumloadarrhythmia,pulmonaryembolipregnancyanddelivery

anemia,bleeding,excessivetransfusionPathophysiologyofheartfailure

Impairedmyocardium↓Cardiacoutput↓,heartfailure↓NeurohumoralstimulationRASandsympathetic-adrenergic↑↓↓VasoconstrictionincreasedheartrateSaltandwaterretentionincreasedenergy(augmentspreload)expenditureHypertrophy↓LeadstodeteriorationanddeathofcardiaccellEffectsofNeurohormonalStimulationinHeartFailureHeartHeartrateContractilityStrokevolumeCardiacoutputConductionvelocityMyocardialoxygenconsumptionPeripheralCirculationArterialvasoconstrictionVenoconstrictionSystemicvascularresistanceRedistributionofbloodflowRenalvasoconstrictionPathophysiologyofHeartFailure:LeftVentricularRemodelingLeft-ventricular(LV)remodelingisdefinedasachangeinLVgeometry,massandvolumethatoccursoveraperiodoftimeHeartFailure_ZhangQingVentricularRemodeling:

CompensatoryMechanismDilationHypertrophyGlobularshapeShortterm: CompensatoryLongterm: Harmful

DETERMINANTSOFVENTRICULARFUNCTION

STROKE

VOLUMEPRELOADCONTRACTILITYCARDIACOUTPUTHEART

RATE-SynergisticLVcontraction

-LVwallintegrity

-ValvularcompetenceAFTERLOADViciousCycleofHeartFailureMyocardialdysfunctionDiminishedCardiacoutputDiminishedrenalbloodflowReninreleaseAngiotensinIIAldosteroneIncreasedSympatheticActivityVasoconstrictionIncreasedforceandrateofmyocardialcontractionIncreasedcardiacworkloadRenalretentionofsodiumandwaterIncreasedvenousreturnEdemaPathophysiologyandTherapeuticApproachestoHeartFailureLVFunctionCardiacOutputNeurohormonalActivationSaltandWaterRetentionPeripheralvasoconstrictionBloodflowVasodialtorsACEInhibitorsDiureticsACEInhibitorsBlockersDigoxinCommonSymptomsofHeartFailureDyspneaonexertionParoxysmalnocturnaldyspneaOrthopneaFatigueLowerextremityedemaCough,usuallyworseatnightNausea,vomiting,anorexia,RUQpain,ascitesNocturiaSleepdisordersIncreasedabdominalgirthCommonPhysicalFindings

ofHeartFailureElevatedjugularvenouspressureHepatojugularrefluxDisplacedapicalimpulseS3gallopPulmonaryralesHepatomegalyPeripheraledemaAscitesClinicalmanifestationLeftheartfailure:SOB,cough,rales,gallopRightheartfailure:gastrointestinalcongestion,anorexia,nausea,asenseoffullnessaftermeals,hepato-jugularreflux,swellingoffeetoranklesLowcardiacoutput:fatigueandweakness,oliguriaBiventricularheartfailure:bothclinicalmanifestationofleftandrightheartfailure,oneofwhichmaybepredominant.FunctionalClassificationAclassificationofpatients

withheartdiseasebasedontherelationbetweensymptomsandtheamountofeffortrequiredtoprovokethemhasbeendevelopedbytheNewYorkHeartAssociation.Class1---Nolimitation

Ordinaryphysicalactivitydoesnotcauseunduefatigue,dyspnea,orpalpitationClass2---Slightlimitationofphysicalactivity

Suchpatientsarecomfortableatrest.Ordinaryphysicalactivityresultsinfatigue,palpitation,dyspnea,oranginaClass3---Markedlimitationofphysicalactivity

Althoughpatientsarecomfortableatrest,lessthanordinaryactivitywillleadtosymptoms.Class4---Inabilitytocarryonanyphysicalactivity

Symptomsofcongestivefailurearepresentevenatrest.Withanyphysicalactivity,increaseddiscomfortisexperienced.ComplicationPulmonaryembolism,Congestivehepatomegaly,Ascites,Hepaticsclerosis,ImbalanceofelectrolytesLaboratoryFindingVenouspressure:elevatedChestroentgenogram:cardiothoracicratio,pulmonaryedema—Kerley’slines,perivascularandsubpleuraledema(butterflyandpleuraleffusion)Invasiveassessmentofcardiacfunction:ventricularpressure,PCWP,EchoandradionuclideDiagnosisanddifferentialdiagnosisLeftheartfailure:Symptoms:orthopneaandparoxysmalnocturnaldyspneaSigns:moistandfinecrepitantrales,PCWP>25mmHgRightheartfailure:Symptoms:anorexia,nausea,asenseoffullnessaftermealsandconstipationSigns:peripheraledema,congestiveheptomegaly,hepatojugularreflux,ascitesDifferentialdiagnosis

Differentiationbetweencardiacandpulmonarydyspnea:Chronicobstructivelungdiseaseisusuallyassociatedwithsputumproduction,thedyspneaisrelievedafterpatientsridthemselvesofsecretionsbycoughingratherthanspecificallybysittingupAcutecardiacasthma(paroxysmalnocturnaldyspneawithprominentwheezing)usuallyoccursinpatientswhohaveobviousclinicalevidenceofheartdiseaseAirwayobstructionanddyspneathatrespondtobronchodilatorsorsmokingcessationfavorapulmonaryoriginofthedyspnea,whiletheresponseofthesemanifestationstodiureticssupportsheartfailureasthecauseofdyspneaTherapyTogetridofinductionfactorsandcomplicationUsesofinotropicagents:digitalis,dobutamineUsesofdiureticsUsesofvasodilatorsOthertreatment:sedativedrugandoxygensupply

Survival Morbidity Exercisecapacity Qualityoflife Neurohormonalchanges ProgressionofCHF SymptomsTREATMENTOBJECTIVES

TREATMENTCorrectionofaggravatingfactorsMEDICATIONSEndocarditisObesityHypertensionPhysicalactivityDietaryexcessPregnancyArrhythmias(AF)InfectionsHyperthyroidismThromboembolism

TREATMENTPHARMACOLOGICTHERAPYDIURETICSINOTROPESVASODILATORSNEUROHORMONALANTAGONISTSOTHERS(Anticoagulants,antiarrhythmics,etc)

PHARMACOLOGICTHERAPYDIURETICS

Improved

symptomsDecreased

mortalityPreventionofCHFyes??Vasodil.(Nitrates)yesyes?DIGOXINyes=minimalINOTROPESyesmort.?Otherneurohormonalcontroldrugsyes+/-?ACEIyesYESyesNeurohumoralControlNOyesnonoYESYES

TREATMENTNormalAsymptomatic

LVdysfunctionEF<40%SymptomaticCHFNYHAIIInotropesSpecializedtherapyTransplantSymptomaticCHFNYHA-IVSymptomaticCHFNYHA-IIISecondarypreventionModificationofphysicalactivityACEIDiureticsmildNeurohormonal

inhibitors

Digoxin?Loop

DiureticsCortexMedullaThiazidesInhibitactiveexchangeofCl-Na

inthecorticaldilutingsegmentofthe

ascendingloopofHenleK-sparingInhibitreabsorptionofNainthedistalconvolutedandcollectingtubuleLoopdiureticsInhibitexchangeofCl-Na-KinthethicksegmentoftheascendingloopofHenleLoopofHenleCollectingtubuleDIURETICSTHIAZIDES

MECHANISMOFACTIONExcrete5-10%offilteredNa+

EliminationofKInhibitcarbonicanhydrase:

increaseeliminationofHCO3

Excretionofuricacid,CaandMgNodose-effectrelationshipLOOPDIURETICS

MECHANISMOFACTIONExcrete15-20%offilteredNa+

EliminationofK+,Ca+andMg++

Resistanceofafferentarterioles-

CorticalflowandGFR-ReleaserenalPGs-NSAIDsmayantagonizediuresisK-SPARINGDIURETICS

MECHANISMOFACTIONEliminate<5%offilteredNa+

InhibitexchangeofNa+forK+orH+Spironolactone=competitive

antagonistforthealdosteronereceptorAmilorideandtriamtereneblock

Na+channelscontrolledbyaldosteroneVolumeandpreloadImprovesymptomsofcongestionNodirecteffectonCO,but

excessivepreloadreductionmay

ImprovesarterialdistensibilityNeurohormonalactivatioLevelsofNA,AngIIandARPException:withspironolactoneDIURETICEFFECTSDIURETICS

ADVERSEREACTIONS

ThiazideandLoopDiureticsChangesinelectrolytes: Volume Na+,K+,Ca++,Mg++

metabolicalkalosisMetabolicchanges: glycemia,uremia,gout LDL-CandTGCutaneousallergicreactionsDIURETICS

ADVERSEREACTIONSK-SPARINGDIURETICSChangesinelectrolytes

Na+,K+,acidosisMusculoskeletal:Cramps,weaknessCutaneousallergicreactions:Na+K+K+Na+Na+Ca++Ca++Na-KATPaseNa-CaExchangeMyofilamentsDIGOXINCONTRACTILITYDIGOXIN

PHARMACOKINETIC

PROPERTIESOralabsorption(%)Proteinbinding(%)Volumeofdistribution(l/Kg)HalflifeEliminationOnset(min)i.v.oralMaximaleffect(h)i.v.oralDurationTherapeuticlevel(ng/ml)60-75256(3-9)36(26-46)hRenal5-3030-902-43-62-6days0.5-2

DIGOXIN

DIGITALIZATIONSTRATEGIES(mg)0.125-0.5/d0.25/di.v0.5+0.25/4hILD:0.75-1oral12-24h0.75+0.25/6h1.25-1.5oral2-5d0.25/6-12h1.5-1.75Loadingdose(mg)MaintenanceDose

ILD=averageINITIALdoserequiredfordigoxinloading

DIGOXIN

HEMODYNAMICEFFECTS

Cardiacoutput

LV

ejectionfraction

LVEDP

Exercise

tolerance Natriuresis

Neurohormonal

activation

DIGOXIN

NEUROHORMONAL

EFFECTS

Plasma

Noradrenaline

Peripheralnervoussystemactivity

RAASactivity

Vagal

tone

WORSENINGOFCHF%p=0.001DIGOXIN:0.125-0.5mg/d(0.7-2.0ng/ml)EF<35%ClassI-III(digoxin+diuretic+ACEI)AlsosignificantlydecreasedexercisetimeandLVEF.DIGOXIN

EFFECTONCHFPROGRESSIONRADIANCENEnglJMed1993;329:1Placebon=93DIGOXINWithdrawalDIGOXINn=853010020100802004060Days

50403020100Placebon=3403DIGOXINn=3397480122436OVERALLMORTALITY%DIGNEnglJMed1997;336:525Monthsp=0.8

DIGOXIN

LONGTERMEFFECTSSurvivalsimilartoplaceboFewerhospitaladmissionsMoreseriousarrhythmiasMoremyocardialinfarctions

DIGOXIN

CLINICAL

USESAFwithrapidventricularresponseCHFrefractorytootherdrugsOtherindications?Canbecombinedwithotherdrugs

DIGOXIN

CONTRAINDICATIONSABSOLUTE: -DigoxintoxicityRELATIVE -AdvancedA-Vblockwithoutpacemaker -BradycardiaorsicksinuswithoutPM -PVC’sandTV -Marked

hypokalemia -W-P-Wwithatrialfibrillation

DIGOXINTOXICITY

CARDIACMANIFESTATIONSARRHYTHMIAS:

-Ventricular(PVCs,TV,VF)

-Supraventricular(PACs,SVT)BLOCKS: -S-AandA-VblocksCHFEXACERBATION

DIGOXINTOXICITY

EXTRACARDIAC

MANIFESTATIONSGASTROINTESTINAL: -

Nausea,vomiting,diarrhea

NERVOUS: -Depression,disorientation,paresthesias

VISUAL:

-

Blurredvision,scotomasandyellow-green

vision

CARDIACGLYCOSIDESSYMPATHOMIMETICSCatecholamines?-adrenergicagonistsPHOSPHODIESTERASEINHIBITORSAmrinoneEnoximoneOthersMilrinonePiroximonePOSITIVEINOTROPES

?-ADRENERGICSTIMULANTSCLASSIFICATIONB1StimulantsIncreasecontractilityDobutamine Doxaminol XamoterolButopamine Prenalterol TazololB2StimulantsProducearterialvasodilatationandreduceSVRPirbuterolCarbuterolRimiterolFenoterolTretoquinolSalbutamolTerbutalineSalmefamolSoterenolQuinterenolMixedDopamine

DOPAMINEANDDOBUTAMINE

EFFECTSReceptorsContractilityHeartRateArterialPress.RenalperfusionArrhythmiaDA(μg/Kg/min)Dobutamine<2DA1/DA2±±±++-2-5?1+++++±>5?1+a++++++±++?1++±+++±

POSITIVEINOTROPES

CONCLUSIONSMayincreasemortalitySaferinlowerdosesUseonlyinrefractoryCHFNOTforuseaschronictherapy

VenousVasodilatation

MIXEDCalciumantagonists

a-adrenergicBlockersACEIAngiotensinIIinhibitors

K+channelactivatorsNitroprussideVENOUSNitratesMolsidomineARTERIALMinoxidilHydralazineVASODILATORSCLASSIFICATIONArterialVasodilatation

1-

VENOUSVASODILATATION

Preload

2-Coronaryvasodilatation

Myocardial

perfusion3-Arterialvasodilatation

Afterload

4-OthersPulmonarycongestion

Ventricularsize

Vent.Wallstress

MVO2NITRATES

HEMODYNAMICEFFECTS?Cardiacoutput

?Bloodpressure

0.6PROBABILITY

OF

DEATH0Placebo(273)

Prazosin(183)

Hz+ISDN(186)MONTHSVHefT-1NEnglJMed1986;314:1547NITRATES

SURVIVAL06121824303642

NITRATESTOLERANCECanbeavoidedorminimized

-Intermittentadministration

-Usethelowestpossibledose

NITRATESCONTRAINDICATIONSPrevioushypersensitivityHypotension(<80mmHg)AMIwithlowventricularfillingpressure1sttrimesterofpregnancyWITHCAUTION:ConstrictivepericarditisIntracranialhypertensionHypertrophic

cardiomyopathy

NITRATES

CLINICAL

USESPulmonarycongestionOrthopneaandparoxysmalnocturnaldyspneaCHFwithmyocardialischemiaInacuteCHFandpulmonaryedema:NTGs.l.ori.v.

VASOCONSTRICTIONVASODILATATIONKininogenKallikreinInactiveFragmentsAngiotensinogenAngiotensinIRENINKininaseIIInhibitorALDOSTERONESYMPATHETICVASOPRESSINPROSTAGLANDINStPAANGIOTENSINIIBRADYKININACE-i.MechanismofActionA.C.E.

ACEIHEMODYNAMICEFFECTSArteriovenousVasodilatation - PAD,PCWPandLVEDP - SVRandBP - COandexercisetoleranceNochangeinHR/contractility

Renal,coronaryandcerebralflow

7595No

Additional

TreatmentNecessary(%)QuinaprilHeartFailureTrialJACC1993;22:1557ACEI

FUNCTIONALCAPACITYQuinaprilcontinuedn=114QuinaprilstoppedPlacebon=110p<0.001100908580WeeksClassII-III1612621048182014

ACEI

ADVANTAGESInhibitLVremodelingpost-MIModifytheprogressionofchronicCHF-

Survival- Hospitalizations-ImprovethequalityoflifeIncontrasttoothersvasodilators,

donotproduceneurohormonalactivation

orreflextachycardia

PlaceboEnalapril12111098765PROBABILITY

OF

DEATHMONTHS0.10.80p<0.001p<0.002CONSENSUSNEnglJMed1987;316:1429ACEISURVIVAL43210

50403020100Months0612p=0.30241830364248Enalapriln=2111Placebon=2117SOLVD(Prevention)

NEnglJMed1992;327:685MORTALITY%ACEISURVIVALn=4228NoCHFsymptomsEF<35

50403020100Months0612p=0.0036MORTALITY%241830364248Enalapriln=1285Placebon=1284SOLVD(Treatment)

NEnglJM1991;325:293ACEISURVIVALn=2589CHF-NYHAII-III-EF<35

Mortality%4SAVENEnglJMed1992;327:669Years3020100123PlaceboCaptopril0n=1115n=1116p=0.0192-19%ACEISURVIVALn=22313-16dayspostAMIEF<4012.5---150mg/dayAsymptomaticventriculardysfunctionpostMI

ISIS-4GISSI-3SAVESMILEAIRE

ACEIBenefitPtSelectionCaptoprilLisinoprilCaptoprilZofenoprilRamipril0.5/5wk0.8/6wk4.2/3.5yr4.1/1yr6/1yrAllwithAMIAllwithAMIEF<40asymptomaticAnt.AMI,NoTRLClinicalCHFTRACETrandolapril7.6/3yrVentDysfx/ClinicalCHFEF<35ACEISURVIVALPOSTMIACEI

INDICATIONSClinicalcardiacinsufficiency

-Allpatients

Asymptomaticventricular

dysfunction -LVEF<35%

ACEI

UNDESIRABLEEFFECTSInherentintheirmechanismofaction

-Hypotension -Hyperkalemia -Angioneuroticedema-Drycough-RenalInsuff.

ACEI

CONTRAINDICATIONS

RenalarterystenosisRenalinsufficiencyHyperkalemiaArterialhypotensionIntolerance(duetosideeffects)

ANGIOTENSINIIINHIBITORS（ARB)MECHANISMOFACTIONRENINAngiotensinogenAngiotensinI

ANGIOTENSINII

ACEOtherpathsVasoconstrictionProliferative

ActionVasodilatation

Antiproliferative

ActionAT1AT2AT1RECEPTORBLOCKERSRECEPTORSAT1RECEPTORBLOCKERSDRUGSLosartanValsartanIrbersartanCandersartanCompetitiveandselectiveblockingofAT1receptors

ALDOSTERONERetentionNa+RetentionH2OExcretionK+ExcretionMg2+CollagendepositionFibrosis-myocardium-vesselsSpironolactoneEdemaArrhythmiasCompetitiveantagonistofthealdosteronereceptor(myocardium,arterialwalls,kidney)ALDOSTERONEINHIBITORS

ALDOSTERONEINHIBITORSINDICATIONSFORDIURETICEFFECT?Pulmonarycongestion(dyspnea)?Systemiccongestion(edema) FORELECTROLYTEEFFECTS ?HypoK+,HypoMg+ ?Arrhythmias

?BetterthanK+supplements FORNEUROHORMONALEFFECTS ?PleaseseeRALESresults,NEnglJ Med1999:341:709-717

?Hyperkalemia?Severe

renalinsufficiency?MetabolicacidosisALDOSTERONEINHIBITORSCONTRAINDICATIONS?-ADRENERGICBLOCKERS

POSSIBLEBENEFICIALEFFECTS

Densityof?1receptorsInhibitcardiotoxicityofcatecholamines

Neurohormonal

activation

HRAntihypertensiveandantianginalAntiarrhythmicAntioxidantAntiproliferative

?BLOCKERSCARVEDILOL4studiesinU.S.;

1inAustralia/NewZealandU.S.stud