opendocument上海交通大学医学院(7)Heart Failure _ZhangQing2opendocument上海交通大学医学院(7)Heart Failure _ZhangQing3opendocument上海交通大学医学院(7)Heart Failure _ZhangQing4opendocument上海交通大学医学院(7)Heart Failure _ZhangQing5opendocument上海交通大学医学院(7)opendocument上海交通大学医学院(7)Heart Failure _ZhangQing7opendocument上海交通大学医学院(7)infection,especially pulmonary infection,fever physical,environmental,or emotional stress increased sodium load arrhythmia,pulmonary emboli pregnancy and delivery anemia,bleeding,excessive transfusionHeart Failure _ZhangQing8opendocument上海交通大学医学院(7)Heart Failure _ZhangQing9opendocument上海交通大学医学院(7)opendocument上海交通大学医学院(7)Heart Failure _ZhangQing11opendocument上海交通大学医学院(7)Heart Failure _ZhangQing12opendocument上海交通大学医学院(7)Heart Failure _ZhangQing13opendocument上海交通大学医学院(7)DETERMINANTS OF VENTRICULAR FUNCTION STROKE VOLUMEPRELOADCONTRACTILITYCARDIAC OUTPUTHEART RATE -AFTERLOADHeart Failure _ZhangQing14opendocument上海交通大学医学院(7)Myocardial dysfunctionDiminished Cardiac outputDiminished renalblood flowRenin releaseAngiotensin IIAldosteroneIncreased SympatheticActivityVasoconstrictionIncreased forceand rate ofmyocardial contractionIncreasedcardiacworkloadRenalretention ofsodium and waterIncreasedvenousreturnEdemaHeart Failure _ZhangQing15opendocument上海交通大学医学院(7)LV FunctionCardiac OutputNeurohormonalActivationSalt and Water RetentionPeripheral vasoconstrictionBlood flowVasodialtorsACE InhibitorsDiureticsACE Inhibitors BlockersDigoxinHeart Failure _ZhangQing16opendocument上海交通大学医学院(7)Heart Failure _ZhangQing17opendocument上海交通大学医学院(7)Heart Failure _ZhangQing18opendocument上海交通大学医学院(7)Heart Failure _ZhangQing19opendocument上海交通大学医学院(7)Heart Failure _ZhangQing20opendocument上海交通大学医学院(7)Heart Failure _ZhangQing21opendocument上海交通大学医学院(7)Heart Failure _ZhangQing22opendocument上海交通大学医学院(7)Heart Failure _ZhangQing23opendocument上海交通大学医学院(7)Heart Failure _ZhangQing24opendocument上海交通大学医学院(7)Heart Failure _ZhangQing25opendocument上海交通大学医学院(7)Heart Failure _ZhangQing26opendocument上海交通大学医学院(7)Heart Failure _ZhangQing27opendocument上海交通大学医学院(7)Heart Failure _ZhangQing28opendocument上海交通大学医学院(7)Heart Failure _ZhangQing29opendocument上海交通大学医学院(7)Heart Failure _ZhangQing30opendocument上海交通大学医学院(7)Heart Failure _ZhangQing31opendocument上海交通大学医学院(7)SurvivalMorbidityExercise capacityQuality of lifeNeurohormonal changes Progression of CHFSymptomsTREATMENT OBJECTIVESHeart Failure _ZhangQing32opendocument上海交通大学医学院(7)TREATMENTCorrection of aggravating factorsMEDICATIONSEndocarditisObesityHypertensionPhysical activityDietary excessPregnancyArrhythmias(AF)InfectionsHyperthyroidismThromboembolismHeart Failure _ZhangQing33opendocument上海交通大学医学院(7)TREATMENTPHARMACOLOGIC THERAPYDIURETICSINOTROPESVASODILATORSNEUROHORMONAL ANTAGONISTSOTHERS(Anticoagulants,antiarrhythmics,etc)Heart Failure _ZhangQing34opendocument上海交通大学医学院(7)PHARMACOLOGIC THERAPYDIURETICS Improved symptomsDecreasedmortalityPreventionof CHFyes?Vasodil.(Nitrates)yesyes?DIGOXINyes=minimalINOTROPESyes mort.?Other neurohormonal control drugsyes+/-?ACEIyesYESyesNeurohumoralControlNOyesnonoYESYESHeart Failure _ZhangQing35opendocument上海交通大学医学院(7)TREATMENTNormalAsymptomaticLV dysfunctionEF 40%Symptomatic CHFNYHA IIInotropesSpecialized therapyTransplantSymptomatic CHFNYHA-IVSymptomatic CHFNYHA-IIISecondary preventionModification of physical activityACEI Diuretics mildNeurohormonal inhibitors Digoxin?Loop DiureticsHeart Failure _ZhangQing36opendocument上海交通大学医学院(7)CortexMedullaThiazidesInhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of HenleK-sparingInhibit reabsorption of Na in thedistal convoluted and collecting tubuleLoop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of HenleLoop of HenleCollecting tubuleDIURETICSHeart Failure _ZhangQing37opendocument上海交通大学医学院(7)THIAZIDESMECHANISM OF ACTIONExcrete 5-10%of filtered Na+Elimination of KInhibit carbonic anhydrase:increase elimination of HCO3Excretion of uric acid,Ca and MgNo dose-effect relationshipHeart Failure _ZhangQing38opendocument上海交通大学医学院(7)LOOP DIURETICSMECHANISM OF ACTIONExcrete 15-20%of filtered Na+Elimination of K+,Ca+and Mg+Resistance of afferent arterioles-Cortical flow and GFR-Release renal PGs-NSAIDs may antagonize diuresisHeart Failure _ZhangQing39opendocument上海交通大学医学院(7)K-SPARING DIURETICS MECHANISM OF ACTIONEliminate 5%of filtered Na+Inhibit exchange of Na+for K+or H+Spironolactone=competitive antagonist for the aldosterone receptorAmiloride and triamterene block Na+channels controlled by aldosteroneHeart Failure _ZhangQing40opendocument上海交通大学医学院(7)Volume and preloadImprove symptoms of congestionNo direct effect on CO,but excessive preload reduction may Improves arterial distensibilityNeurohormonal activatioLevels of NA,Ang II and ARPException:with spironolactoneDIURETIC EFFECTSHeart Failure _ZhangQing41opendocument上海交通大学医学院(7)DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Changes in electrolytes:Volume Na+,K+,Ca+,Mg+metabolic alkalosis Metabolic changes:glycemia,uremia,gout LDL-C and TGCutaneous allergic reactionsHeart Failure _ZhangQing42opendocument上海交通大学医学院(7)DIURETICSADVERSE REACTIONSK-SPARING DIURETICSChanges in electrolytes Na+,K+,acidosisMusculoskeletal:Cramps,weaknessCutaneous allergic reactions:Heart Failure _ZhangQing43opendocument上海交通大学医学院(7)Na+K+K+Na+Na+Ca+Ca+Na-K ATPaseNa-Ca ExchangeMyofilamentsDIGOXINCONTRACTILITYHeart Failure _ZhangQing44opendocument上海交通大学医学院(7)DIGOXIN PHARMACOKINETIC PROPERTIESOral absorption(%)Protein binding(%)Volume of distribution(l/Kg)Half lifeEliminationOnset(min)i.v.oralMaximal effect(h)i.v.oralDurationTherapeutic level(ng/ml)60-75256(3-9)36(26-46)hRenal5-3030-902-43-62-6 days0.5-2Heart Failure _ZhangQing45opendocument上海交通大学医学院(7)DIGOXINDIGITALIZATION STRATEGIES(mg)0.125-0.5/d0.25/di.v0.5+0.25/4 hILD:0.75-1oral 12-24 h0.75+0.25/6 h1.25-1.5oral 2-5 d0.25/6-12 h1.5-1.75Loading dose(mg)Maintenance Dose ILD=average INITIAL dose required for digoxin loadingHeart Failure _ZhangQing46opendocument上海交通大学医学院(7)DIGOXINHEMODYNAMIC EFFECTSCardiac outputLV ejection fractionLVEDPExercise toleranceNatriuresisNeurohormonal activationHeart Failure _ZhangQing47opendocument上海交通大学医学院(7)DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal toneHeart Failure _ZhangQing48opendocument上海交通大学医学院(7)WORSENING OF CHF%p=0.001DIGOXIN:0.125-0.5 mg/d(0.7-2.0 ng/ml)EF 35%Class I-III(digoxin+diuretic+ACEI)Also significantly decreased exercisetime and LVEF.DIGOXIN EFFECT ON CHF PROGRESSIONRADIANCEN Engl J Med 1993;329:1Placebo n=93DIGOXIN WithdrawalDIGOXIN n=853010020100802004060DaysHeart Failure _ZhangQing49opendocument上海交通大学医学院(7)50403020100Placebon=3403DIGOXINn=3397480122436OVERALL MORTALITY%DIGN Engl J Med 1997;336:525Monthsp=0.8Heart Failure _ZhangQing50opendocument上海交通大学医学院(7)DIGOXIN LONG TERM EFFECTSSurvival similar to placeboFewer hospital admissionsMore serious arrhythmiasMore myocardial infarctionsHeart Failure _ZhangQing51opendocument上海交通大学医学院(7)DIGOXIN CLINICAL USESAF with rapid ventricular responseCHF refractory to other drugs Other indications?Can be combined with other drugsHeart Failure _ZhangQing52opendocument上海交通大学医学院(7)DIGOXINCONTRAINDICATIONSABSOLUTE:-Digoxin toxicityRELATIVE-Advanced A-V block without pacemaker-Bradycardia or sick sinus without PM-PVCs and TV-Marked hypokalemia-W-P-W with atrial fibrillationHeart Failure _ZhangQing53opendocument上海交通大学医学院(7)DIGOXIN TOXICITYCARDIAC MANIFESTATIONSARRHYTHMIAS:-Ventricular(PVCs,TV,VF)-Supraventricular(PACs,SVT)BLOCKS:-S-A and A-V blocksCHF EXACERBATIONHeart Failure _ZhangQing54opendocument上海交通大学医学院(7)DIGOXIN TOXICITYEXTRACARDIAC MANIFESTATIONSGASTROINTESTINAL:-Nausea,vomiting,diarrhea NERVOUS:-Depression,disorientation,paresthesias VISUAL:-Blurred vision,scotomas and yellow-green vision Heart Failure _ZhangQing55opendocument上海交通大学医学院(7)CARDIAC GLYCOSIDESSYMPATHOMIMETICSCatecholamines-adrenergic agonistsPHOSPHODIESTERASE INHIBITORS Amrinone EnoximoneOthersMilrinonePiroximonePOSITIVE INOTROPESHeart Failure _ZhangQing56opendocument上海交通大学医学院(7)-ADRENERGIC STIMULANTSCLASSIFICATIONB1 StimulantsIncrease contractilityDobutamineDoxaminolXamoterolButopaminePrenalterolTazololB2 StimulantsProduce vasodilatation and reduce SVRPirbuterolCarbuterolRimiterolFenoterolTretoquinolSalbutamolTerbutalineSalmefamolSoterenolQuinterenolMixedDopamineHeart Failure _ZhangQing57opendocument上海交通大学医学院(7)DOPAMINE AND DOBUTAMINEEFFECTSReceptorsContractilityHeart RateArterial Press.Renal perfusionArrhythmiaDA(g/Kg/min)Dobutamine 51+a a+1+Heart Failure _ZhangQing58opendocument上海交通大学医学院(7)POSITIVE INOTROPES CONCLUSIONSMay increase mortalitySafer in lower dosesUse only in refractory CHF NOT for use as chronic therapyHeart Failure _ZhangQing59opendocument上海交通大学医学院(7)Venous VasodilatationMIXEDCalcium antagonists a-adrenergic BlockersACEIAngiotensin II inhibitors K+channel activatorsNitroprussideVENOUSNitratesMolsidomineARTERIALMinoxidilHydralazineVASODILATORSCLASSIFICATIONArterial VasodilatationHeart Failure _ZhangQing60opendocument上海交通大学医学院(7)1-VENOUS VASODILATATION Preload2-Coronary vasodilatation Myocardial perfusion3-Arterial vasodilatation Afterload4-OthersPulmonary congestionVentricular sizeVent.Wall stressMVO2NITRATESHEMODYNAMIC EFFECTS Cardiac output Blood pressureHeart Failure _ZhangQing61opendocument上海交通大学医学院(7)0.6PROBABILITYOF DEATH0Placebo(273)Prazosin(183)Hz+ISDN(186)MONTHS0.70.50.30.40.20.1VHefT-1N Engl J Med 1986;314:1547NITRATESSURVIVAL06121824303642Heart Failure _ZhangQing62opendocument上海交通大学医学院(7)NITRATESTOLERANCECan be avoided or minimized-Intermittent administration-Use the lowest possible doseHeart Failure _ZhangQing63opendocument上海交通大学医学院(7)NITRATESCONTRAINDICATIONSPrevious hypersensitivityHypotension(80 mmHg)AMI with low ventricular filling pressure 1st trimester of pregnancyWITH CAUTION:Constrictive pericarditisIntracranial hypertensionHypertrophic cardiomyopathyHeart Failure _ZhangQing64opendocument上海交通大学医学院(7)NITRATES CLINICAL USESPulmonary congestionOrthopnea and paroxysmal nocturnal dyspneaCHF with myocardial ischemiaIn acute CHF and pulmonary edema:NTG s.l.or i.v.Heart Failure _ZhangQing65opendocument上海交通大学医学院(7)VASOCONSTRICTIONVASODILATATION KininogenKallikreinInactive FragmentsAngiotensinogenAngiotensin IRENINKininase IIInhibitorALDOSTERONESYMPATHETICVASOPRESSINPROSTAGLANDINStPAANGIOTENSIN IIBRADYKININACE-i.Mechanism of ActionA.C.E.Heart Failure _ZhangQing66opendocument上海交通大学医学院(7)ACEIHEMODYNAMIC EFFECTSArteriovenous Vasodilatation-PAD,PCWP and LVEDP-SVR and BP-CO and exercise toleranceNo change in HR/contractilityRenal,coronary and cerebral flowHeart Failure _ZhangQing67opendocument上海交通大学医学院(7)7595No Additional TreatmentNecessary(%)Quinapril Heart Failure TrialJACC 1993;22:1557ACEIFUNCTIONAL CAPACITYQuinaprilcontinuedn=114QuinaprilstoppedPlacebon=110p0.001100908580WeeksClass II-III1612621048182014Heart Failure _ZhangQing68opendocument上海交通大学医学院(7)ACEIADVANTAGESInhibit LV remodeling post-MIModify the progression of chronic CHF-Survival-Hospitalizations-Improve the quality of lifeIn contrast to others vasodilators,do not produce neurohormonal activationor reflex tachycardiaHeart Failure _ZhangQing69opendocument上海交通大学医学院(7)PlaceboEnalapril12111098765PROBABILITYOF DEATHMONTHS0.10.800.20.30.70.40.50.6p 0.001p 0.002CONSENSUSN Engl J Med 1987;316:1429ACEI SURVIVAL43210Heart Failure _ZhangQing70opendocument上海交通大学医学院(7)50403020100Months0612p =0.30241830364248Enalapriln=2111Placebon=2117SOLVD(Prevention)N Engl J Med 1992;327:685MORTALITY%ACEI SURVIVALn=4228No CHF symptomsEF 35Heart Failure _ZhangQing71opendocument上海交通大学医学院(7)50403020100Months0612p =0.0036MORTALITY%241830364248Enalapriln=1285Placebon=1284SOLVD(Treatment)N Engl J M 1991;325:293ACEI SURVIVALn=2589CHF-NYHA II-III-EF 35Heart Failure _ZhangQing72opendocument上海交通大学医学院(7)Mortality%4SAVEN Engl J Med 1992;327:669Years3020100123PlaceboCaptopril0n=1115n=1116p=0.019-19%ACEI SURVIVALn=22313-16 days post AMIEF 4012.5-150 mg /dayAsymptomatic ventriculardysfunction post MIHeart Failure _ZhangQing73opendocument上海交通大学医学院(7)ISIS-4GISSI-3SAVESMILEAIRE ACEIBenefitPt SelectionCaptoprilLisinoprilCaptoprilZofenoprilRamipril0.5/5 wk0.8/6 wk4.2/3.5 yr4.1/1 yr6/1 yrAll with AMIAll with AMIEF 40asymptomaticAnt.AMI,No TRLClinical CHFTRACETrandolapril7.6/3 yrVent Dysfx/Clinical CHFEF 35ACEISURVIVAL POST MIHeart Failure _ZhangQing74opendocument上海交通大学医学院(7)ACEIINDICATIONSClinical cardiac insufficiency-All patients Asymptomatic ventricular dysfunction-LVEF 35%Heart Failure _ZhangQing75opendocument上海交通大学医学院(7)ACEIUNDESIRABLE EFFECTSInherent in their mechanism of action-Hypotension-Hyperkalemia-Angioneurotic edema-Dry cough-Renal Insuff.Heart Failure _ZhangQing76opendocument上海交通大学医学院(7)ACEICONTRAINDICATIONSRenal artery stenosisRenal insufficiencyHyperkalemiaArterial hypotensionIntolerance(due to side effects)Heart Failure _ZhangQing77opendocument上海交通大学医学院(7)ANGIOTENSIN II INHIBITORS（ARB)MECHANISM OF ACTIONRENINAngiotensinogenAngiotensin IANGIOTENSIN II ACEOther pathsVasoconstrictionProliferative ActionVasodilatation Antiproliferative ActionAT1 AT2AT1 RECEPTOR BLOCKERSRECEPTORSHeart Failure _ZhangQing78opendocument上海交通大学医学院(7)AT1 RECEPTOR BLOCKERSDRUGSLosartanValsartanIrbersartanCandersartanCompetitive and selective blocking of AT1 receptorsHeart Failure _ZhangQing79opendocument上海交通大学医学院(7)ALDOSTERONERetention Na+Retention H2OExcretion K+Excretion Mg2+Collagen depositionFibrosis -myocardium-vesselsSpironolactone Edema ArrhythmiasCompetitive antagonist of thealdosterone receptor(myocardium,arterial walls,kidney)ALDOSTERONE INHIBITORSHeart Failure _ZhangQing80opendocument上海交通大学医学院(7)ALDOSTERONE INHIBITORSINDICATIONSFOR DIURETIC EFFECT Pulmonary congestion(dyspnea)Systemic congestion(edema)FOR ELECTROLYTE EFFECTS Hypo K+,Hypo Mg+Arrhythmias Better than K+supplementsFOR NEUROHORMONAL EFFECTS Please see RALES results,N Engl J Med 1999:341:709-717Heart Failure _ZhangQing81opendocument上海交通大学医学院(7)Hyperkalemia Severe renal insufficiency Metabolic acidosisALDOSTERONE INHIBITORSCONTRAINDICATIONSHeart Failure _ZhangQing82opendocument上海交通大学医学院(7)-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Density of 1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HRAntihypertensive and antianginalAntiarrhythmicAntioxidantAntiproliferativeHeart Failure _ZhangQing83opendocument上海交通大学医学院(7)BLOCKERSCARVEDILOL4 studies in U.S.;1 in Australia/New ZealandU.S.studies with control groupMortality with Placebo8.2%Mortality with Carvedilol2.9%Initial low doses,progressivep 0.0001Heart Failure _ZhangQing84opendocument上海交通大学医学院(7)-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATIONBegin with very low doses Slow augmentation of doseSlow withdrawal?Heart Failure _ZhangQing85opendocument上海交通大学医学院(7)-ADRENERGIC BLOCKERSIDEAL CANDIDATE?Suspected adrenergic activationArrhythmiasHypertensionAnginaHeart Failure _ZhangQing86opendocument上海交通大学医学院(7)-ADRENERGIC BLOCKERSCONTRAINDICATIONSHypotension:BP 100 mmHgBradycardia:HR 50 bpmClinical instabilityChronic bronchitis,ASTHMASevere chronic renal insufficiencyHeart Failure _ZhangQing87opendocument上海交通大学医学院(7)CALCIUM ANTAGONISTSPOTENTIAL EFFECTSAntiischemicPeripheral Vasodilatation InotropyHeart Failure _ZhangQing88opendocument上海交通大学医学院(7)CALCIUM ANTAGONISTSPOSSIBLE UTILITYDiltiazem contraindicatedVerapamil and Nifedipine not recommendedVasoselective(amlodipine,nisoldipine),may be useful in ischemia+CHFHeart Failure _ZhangQing89opendocument上海交通大学医学院(7)ANTICOAGULANTSPREVIOUS EMBOLIC EPISODEATRIAL FIBRILLATIONIdentified thrombusLV Aneurysm(3-6 mo post MI)Class III-IV in the presence of:-EF 30-Aneurysm or very dilated LVHeart Failure _ZhangQing90opendocument上海交通大学医学院(7)ANTIARRHYTHMICSSustained VT,with/without symptoms-Blockers-AmiodaroneSudden death from VF-Consider implantable defibrillatorHeart Failure _ZhangQing91opendocument上海交通大学医学院(7)Heart Failure _ZhangQing92opendocument上海交通大学医学院(7)Heart Failure _ZhangQing93opendocument上海交通大学医学院(7)Heart Failure _ZhangQing94opendocument上海交通大学医学院(7)Heart Failure _ZhangQing95opendocument上海交通大学医学院(7)Heart Failure _ZhangQing96opendocument上海交通大学医学院(7)Heart Failure _ZhangQing97opendocument上海交通大学医学院(7)Heart Failure _ZhangQing98opendocument上海交通大学医学院(7)opendocument上海交通大学医学院(7)Heart Failure _ZhangQing100opendocument上海交通大学医学院(7)Heart Failure _ZhangQing101opendocument上海交通大学医学院(7)Heart Failure _ZhangQing102opendocument上海交通大学医学院(7)Heart Failure _ZhangQing103opendocument上海交通大学医学院(7)Heart Failure _ZhangQing104opendocument上海交通大学医学院(7)Heart Failure _ZhangQing105opendocument上海交通大学医学院(7)Heart Failure _ZhangQing106opendocument上海交通大学医学院(7)Heart Failure _ZhangQing107opendocument上海交通大学医学院(7)Heart Failure _ZhangQing108opendocument上海交通大学医学院(7)Heart Failure _ZhangQing109opendocument上海交通大学医学院(7)Heart Failure _ZhangQing110opendocument上海交通大学医学院(7)Heart Failure _ZhangQing111opendocument上海交通大学医学院(7)Heart Failure _ZhangQing112opendocument上海交通大学医学院(7)Heart Failure _ZhangQing113opendocument上海交通大学医学院(7)Heart Failure _ZhangQing114opendocument上海交通大学医学院(7)Heart Failure _ZhangQing115opendocument上海交通大学医学院(7)Heart Failure _ZhangQing116opendocument上海交通大学医学院(7)Heart Failure _ZhangQing117opendocument上海交通大学医学院(7)Heart Failure _ZhangQing118opendocument上海交通大学医学院(7)Heart Failure _ZhangQing119opendocument上海交通大学医学院(7)Heart Failure _ZhangQing120opendocument上海交通大学医学院(7)The Endopendocument上海交通大学医学院(7)。