Chapter 234. Heart Failure and Cor Pulmonale

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Heart Failure and Cor Pulmonale
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HEARTFAILURE Definition
Heartfailure(HF)isaclinicalsyndromethatoccursinpatientswho,becauseofaninheritedoracquiredabnormalityofcardiacstructureand/or function,developaconstellationofclinicalsymptoms(dyspneaandfatigue)andsigns(edemaandrales)thatleadtofrequenthospitalizations,a poorqualityoflife,andashortenedlifeexpectancy.
Epidemiology
HFisaburgeoningproblemworldwide,withmorethan20millionpeopleaffected.TheoverallprevalenceofHFintheadultpopulationin developedcountriesis2%.HFprevalencefollowsanexponentialpattern,risingwithage,andaffects610%ofpeopleoverage65.Although therelativeincidenceofHFislowerinwomenthaninmen,womenconstituteatleastone-halfthecasesofHFbecauseoftheirlongerlife expectancy.InNorthAmericaandEurope,thelifetimeriskofdevelopingHFisapproximatelyoneinfivefora40-year-old.Theoverall prevalenceofHFisthoughttobeincreasing,inpartbecausecurrenttherapiesforcardiacdisorders,suchasmyocardialinfarction(MI),valvular heartdisease,andarrhythmias,areallowingpatientstosurvivelonger.VerylittleisknownabouttheprevalenceorriskofdevelopingHFin emergingnationsbecauseofthelackofpopulation-basedstudiesinthosecountries.AlthoughHFoncewasthoughttoariseprimarilyinthe settingofadepressedleftventricular(LV)ejectionfraction(EF),epidemiologicstudieshaveshownthatapproximatelyone-halfofpatientswho developHFhaveanormalorpreservedEF(EF 4050%).Accordingly,HFpatientsarenowbroadlycategorizedintooneoftwogroups:(1)HF withadepressedEF(commonlyreferredtoassystolic failure)or(2)HFwithapreservedEF(commonlyreferredtoasdiastolic failure).
Etiology
AsshowninTable234-1,anyconditionthatleadstoanalterationinLVstructureorfunctioncanpredisposeapatienttodevelopingHF. AlthoughtheetiologyofHFinpatientswithapreservedEFdiffersfromthatofpatientswithdepressedEF,thereisconsiderableoverlapbetween theetiologiesofthesetwoconditions.Inindustrializedcountries,coronaryarterydisease(CAD)hasbecomethepredominantcauseinmenand womenandisresponsiblefor6075%ofcasesofHF.HypertensioncontributestothedevelopmentofHFin75%ofpatients,includingmost patientswithCAD.BothCADandhypertensioninteracttoaugmenttheriskofHF,asdoesdiabetesmellitus.
Table234-1EtiologiesofHeartFailure
DepressedEjectionFraction(<40%) Coronaryarterydisease Myocardialinfarctiona Myocardialischemiaa Chronicpressureoverload Hypertension Obstructivevalvulardiseasea Chronicvolumeoverload Regurgitantvalvulardisease Intracardiac(left-to-right)shunting Extracardiacshunting PreservedEjectionFraction(>4050%) Pathologichypertrophy Primary(hypertrophiccardiomyopathies) Restrictivecardiomyopathy Infiltrativedisorders(amyloidosis,sarcoidosis) Chagas'disease Disordersofrateandrhythm Chronicbradyarrhythmias Chronictachyarrhythmias
a
Nonischemicdilatedcardiomyopathy Familial/geneticdisorders
Infiltrativedisordersa Toxic/drug-induceddamage Metabolicdisordera Viral
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Secondary(hypertension) Aging PulmonaryHeartDisease Corpulmonale Pulmonaryvasculardisorders High-OutputStates Metabolicdisorders Thyrotoxicosis Nutritionaldisorders(beriberi)
Storagediseases(hemochromatosis) Fibrosis Endomyocardialdisorders
Excessiveblood-flowrequirements Systemicarteriovenousshunting Chronicanemia
Note: aIndicatesconditionsthatcanalsoleadtoheartfailurewithapreservedejectionfraction. In2030%ofthecasesofHFwithadepressedEF,theexactetiologicbasisisnotknown.Thesepatientsarereferredtoashavingnonischemic, dilated,oridiopathiccardiomyopathyifthecauseisunknown(Chap.238).Priorviralinfectionortoxinexposure(e.g.,alcoholicor chemotherapeutic)alsomayleadtoadilatedcardiomyopathy.Moreover,itisbecomingincreasinglyclearthatalargenumberofcasesofdilated cardiomyopathyaresecondarytospecificgeneticdefects,mostnotablythoseinthecytoskeleton.Mostformsoffamilialdilatedcardiomyopathy areinheritedinanautosomaldominantfashion.Mutationsofgenesthatencodecytoskeletalproteins(desmin,cardiacmyosin,vinculin)and nuclearmembraneproteins(laminin)havebeenidentifiedthusfar.DilatedcardiomyopathyalsoisassociatedwithDuchenne's,Becker's,and limb-girdlemusculardystrophies.Conditionsthatleadtoahighcardiacoutput(e.g.,arteriovenousfistula,anemia)areseldomresponsiblefor thedevelopmentofHFinanormalheart;however,inthepresenceofunderlyingstructuralheartdisease,theseconditionscanleadtoovertHF.
GlobalConsiderations
RheumaticheartdiseaseremainsamajorcauseofHFinAfricaandAsia,especiallyintheyoung.HypertensionisanimportantcauseofHFinthe AfricanandAfrican-Americanpopulations.Chagas'diseaseisstillamajorcauseofHFinSouthAmerica.Notsurprisingly,anemiaisafrequent concomitantfactorinHFinmanydevelopingnations.Asdevelopingnationsundergosocioeconomicdevelopment,theepidemiologyofHFis becomingsimilartothatofWesternEuropeandNorthAmerica,withCADemergingasthesinglemostcommoncauseofHF.Althoughthe contributionofdiabetesmellitustoHFisnotwellunderstood,diabetesacceleratesatherosclerosisandoftenisassociatedwithhypertension.
Prognosis
DespitemanyrecentadvancesintheevaluationandmanagementofHF,thedevelopmentofsymptomaticHFstillcarriesapoorprognosis. Community-basedstudiesindicatethat3040%ofpatientsdiewithin1yearofdiagnosisand6070%diewithin5years,mainlyfromworsening HForasasuddenevent(probablybecauseofaventriculararrhythmia).Althoughitisdifficulttopredictprognosisinanindividual,patientswith symptomsatrest[NewYorkHeartAssociation(NYHA)classIV]havea3070%annualmortalityrate,whereaspatientswithsymptomswith moderateactivity(NYHAclassII)haveanannualmortalityrateof510%.Thus,functionalstatusisanimportantpredictorofpatientoutcome (Table234-2).
Table234-2NewYorkHeartAssociationClassification
Functional Capacity ClassI
ObjectiveAssessment
Patientswithcardiacdiseasebutwithoutresultinglimitationofphysicalactivity.Ordinaryphysicalactivitydoesnotcause unduefatigue,palpitations,dyspnea,oranginalpain.
ClassII
Patientswithcardiacdiseaseresultinginslightlimitationofphysicalactivity.Theyarecomfortableatrest.Ordinaryphysical activityresultsinfatigue,palpitation,dyspnea,oranginalpain.
ClassIII
Patientswithcardiacdiseaseresultinginmarkedlimitationofphysicalactivity.Theyarecomfortableatrest.Lessthan ordinaryactivitycausesfatigue,palpitation,dyspnea,oranginalpain.
ClassIV
Patientswithcardiacdiseaseresultingininabilitytocarryonanyphysicalactivitywithoutdiscomfort.Symptomsofheart failureortheanginalsyndromemaybepresentevenatrest.Ifanyphysicalactivityisundertaken,discomfortisincreased.
Source:AdaptedfromNewYorkHeartAssociation,Inc.,Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis,6th ed.Boston,LittleBrown,1964,p.114.
Pathogenesis
Figure234-1providesageneralconceptualframeworkforconsideringthedevelopmentandprogressionofHFwithadepressedEF.Asshown, HFmaybeviewedasaprogressivedisorderthatisinitiatedafteranindex eventeitherdamagestheheartmuscle,witharesultantlossof
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functioningcardiacmyocytes,or,alternatively,disruptstheabilityofthemyocardiumtogenerateforce,therebypreventingtheheartfrom contractingnormally.Thisindexeventmayhaveanabruptonset,asinthecaseofamyocardialinfarction(MI);itmayhaveagradualor insidiousonset,asinthecaseofhemodynamicpressureorvolumeoverloading;oritmaybehereditary,asinthecaseofmanyofthegenetic cardiomyopathies.Regardlessofthenatureoftheincitingevent,thefeaturethatiscommontoeachoftheseindexeventsisthattheyallin somemannerproduceadeclineinthepumpingcapacityoftheheart.Inmostinstances,patientsremainasymptomaticorminimally symptomaticaftertheinitialdeclineinpumpingcapacityoftheheartordevelopsymptomsonlyafterthedysfunctionhasbeenpresentforsome time.
Figure234-1
Pathogenesisofheartfailurewithadepressedejectionfraction.Heartfailurebeginsafteranindexeventproducesaninitialdeclineintheheart's pumpingcapacity.Afterthisinitialdeclineinpumpingcapacity,avarietyofcompensatorymechanismsareactivated,includingtheadrenergicnervous system,therenin-angiotensin-aldosteronesystem,andthecytokinesystem.Intheshortterm,thesesystemsareabletorestorecardiovascularfunctionto anormalhomeostaticrangewiththeresultthatthepatientremainsasymptomatic.However,withtimethesustainedactivationofthesesystemscanlead tosecondaryend-organdamagewithintheventricle,withworseningleftventricularremodelingandsubsequentcardiacdecompensation.(From D Mann: Circulation 100:999, 1999.)
AlthoughtheprecisereasonswhypatientswithLVdysfunctionmayremainasymptomaticisnotcertain,onepotentialexplanationisthata numberofcompensatorymechanismsbecomeactivatedinthepresenceofcardiacinjuryand/orLVdysfunctionallowingpatientstosustainand modulateLVfunctionforaperiodofmonthstoyears.Thelistofcompensatorymechanismsthathavebeendescribedthusfarinclude(1) activationoftherenin-angiotensin-aldosterone(RAA)andadrenergicnervoussystems,whichareresponsibleformaintainingcardiacoutput throughincreasedretentionofsaltandwater(Fig.234-2),and(2)increasedmyocardialcontractility.Inaddition,thereisactivationofafamily ofcountervailingvasodilatorymolecules,includingtheatrialandbrainnatriureticpeptides(ANPandBNP),prostaglandins(PGE2andPGI2),and nitricoxide(NO),thatoffsetstheexcessiveperipheralvascularvasoconstriction.Geneticbackground,sex,age,orenvironmentmayinfluence thesecompensatorymechanisms,whichareabletomodulateLVfunctionwithinaphysiologic/homeostaticrangesothatthefunctionalcapacity ofthepatientispreservedorisdepressedonlyminimally.Thus,patientsmayremainasymptomaticorminimallysymptomaticforaperiodof years;however,atsomepointpatientsbecomeovertlysymptomatic,witharesultantstrikingincreaseinmorbidityandmortalityrates.Although theexactmechanismsthatareresponsibleforthistransitionarenotknown,aswillbediscussedbelow,thetransitiontosymptomaticHFis accompaniedbyincreasingactivationofneurohormonal,adrenergic,andcytokinesystemsthatleadtoaseriesofadaptivechangeswithinthe myocardiumcollectivelyreferredtoasLV remodeling.
Figure234-2
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Activationofneurohormonalsystemsinheartfailure.ThedecreasedcardiacoutputinHFpatientsresultsinan"unloading"ofhigh-pressure baroceptors(circles)intheleftventricle,carotidsinus,andaorticarch.Thisunloadingoftheperipheralbaroreceptorsleadstoalossofinhibitory parasympathetictonetothecentralnervoussystem(CNS),witharesultantgeneralizedincreaseinefferentsympathetictone,andnon-osmoticreleaseof argininevasopressin(AVP)fromthepituitary.AVP[orantidiuretichormone(ADH)]isapowerfulvasoconstrictorthatincreasesthepermeabilityoftherenal collectingducts,leadingtothereabsorptionoffreewater.TheseafferentsignalstotheCNSalsoactivateefferentsympatheticnervoussystempathways thatinnervatetheheart,kidney,peripheralvasculature,andskeletalmuscles. Sympatheticstimulationofthekidneyleadstothereleaseofrenin,witharesultantincreaseinthecirculatinglevelsofangiotensinIIandaldosterone.The activationoftherenin-angiotensin-aldosteronesystempromotessaltandwaterretentionandleadstovasoconstrictionoftheperipheralvasculature, myocytehypertrophy,myocytecelldeath,andmyocardialfibrosis.Althoughtheseneurohormonalmechanismsfacilitateshort-termadaptationby maintainingbloodpressure,andhenceperfusiontovitalorgans,thesameneurohormonalmechanismsarebelievedtocontributetoend-organchangesin theheartandthecirculationandtotheexcessivesaltandwaterretentioninadvancedHF.[Modified from A Nohria et al: Neurohormonal, renal and vascular adjustments, in Atlas of Heart Failure: Cardiac Function and Dysfunction, 4th ed, WS Colucci (ed). Philadelphia, Current Medicine Group 2002, p. 104.]
IncontrasttoourunderstandingofthepathogenesisofHFwithadepressedEF,ourunderstandingofthemechanismsthatcontributetothe developmentofHFwithapreservedEFisstillevolving.Thatis,althoughdiastolicdysfunction(seebelow)wasthoughttobetheonly
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mechanismresponsibleforthedevelopmentofHFwithapreservedEF,community-basedstudiessuggestthatadditionalextracardiac mechanismsmaybeimportant,suchasincreasedvascularstiffnessandimpairedrenalfunction.
BasicMechanismsofHeartFailure
SYSTOLICDYSFUNCTION
LVremodelingdevelopsinresponsetoaseriesofcomplexeventsthatoccuratthecellularandmolecularlevels(Table234-3).Thesechanges include(1)myocytehypertrophy,(2)alterationsinthecontractilepropertiesofthemyocyte,(3)progressivelossofmyocytesthroughnecrosis, apoptosis,andautophagiccelldeath,(4) -adrenergicdesensitization,(5)abnormalmyocardialenergeticsandmetabolism,and(6) reorganizationoftheextracellularmatrixwithdissolutionoftheorganizedstructuralcollagenweavesurroundingmyocytesandsubsequent replacementbyaninterstitialcollagenmatrixthatdoesnotprovidestructuralsupporttothemyocytes.Thebiologicstimulifortheseprofound changesincludemechanicalstretchofthemyocyte,circulatingneurohormones(e.g.,norepinephrine,angiotensinII),inflammatorycytokines [e.g.,tumornecrosisfactor(TNF)],otherpeptidesandgrowthfactors(e.g.,endothelin),andreactiveoxygenspecies(e.g.,superoxide).The sustainedoverexpressionofthesebiologicallyactivemoleculesisbelievedtocontributetotheprogressionofHFbyvirtueofthedeleterious effectstheyexertontheheartandthecirculation.Indeed,thisinsightformstheclinicalrationaleforusingpharmacologicagentsthat antagonizethesesystems[e.g.,angiotensin-convertingenzyme(ACE)inhibitorsandbetablockers]intreatingpatientswithHF.
Table234-3OverviewofLeftVentricularRemodeling
AlterationsinMyocyteBiology Excitation-contractioncoupling Myosinheavychain(fetal)geneexpression -adrenergicdesensitization Hypertrophy Myocytolysis Cytoskeletalproteins MyocardialChanges Myocyteloss Necrosis Apoptosis Autophagy Alterationsinextracellularmatrix Matrixdegradation Myocardialfibrosis AlterationsinLeftVentricularChamberGeometry Leftventricular(LV)dilation IncreasedLVsphericity LVwallthinning Mitralvalveincompetence
Source:AdaptedfromDMann:Pathophysiologyofheartfailure,inBraunwald's Heart Disease,8thed,PLLibbyetal(eds).Philadelphia, Elsevier,2008,p.550. InordertounderstandhowthechangesthatoccurinthefailingcardiacmyocytecontributetodepressedLVsystolicfunctioninHF,itis instructivefirsttoreviewthebiologyofthecardiacmusclecell(Chap.224).Sustainedneurohormonalactivationandmechanicaloverloadresult intranscriptionalandposttranscriptionalchangesinthegenesandproteinsthatregulateexcitation-contractioncouplingandcross-bridge interaction(seeFigs.224-6and224-7).Thechangesthatregulateexcitation-contractionincludedecreasedfunctionofsarcoplasmicreticulum Ca2+adenosinetriphosphatase(SERCA2A),resultingindecreasedcalciumuptakeintothesarcoplamsicreticulum(SR),and hyperphosphorylationoftheryanodinereceptor,leadingtocalciumleakagefromtheSR.Thechangesthatoccurinthecross-bridgesinclude decreasedexpressionof -myosinheavychainandincreasedexpressionof -myosinheavychain,myocytolysis,anddisruptionofthe cytoskeletallinksbetweenthesarcomeresandtheextracellularmatrix.Collectively,thesechangesimpairtheabilityofthemyocytetocontract andthereforecontributetothedepressedLVsystolicfunctionobservedinpatientswithHF.
DIASTOLICDYSFUNCTION
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Myocardialrelaxationisanadenosinetriphosphate(ATP)-dependentprocessthatisregulatedbyuptakeofcytoplasmiccalciumintotheSRby SERCA2Aandextrusionofcalciumbysarcolemmalpumps(seeFig.224-7).Accordingly,reductionsinATPconcentration,asoccursinischemia, mayinterferewiththeseprocessesandleadtoslowedmyocardialrelaxation.Alternatively,ifLVfillingisdelayedbecauseLVcomplianceis reduced(e.g.,fromhypertrophyorfibrosis),LVfillingpressureswillsimilarlyremainelevatedatenddiastole(seeFig.224-11).Anincreasein heartratedisproportionatelyshortensthetimefordiastolicfilling,whichmayleadtoelevatedLVfillingpressures,particularlyinnoncompliant ventricles.ElevatedLVend-diastolicfillingpressuresresultinincreasesinpulmonarycapillarypressures,whichcancontributetothedyspnea experiencedbypatientswithdiastolicdysfunction.Inadditiontoimpairedmyocardialrelaxation,increasedmyocardialstiffnesssecondaryto cardiachypertrophyandincreasedmyocardialcollagencontentmaycontributetodiastolicfailure.Importantly,diastolicdysfunctioncanoccur aloneorincombinationwithsystolicdysfunctioninpatientswithHF.
LEFTVENTRICULARREMODELING
Ventricular remodelingreferstothechangesinLVmass,volume,andshapeandthecompositionoftheheartthatoccuraftercardiacinjury and/orabnormalhemodynamicloadingconditions.LVremodelingmaycontributeindependentlytotheprogressionofHFbyvirtueofthe mechanicalburdensthatareengenderedbythechangesinthegeometryoftheremodeledLV.InadditiontotheincreaseinLVend-diastolic volume,LVwallthinningoccursastheleftventriclebeginstodilate.Theincreaseinwallthinning,alongwiththeincreaseinafterloadcreatedby LVdilation,leadstoafunctionalafterload mismatchthatmaycontributefurthertoadecreaseinstrokevolume.Moreover,thehighend-diastolic wallstressmightbeexpectedtoleadto(1)hypoperfusionofthesubendocardium,withresultantworseningofLVfunction,(2)increased oxidativestress,withtheresultantactivationoffamiliesofgenesthataresensitivetofreeradicalgeneration(e.g.,TNFandinterleukin1 ),and (3)sustainedexpressionofstretch-activatedgenes(angiotensinII,endothelin,andTNF)and/orstretchactivationofhypertrophicsignaling pathways.IncreasingLVdilationalsoresultsintetheringofthepapillarymuscleswithresultingincompetenceofthemitralvalveapparatusand functionalmitralregurgitation,whichinturnleadstofurtherhemodynamicoverloadingoftheventricle.Takentogether,themechanicalburdens thatareengenderedbyLVremodelingcontributetotheprogressionofHF.
ClinicalManifestations
SYMPTOMS
ThecardinalsymptomsofHFarefatigueandshortnessofbreath.Althoughfatiguetraditionallyhasbeenascribedtothelowcardiacoutputin HF,itislikelythatskeletal-muscleabnormalitiesandothernoncardiaccomorbidities(e.g.,anemia)alsocontributetothissymptom.Intheearly stagesofHF,dyspneaisobservedonlyduringexertion;however,asthediseaseprogresses,dyspneaoccurswithlessstrenuousactivity,andit ultimatelymayoccurevenatrest.TheoriginofdyspneainHFisprobablymultifactorial(Chap.33).Themostimportantmechanismis pulmonarycongestionwithaccumulationofinterstitialorintra-alveolarfluid,whichactivatesjuxtacapillaryJreceptors,whichinturnstimulate therapid,shallowbreathingcharacteristicofcardiacdyspnea.Otherfactorsthatcontributetodyspneaonexertionincludereductionsin pulmonarycompliance,increasedairwayresistance,respiratorymuscleand/ordiaphragmfatigue,andanemia.Dyspneamaybecomeless frequentwiththeonsetofrightventricular(RV)failureandtricuspidregurgitation.
Orthopnea
Orthopnea,whichisdefinedasdyspneaoccurringintherecumbentposition,isusuallyalatermanifestationofHFthanisexertionaldyspnea.It resultsfromredistributionoffluidfromthesplanchniccirculationandlowerextremitiesintothecentralcirculationduringrecumbency,witha resultantincreaseinpulmonarycapillarypressure.Nocturnalcoughisacommonmanifestationofthisprocessandafrequentlyoverlooked symptomofHF.Orthopneagenerallyisrelievedbysittinguprightorsleepingwithadditionalpillows.Althoughorthopneaisarelativelyspecific symptomofHF,itmayoccurinpatientswithabdominalobesityorascitesandpatientswithpulmonarydiseasewhoselungmechanicsfavoran uprightposture.
ParoxysmalNocturnalDyspnea(PND)
Thistermreferstoacuteepisodesofsevereshortnessofbreathandcoughingthatgenerallyoccuratnightandawakenthepatientfromsleep, usually13hoursafterthepatientretires.PNDmaybemanifestbycoughingorwheezing,possiblybecauseofincreasedpressureinthe bronchialarteriesleadingtoairwaycompression,alongwithinterstitialpulmonaryedemathatleadstoincreasedairwayresistance.Whereas orthopneamayberelievedbysittinguprightatthesideofthebedwiththelegsinadependentposition,patientswithPNDoftenhavepersistent coughingandwheezingevenaftertheyhaveassumedtheuprightposition.Cardiac asthmaiscloselyrelatedtoPND,ischaracterizedby wheezingsecondarytobronchospasm,andmustbedifferentiatedfromprimaryasthmaandpulmonarycausesofwheezing.
Cheyne-StokesRespiration
Alsoreferredtoasperiodicrespirationorcyclicrespiration,Cheyne-Stokesrespirationispresentin40%ofpatientswithadvancedHFand usuallyisassociatedwithlowcardiacoutput.Cheyne-Stokesrespirationiscausedbyadiminishedsensitivityoftherespiratorycentertoarterial Pco2.Thereisanapneicphase,duringwhicharterialP o2fallsandarterialPco2rises.Thesechangesinthearterialbloodgascontentstimulate thedepressedrespiratorycenter,resultinginhyperventilationandhypocapnia,followedbyrecurrenceofapnea.Cheyne-Stokesrespirationsmay beperceivedbythepatientorthepatient'sfamilyasseveredyspneaorasatransientcessationofbreathing.
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AcutePulmonaryEdema
SeeChap.272
OTHERSYMPTOMS
PatientswithHFalsomaypresentwithgastrointestinalsymptoms.Anorexia,nausea,andearlysatietyassociatedwithabdominalpainand fullnessarecommoncomplaintsandmayberelatedtoedemaofthebowelwalland/oracongestedliver.Congestionoftheliverandstretching ofitscapsulemayleadtoright-upper-quadrantpain.Cerebralsymptomssuchasconfusion,disorientation,andsleepandmooddisturbances maybeobservedinpatientswithsevereHF,particularlyelderlypatientswithcerebralarteriosclerosisandreducedcerebralperfusion.Nocturiais commoninHFandmaycontributetoinsomnia.
PhysicalExamination
AcarefulphysicalexaminationisalwayswarrantedintheevaluationofpatientswithHF.Thepurposeoftheexaminationistohelpdeterminethe causeofHFaswellastoassesstheseverityofthesyndrome.Obtainingadditionalinformationaboutthehemodynamicprofileandtheresponse totherapyanddeterminingtheprognosisareimportantadditionalgoalsofthephysicalexamination.
GENERALAPPEARANCEANDVITALSIGNS
InmildormoderatelysevereHF,thepatientappearstobeinnodistressatrestexceptforfeelinguncomfortablewhenlyingflatformorethana fewminutes.InmoresevereHF,thepatientmustsitupright,mayhavelaboredbreathing,andmaynotbeabletofinishasentencebecauseof shortnessofbreath.SystolicbloodpressuremaybenormalorhighinearlyHF,butitgenerallyisreducedinadvancedHFbecauseofsevereLV dysfunction.Thepulsepressuremaybediminished,reflectingareductioninstrokevolume.Sinustachycardiaisanonspecificsigncausedby increasedadrenergicactivity.Peripheralvasoconstrictionleadingtocoolperipheralextremitiesandcyanosisofthelipsandnailbedsisalso causedbyexcessiveadrenergicactivity.
JUGULARVEINS
(SeealsoChap.227)Examinationofthejugularveinsprovidesanestimationofrightatrialpressure.Thejugularvenouspressureisbest appreciatedwiththepatientlyingrecumbent,withtheheadtiltedat45.Thejugularvenouspressureshouldbequantifiedincentimetersof water(normal 8cm)byestimatingtheheightofthevenouscolumnofbloodabovethesternalangleincentimetersandthenadding5cm.In theearlystagesofHF,thevenouspressuremaybenormalatrestbutmaybecomeabnormallyelevatedwithsustained( 1min)pressureon theabdomen(positiveabdominojugularreflux).Giantvwavesindicatethepresenceoftricuspidregurgitation.
PULMONARYEXAMINATION
Pulmonarycrackles(ralesorcrepitations)resultfromthetransudationoffluidfromtheintravascularspaceintothealveoli.Inpatientswith pulmonaryedema,ralesmaybeheardwidelyoverbothlungfieldsandmaybeaccompaniedbyexpiratorywheezing(cardiacasthma).When presentinpatientswithoutconcomitantlungdisease,ralesarespecificforHF.Importantly,ralesarefrequentlyabsentinpatientswithchronic HF,evenwhenLVfillingpressuresareelevated,becauseofincreasedlymphaticdrainageofalveolarfluid.Pleuraleffusionsresultfromthe elevationofpleuralcapillarypressureandtheresultingtransudationoffluidintothepleuralcavities.Sincethepleuralveinsdrainintoboththe systemicandthepulmonaryveins,pleuraleffusionsoccurmostcommonlywithbiventricularfailure.Althoughpleuraleffusionsareoftenbilateral inHF,whentheyareunilateral,theyoccurmorefrequentlyintherightpleuralspace.
CARDIACEXAMINATION
Examinationoftheheart,althoughessential,frequentlydoesnotprovideusefulinformationabouttheseverityofHF.Ifcardiomegalyispresent, thepointofmaximalimpulse(PMI)usuallyisdisplacedbelowthefifthintercostalspaceand/orlateraltothemidclavicularline,andtheimpulse ispalpableovertwointerspaces.SevereLVhypertrophyleadstoasustainedPMI.Insomepatients,athirdheartsound(S3)isaudibleand palpableattheapex.Patientswithenlargedorhypertrophiedrightventriclesmayhaveasustainedandprolongedleftparasternalimpulse extendingthroughoutsystole.AnS3(orprotodiastolic gallop)ismostcommonlypresentinpatientswithvolumeoverloadwhohavetachycardia andtachypnea,anditoftensignifiesseverehemodynamiccompromise.Afourthheartsound(S4)isnotaspecificindicatorofHFbutisusually presentinpatientswithdiastolicdysfunction.Themurmursofmitralandtricuspidregurgitationarefrequentlypresentinpatientswithadvanced HF.
ABDOMENANDEXTREMITIES
HepatomegalyisanimportantsigninpatientswithHF.Whenitispresent,theenlargedliverisfrequentlytenderandmaypulsateduringsystole iftricuspidregurgitationispresent.Ascites,alatesign,occursasaconsequenceofincreasedpressureinthehepaticveinsandtheveins drainingtheperitoneum.Jaundice,alsoalatefindinginHF,resultsfromimpairmentofhepaticfunctionsecondarytohepaticcongestionand hepatocellularhypoxemiaandisassociatedwithelevationsofbothdirectandindirectbilirubin. PeripheraledemaisacardinalmanifestationofHF,butitisnonspecificandusuallyisabsentinpatientswhohavebeentreatedadequatelywith diuretics.PeripheraledemaisusuallysymmetricanddependentinHFandoccurspredominantlyintheanklesandthepretibialregionin
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ambulatorypatients.Inbedriddenpatients,edemamaybefoundinthesacralarea(presacral edema)andthescrotum.Long-standingedema maybeassociatedwithinduratedandpigmentedskin.
CARDIACCACHEXIA
WithseverechronicHF,theremaybemarkedweightlossandcachexia.Althoughthemechanismofcachexiaisnotentirelyunderstood,itis probablymultifactorialandincludeselevationoftherestingmetabolicrate;anorexia,nausea,andvomitingduetocongestivehepatomegalyand abdominalfullness;elevationofcirculatingconcentrationsofcytokinessuchasTNF;andimpairmentofintestinalabsorptionduetocongestionof theintestinalveins.Whenpresent,cachexiaaugursapooroverallprognosis.
Diagnosis
ThediagnosisofHFisrelativelystraightforwardwhenthepatientpresentswithclassicsignsandsymptomsofHF;however,thesignsand symptomsofHFareneitherspecificnorsensitive.Accordingly,thekeytomakingthediagnosisistohaveahighindexofsuspicion,particularly forhigh-riskpatients.WhenthesepatientspresentwithsignsorsymptomsofHF,additionallaboratorytestingshouldbeperformed.
ROUTINELABORATORYTESTING
Patientswithnew-onsetHFandthosewithchronicHFandacutedecompensationshouldhaveacompletebloodcount,apanelofelectrolytes, bloodureanitrogen,serumcreatinine,hepaticenzymes,andaurinalysis.Selectedpatientsshouldhaveassessmentfordiabetesmellitus (fastingserumglucoseororalglucosetolerancetest),dyslipidemia(fastinglipidpanel),andthyroidabnormalities(thyroid-stimulatinghormone level).
ELECTROCARDIOGRAM(ECG)
Aroutine12-leadECGisrecommended.ThemajorimportanceoftheECGistoassesscardiacrhythmanddeterminethepresenceofLV hypertrophyorapriorMI(presenceorabsenceofQwaves)aswellastodetermineQRSwidthtoascertainwhetherthepatientmaybenefit fromresynchronizationtherapy(seebelow).AnormalECGvirtuallyexcludesLVsystolicdysfunction.
CHESTX-RAY
Achestx-rayprovidesusefulinformationaboutcardiacsizeandshape,aswellasthestateofthepulmonaryvasculature,andmayidentify noncardiaccausesofthepatient'ssymptoms.AlthoughpatientswithacuteHFhaveevidenceofpulmonaryhypertension,interstitialedema, and/orpulmonaryedema,themajorityofpatientswithchronicHFdonot.TheabsenceofthesefindingsinpatientswithchronicHFreflectsthe increasedcapacityofthelymphaticstoremoveinterstitialand/orpulmonaryfluid.
ASSESSMENTOFLVFUNCTION
Noninvasivecardiacimaging(Chap.229)isessentialforthediagnosis,evaluation,andmanagementofHF.Themostusefultestisthetwodimensional(2-D)echocardiogram/Doppler,whichcanprovideasemiquantitativeassessmentofLVsizeandfunctionaswellasthepresenceor absenceofvalvularand/orregionalwallmotionabnormalities(indicativeofapriorMI).ThepresenceofleftatrialdilationandLVhypertrophy, togetherwithabnormalitiesofLVdiastolicfillingprovidedbypulse-waveandtissueDoppler,isusefulfortheassessmentofHFwithapreserved EF.The2-Dechocardiogram/DopplerisalsoinvaluableinassessingRVsizeandpulmonarypressures,whicharecriticalintheevaluationand managementofcorpulmonale(seebelow).Magneticresonanceimaging(MRI)alsoprovidesacomprehensiveanalysisofcardiacanatomyand functionandisnowthegoldstandardforassessingLVmassandvolumes.MRIalsoisemergingasausefulandaccurateimagingmodalityfor evaluatingpatientswithHF,bothintermsofassessingLVstructureandfordeterminingthecauseofHF(e.g.,amyloidosis,ischemic cardiomyopathy,hemochromatosis). ThemostusefulindexofLVfunctionistheEF(strokevolumedividedbyend-diastolicvolume).BecausetheEFiseasytomeasureby noninvasivetestingandeasytoconceptualize,ithasgainedwideacceptanceamongclinicians.Unfortunately,theEFhasanumberoflimitations asatruemeasureofcontractility,sinceitisinfluencedbyalterationsinafterloadand/orpreload.Nonetheless,withtheexceptionsindicated above,whentheEFisnormal( 50%),systolicfunctionisusuallyadequate,andwhentheEFissignificantlydepressed(<3040%),contractility isusuallydepressed.
BIOMARKERS
CirculatinglevelsofnatriureticpeptidesareusefuladjunctivetoolsinthediagnosisofpatientswithHF.BothB-typenatriureticpeptide(BNP) andN-terminalpro-BNP,whicharereleasedfromthefailingheart,arerelativelysensitivemarkersforthepresenceofHFwithdepressedEF; theyalsoareelevatedinHFpatientswithapreservedEF,albeittoalesserdegree.However,itisimportanttorecognizethatnatriureticpeptide levelsincreasewithageandrenalimpairment,aremoreelevatedinwomen,andcanbeelevatedinrightHFfromanycause.Levelscanbe falselylowinobesepatientsandmaynormalizeinsomepatientsafterappropriatetreatment.Atpresent,serialmeasurementsofBNParenot recommendedasaguidetoHFtherapy.Otherbiomarkers,suchastroponinTandI,C-reactiveprotein,TNFreceptors,anduricacid,maybe elevatedinHFandprovideimportantprognosticinformation.Serialmeasurementsofoneormorebiomarkersultimatelymayhelpguidetherapy inHF,buttheyarenotcurrentlyrecommendedforthispurpose.
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EXERCISETESTING
TreadmillorbicycleexercisetestingisnotroutinelyadvocatedforpatientswithHF,buteitherisusefulforassessingtheneedforcardiac transplantationinpatientswithadvancedHF(Chap.235).Apeakoxygenuptake(Vo2)<14mL/kgperminisassociatedwitharelativelypoor prognosis.PatientswithaVo2<14mL/kgperminhavebeenshown,ingeneral,tohavebettersurvivalwhentransplantedthanwhentreated medically.
DifferentialDiagnosis
HFresemblesbutshouldbedistinguishedfrom(1)conditionsinwhichthereiscirculatorycongestionsecondarytoabnormalsaltandwater retentionbutinwhichthereisnodisturbanceofcardiacstructureorfunction(e.g.,renalfailure)and(2)noncardiaccausesofpulmonaryedema (e.g.,acuterespiratorydistresssyndrome).InmostpatientswhopresentwithclassicsignsandsymptomsofHF,thediagnosisisrelatively straightforward.However,evenexperiencedclinicianshavedifficultydifferentiatingthedyspneathatarisesfromcardiacandpulmonarycauses (Chap.33).Inthisregard,noninvasivecardiacimaging,biomarkers,pulmonaryfunctiontesting,andchestx-raymaybeuseful.AverylowBNP orN-terminalpro-BNPmaybehelpfulinexcludingacardiaccauseofdyspneainthissetting.Ankleedemamayarisesecondarytovaricose veins,obesity,renaldisease,orgravitationaleffects.WhenHFdevelopsinpatientswithapreservedEF,itmaybedifficulttodeterminethe relativecontributionofHFtothedyspneathatoccursinchroniclungdiseaseand/orobesity.
Treatment:HeartFailure
HFshouldbeviewedasacontinuumthatiscomposedoffourinterrelatedstages.Stage Aincludespatientswhoareathighriskfordeveloping HFbutdonothavestructuralheartdiseaseorsymptomsofHF(e.g.,patientswithdiabetesmellitusorhypertension).Stage Bincludespatients whohavestructuralheartdiseasebutdonothavesymptomsofHF(e.g.,patientswithapreviousMIandasymptomaticLVdysfunction).Stage CincludespatientswhohavestructuralheartdiseaseandhavedevelopedsymptomsofHF(e.g.,patientswithapreviousMIwithdyspneaand fatigue).Stage DincludespatientswithrefractoryHFrequiringspecialinterventions(e.g.,patientswithrefractoryHFwhoareawaitingcardiac transplantation).Inthiscontinuum,everyeffortshouldbemadetopreventHFnotonlybytreatingthepreventablecausesofHF(e.g., hypertension)butalsobytreatingthepatientinstagesBandCwithdrugsthatpreventdiseaseprogression(e.g.,ACEinhibitorsandbeta blockers)andbysymptomaticmanagementofpatientsinstageD.
DEFININGANAPPROPRIATETHERAPEUTICSTRATEGYFORCHRONICHF
Oncepatientshavedevelopedstructuralheartdisease,theirtherapydependsontheirNYHAfunctionalclassification(Table234-2).Althoughthis classificationsystemisnotoriouslysubjectiveandhaslargeinterobservervariability,ithaswithstoodthetestoftimeandcontinuestobewidely appliedtopatientswithHF.ForpatientswhohavedevelopedLVsystolicdysfunctionbutremainasymptomatic(classI),thegoalshouldbeto slowdiseaseprogressionbyblockingneurohormonalsystemsthatleadtocardiacremodeling(seebelow).Forpatientswhohavedeveloped symptoms(classIIIV),theprimarygoalshouldbetoalleviatefluidretention,lessendisability,andreducetheriskoffurtherdisease progressionanddeath.Thesegoalsgenerallyrequireastrategythatcombinesdiuretics(tocontrolsaltandwaterretention)withneurohormonal interventions(tominimizecardiacremodeling).
MANAGEMENTOFHFWITHDEPRESSEDEJECTIONFRACTION(<40%) GeneralMeasures
Cliniciansshouldaimtoscreenforandtreatcomorbiditiessuchashypertension,CAD,diabetesmellitus,anemia,andsleep-disordered breathing,astheseconditionstendtoexacerbateHF.HFpatientsshouldbeadvisedtostopsmokingandtolimitalcoholconsumptiontotwo standarddrinksperdayinmenoroneperdayinwomen.Patientssuspectedofhavinganalcohol-inducedcardiomyopathyshouldbeurgedto abstainfromalcoholconsumptionindefinitely.Extremesoftemperatureandheavyphysicalexertionshouldbeavoided.Certaindrugsareknown tomakeHFworseandshouldbeavoided(Table234-4).Forexample,nonsteroidalanti-inflammatorydrugs,includingcyclooxygenase2 inhibitors,arenotrecommendedinpatientswithchronicHFbecausetheriskofrenalfailureandfluidretentionismarkedlyincreasedinthe presenceofreducedrenalfunctionorACEinhibitortherapy.Patientsshouldreceiveimmunizationwithinfluenzaandpneumococcalvaccinesto preventrespiratoryinfections.ItisequallyimportanttoeducatethepatientandfamilyaboutHF,theimportanceofproperdiet,andthe importanceofcompliancewiththemedicalregimen.Supervisionofoutpatientcarebyaspeciallytrainednurseorphysicianassistantand/orin specializedHFclinicshasbeenfoundtobehelpful,particularlyinpatientswithadvanceddisease.
Table234-4FactorsThatMayPrecipitateAcuteDecompensationinPatientswithChronicHeartFailure
Dietaryindiscretion Myocardialischemia/infarction Arrhythmias(tachycardiaorbradycardia) DiscontinuationofHFtherapy
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Infection Anemia InitiationofmedicationsthatworsenHF Calciumantagonists(verapamil,diltiazem) Betablockers Nonsteroidalanti-inflammatorydrugs Antiarrhythmicagents[allclassIagents,sotalol(classIII)] Anti-TNFantibodies Alcoholconsumption Pregnancy Worseninghypertension Acutevalvularinsufficiency
Abbreviations:HF,heartfailure;TNF,tumornecrosisfactor.
Activity
AlthoughheavyphysicallaborisnotrecommendedinHF,routinemodestexercisehasbeenshowntobebeneficialinpatientswithNYHAclassI IIIHF.Foreuvolemicpatients,regularisotonicexercisesuchaswalkingorridingastationary-bicycleergometer,astolerated,shouldbe encouraged.ExercisetrainingresultsinreducedHFsymptoms,increasedexercisecapacity,andimprovedqualityoflife.
Diet
Dietaryrestrictionofsodium(23gdaily)isrecommendedinallpatientswithHFandpreservedordepressedEF.Furtherrestriction(<2gdaily) maybeconsideredinmoderatetosevereHF.Fluidrestrictionisgenerallyunnecessaryunlessthepatientdevelopshyponatremia(<130meq/L), whichmaydevelopbecauseofactivationoftherenin-angiotensinsystem,excessivesecretionofantidiuretichormone,orlossofsaltinexcessof waterfromdiureticuse.Fluidrestriction(<2L/day)shouldbeconsideredinhyponatremicpatientsorthosewhosefluidretentionisdifficultto controldespitehighdosesofdiureticsandsodiumrestriction.Vasopressinantagonistsalsomaybeusefulinseverehyponatremia.Caloric supplementationisrecommendedforpatientswithadvancedHFandunintentionalweightlossormusclewasting(cardiaccachexia);however, anabolicsteroidsarenotrecommendedforthesepatientsbecauseofthepotentialproblemswithvolumeretention.Theuseofdietary supplements("nutriceuticals")shouldbeavoidedinthemanagementofsymptomaticHFbecauseofthelackofprovenbenefitandthepotential forsignificant(adverse)interactionswithprovenHFtherapies.
Diuretics
ManyoftheclinicalmanifestationsofmoderatetosevereHFresultfromexcessivesaltandwaterretentionthatleadstovolumeexpansionand congestivesymptoms.Diuretics(Table234-5)aretheonlypharmacologicagentsthatcanadequatelycontrolfluidretentioninadvancedHF, andtheyshouldbeusedtorestoreandmaintainnormalvolumestatusinpatientswithcongestivesymptoms(dyspnea,orthopnea,edema)or signsofelevatedfillingpressures(rales,jugularvenousdistention,peripheraledema).Furosemide,torsemide,andbumetanideactattheloopof Henle(loop diuretics)byreversiblyinhibitingthereabsorptionofNa +,K+,andClinthethickascendinglimbofHenle'sloop;thiazidesand metolazonereducethereabsorptionofNa+andClinthefirsthalfofthedistalconvolutedtubule;andpotassium-sparingdiureticssuchas spironolactoneactatthelevelofthecollectingduct.
Table234-5DrugsfortheTreatmentofChronicHeartFailure(EF<40%)
Diuretics Furosemide
InitiatingDose
MaximalDose
2040mgqdorbid
400mg/da
Torsemide
1020mgqdbid
200mg/da
Bumetanide
0.51mgqdorbid
10mg/da
Hydrochlorthiazide
25mgqd
100mg/da
Metolazone
2.55mgqdorbid
20mg/da
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Angiotensin-ConvertingEnzymeInhibitors Captopril Enalapril Lisinopril Ramipril Trandolapri AngiotensinReceptorBlockers Valsartan Candesartan Irbesartan 40mgbid 4mgqd 75mgqd 160mgbid 32mgqd 300mgqdb Losartan ReceptorBlockers Carvedilol Bisoprolol MetoprololsuccinateCR AdditionalTherapies Spironolactone Eplerenone 12.525mgqd 25mgqd 2550mgqd 50mgqd 75mg/40mgtid 3.125mgbid 1.25mgqd 12.525mgqd 2550mgbid 10mgqd Targetdose200mgqd 12.5mgqd 50mgqd l6.25mgtid 2.5mgbid 2.55mgqd 1.252.5mgbid 0.5mgqd 50mgtid 10mgbid 2035mgqd 2.55mgbid 4mgqd
Combinationofhydralazine/isosorbidedinitrate 1025mg/10mgtid Fixeddoseofhydralazine/isosorbidedinitrate Digoxin
37.5mg/20mg(onetablet)tid 75mg/40mg(twotablets)tid 0.125mgqd 0.375mg/db
Notes: aDosemustbetitratedtoreducethepatient'scongestivesymptoms. bTargetdosenotestablished. Althoughalldiureticsincreasesodiumexcretionandurinaryvolume,theydifferintheirpotencyandpharmacologicproperties.Whereasloop diureticsincreasethefractionalexcretionofsodiumby2025%,thiazidediureticsincreaseitbyonly510%andtendtolosetheireffectiveness inpatientswithmoderateorsevererenalinsufficiency(creatinine>2.5mg/dL).Hence,loopdiureticsgenerallyarerequiredtorestorenormal volumestatusinpatientswithHF.Diureticsshouldbeinitiatedinlowdoses(Table234-5)andthencarefullytitratedupwardtorelievesignsand symptomsoffluidoverloadinanattempttoobtainthepatient's"dryweight."Thistypicallyrequiresmultipledoseadjustmentsovermanydays andoccasionallyweeksinpatientswithseverefluidoverload.Intravenousadministrationofdiureticsmaybenecessarytorelievecongestion acutelyandcanbedonesafelyintheoutpatientsetting.Oncethecongestionhasbeenrelieved,treatmentwithdiureticsshouldbecontinuedto preventtherecurrenceofsaltandwaterretention. Refractorinesstodiuretictherapymayrepresentpatientnonadherence,adirecteffectofchronicdiureticuseonthekidney,orprogressionof underlyingHF.Theadditionofthiazidesormetolazone,onceortwicedaily,toloopdiureticsmaybeconsideredinpatientswithpersistentfluid retentiondespitehigh-doseloopdiuretictherapy.Metolazoneisgenerallymorepotentandmuchlonger-actingthanthethiazidesinthissetting aswellasinpatientswithchronicrenalinsufficiency.However,chronicdailyuse,especiallyofmetolazone,shouldbeavoidedifpossiblebecause ofthepotentialforelectrolyteshiftsandvolumedepletion.Ultrafiltrationanddialysismaybeusedincasesofrefractoryfluidretentionthatare unresponsivetohighdosesofdiureticsandhavebeenshowntobehelpfulintheshortterm.
Adverse Effects
Diureticshavethepotentialtoproduceelectrolyteandvolumedepletionaswellasworseningazotemia.Inaddition,theymayleadtoworsening neurohormonalactivationanddiseaseprogression.Oneofthemostimportantadverseconsequencesofdiuresisisalterationsinpotassium homeostasis(hypokalemiaorhyperkalemia),whichincreasetheriskoflife-threateningarrhythmias.Ingeneral,bothloop-andthiazide-type diureticsleadtohypokalemia,whereasspironolactone,eplerenone,andtriamtereneleadtohyperkalemia.
PREVENTINGDISEASEPROGRESSION(TABLE234-5)
DrugsthatinterferewithexcessiveactivationoftheRAAsystemandtheadrenergicnervoussystemcanrelievethesymptomsofHFwitha
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depressedEFbystabilizingand/orreversingcardiacremodeling.Inthisregard,ACEinhibitorsandbetablockershaveemergedasthe cornerstonesofmoderntherapyforHFwithadepressedEF.
ACEInhibitors
ThereisoverwhelmingevidencethatACEinhibitorsshouldbeusedinsymptomaticandasymptomaticpatients(Figs.234-3and234-4)witha depressedEF(<40%).ACEinhibitorsinterferewiththerenin-angiotensinsystembyinhibitingtheenzymethatisresponsiblefortheconversion ofangiotensinItoangiotensinII.However,becauseACEinhibitorsalsoinhibitkininaseII,theymayleadtotheupregulationofbradykinin, whichmayfurtherenhancethebeneficialeffectsofangiotensinsuppression.ACEinhibitorsstabilizeLVremodeling,improvesymptoms,reduce hospitalization,andprolonglife.BecausefluidretentioncanattenuatetheeffectsofACEinhibitors,itispreferabletooptimizethedoseof diureticbeforestartingtheACEinhibitor.However,itmaybenecessarytoreducethedoseofdiureticduringtheinitiationofACEinhibitionto preventsymptomatichypotension.ACEinhibitorsshouldbeinitiatedinlowdoses,followedbygradualincrementsifthelowerdoseshavebeen welltolerated.ThedosesofACEinhibitorsshouldbeincreaseduntiltheyaresimilartothosewhichhavebeenshowntobeeffectiveinclinical trials(Table234-5).Higherdosesaremoreeffectivethanlowerdosesinpreventinghospitalization.
Figure234-3
Meta-analysisofangiotensin-convertingenzyme(ACE)inhibitorsinheartfailurepatientswithadepressedejectionfraction. A.TheKaplan-Meiercurvesformortalityfor5966HFpatientswithadepressedEFtreatedwithanACEinhibitorafteracutemyocardialinfarction(three
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trials). B.TheKaplan-Meiercurvesformortalityfor12,763HFpatientswithadepressedEFtreatedwithanACEinhibitorinfiveclinicaltrials,including postinfarctiontrials.ThebenefitsofACEinhibitorswereobservedearlyandpersistedlong-term.(Modified from MD Flather et al: Lancet 355:1575, 2000.)
Figure234-4
Treatmentalgorithmforchronicheartfailurepatientswithadepressedejectionfraction.AftertheclinicaldiagnosisofHFismade,itisimportant totreatthepatient'sfluidretentionbeforestartinganACEinhibitor(oranARBifthepatientisACE-intolerant).Betablockersshouldbestartedafterthe fluidretentionhasbeentreatedand/ortheACEinhibitorhasbeenuptitrated.Ifthepatientremainssymptomatic,anARB,analdosteroneantagonist,or digoxincanbeaddedas"tripletherapy."Thefixed-dosecombinationofhydralazine/isosorbidedinitrateshouldbeaddedtoanACEinhibitorandabeta blockerinAfrican-AmericanpatientswithNYHAclassIIIVHF.Devicetherapyshouldbeconsideredinadditiontopharmacologictherapyinappropriate patients.HF,heartfailure;ACE,angiotensin-convertingenzyme;ARB,angiotensinreceptorblocker;NYHA,NewYorkHeartAssociation;CRT,cardiac resynchronizationtherapy;ICD,implantablecardiacdefibrillator.
Adverse Effects
Themajorityofadverseeffectsarerelatedtosuppressionoftherenin-angiotensinsystem.Thedecreasesinbloodpressureandmildazotemia thatmayoccurduringtheinitiationoftherapygenerallyarewelltoleratedanddonotrequireadecreaseinthedoseoftheACEinhibitor. However,ifhypotensionisaccompaniedbydizzinessoriftherenaldysfunctionbecomessevere,itmaybenecessarytoreducethedoseofthe inhibitor.Potassiumretentionmayalsobecomeproblematicifthepatientisreceivingpotassiumsupplementsorapotassium-sparingdiuretic. PotassiumretentionthatisnotresponsivetothesemeasuresmayrequireareductioninthedoseofACEinhibitor. ThesideeffectsofACEinhibitorsrelatedtokininpotentiationincludeanonproductivecough(1015%ofpatients)andangioedema(1%of patients).InpatientswhocannottolerateACEinhibitorsbecauseofcoughorangioedema,angiotensinreceptorblockers(ARBs)arethe recommendedfirstlineoftherapy(seebelow).PatientsintolerantofACEinhibitorsbecauseofhyperkalemiaorrenalinsufficiencyarelikelyto experiencethesamesideeffectswithARBs.Inthesecases,thecombinationofhydralazineandanoralnitrateshouldbeconsidered(Table2345).
AngiotensinReceptorBlockers
ThesedrugsarewelltoleratedinpatientswhoareintolerantofACEinhibitorsbecauseofcough,skinrash,andangioedema.ARBsshouldbe usedinsymptomaticandasymptomaticpatientswithanEF<40%whoareACE-intolerantforreasonsotherthanhyperkalemiaorrenal insufficiency(Table234-5).AlthoughACEinhibitorsandARBsinhibittherenin-angiotensinsystem,theydosobydifferentmechanisms.Whereas ACEinhibitorsblocktheenzymeresponsibleforconvertingangiotensinItoangiotensinII,ARBsblocktheeffectsofangiotensinIIonthe angiotensintype1receptor.SomeclinicaltrialshavedemonstratedatherapeuticbenefitfromtheadditionofanARBtoanACEinhibitorin
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patientswithchronicHF.Whengiveninconcertwithbetablockers,ARBsreversetheprocessofLVremodeling,improvepatientsymptoms, preventhospitalization,andprolonglife.
Adverse Effects
BothACEinhibitorsandARBshavesimilareffectsonbloodpressure,renalfunction,andpotassium.Therefore,theproblemsofsymptomatic hypotension,azotemia,andhyperkalemiaaresimilarforbothoftheseagents.
-AdrenergicReceptorBlockers
Beta-blockertherapyrepresentsamajoradvanceinthetreatmentofpatientswithadepressedEF(Fig.234-5).Thesedrugsinterferewiththe harmfuleffectsofsustainedactivationoftheadrenergicnervoussystembycompetitivelyantagonizingoneormoreadrenergicreceptors( 1,
1,and 2).Althoughthereareanumberofpotentialbenefitstoblockingallthreereceptors,mostofthedeleteriouseffectsofadrenergic
activationaremediatedbythe 1receptor.WhengiveninconcertwithACEinhibitors,betablockersreversetheprocessofLVremodeling, improvepatientsymptoms,preventhospitalization,andprolonglife.Therefore,betablockersareindicatedforpatientswithsymptomaticor asymptomaticHFandadepressedEF<40%.
Figure234-5
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Meta-analysisofbetablockersonmortalityratesinHFpatientswithadepressedEF.Effectofbetablockersvs.placeboinpatientswhowerenot (A)orwhowere(B)receivinganangiotensin-convertingenzyme(ACE)inhibitororanangiotensinreceptorblocker(ARB)atbaselineinsixclinicaltrials. Therewasasimilarimpactofbeta-blockertherapyontheendpointsofall-causemortalityaswellasdeathandheartfailurehospitalizationinboththe presenceandtheabsenceofACEinhibitororARBatbaseline.BEST,Beta-BlockerEvaluationofSurvivalTrial(bucindolol);CIBIS,CardiacInsufficiency BisoprololStudy(bisoprolol);COPERNICUS,CarvedilolprOsPEctiveRaNdomIzedCumulativeSurvival(carvedilol);MERIT-HF,MetoprololCR/XLRandomized InterventionTrialinHeartFailure(metoprololCR/XL).(Modified from H Krum et al: Eur Heart J 26:2154, 2005.)
AnalogoustotheuseofACEinhibitors,betablockersshouldbeinitiatedinlowdoses(Table234-5),followedbygradualincrementsinthedose iflowerdoseshavebeenwelltolerated.Thedoseofbetablockershouldbeincreaseduntilthedosesusedaresimilartothosewhichhavebeen reportedtobeeffectiveinclinicaltrials(Table234-5).However,unlikeACEinhibitors,whichmaybetitratedupwardrelativelyrapidly,the titrationofbetablockersshouldproceednomorerapidlythanat2-weekintervals,becausetheinitiationand/orincreaseddosingoftheseagents mayleadtoworseningfluidretentionconsequenttothewithdrawalofadrenergicsupporttotheheartandthecirculation.Thus,itisimportantto optimizethedoseofdiureticbeforestartingtherapywithbetablockers.Ifworseningfluidretentiondoesoccur,itislikelytodosowithin35 daysoftheinitiationoftherapy,anditwillbemanifestasanincreaseinbodyweightand/orsymptomsofworseningHF.Theincreasedfluid retentionusuallycanbemanagedbyincreasingthedoseofdiuretics.Insomepatientsthedoseofthebetablockermayhavetobereduced. Contrarytoearlyreports,theaggregateresultsofclinicaltrialssuggestthatbeta-blockertherapyiswelltoleratedbythegreatmajority( 85%) ofHFpatients,includingpatientswithcomorbidconditionssuchasdiabetesmellitus,chronicobstructivelungdisease,andperipheralvascular disease.Nonetheless,thereisasubsetofpatients(1015%)whoremainintoleranttobetablockersbecauseofworseningfluidretentionor symptomatichypotensionorbradycardia.
Adverse Effects
Theadverseeffectsofbeta-blockerusegenerallyarerelatedtothepredictablecomplicationsthatarisefrominterferingwiththeadrenergic nervoussystem.Thesereactionsgenerallyoccurwithinseveraldaysoftheinitiationoftherapyandgenerallyareresponsivetoadjustmentsof concomitantmedications,asdescribedabove.Therapywithbetablockerscanleadtobradycardiaand/orexacerbateheartblock.Accordingly, thedoseofbetablockershouldbereducediftheheartratedecreasesto<50beats/minand/orsecond-orthird-degreeheartblockor symptomatichypotensiondevelops.Betablockersarenotrecommendedforpatientswhohaveasthmawithactivebronchospasm.Betablockers thatalsoblockthe 1receptorcanleadtovasodilatorysideeffects.
AldosteroneAntagonists
Althoughclassifiedaspotassium-sparingdiuretics,drugsthatblocktheeffectsofaldosterone(spironolactoneoreplerenone)havebeneficial effectsthatareindependentoftheeffectsoftheseagentsonsodiumbalance.AlthoughACEinhibitionmaytransientlydecreasealdosterone secretion,withchronictherapythereisarapidreturnofaldosteronetolevelssimilartothosebeforeACEinhibition.Accordingly,the administrationofanaldosteroneantagonistisrecommendedforpatientswithNYHAclassIVorclassIII(previouslyclassIV)HFwhohavea depressedEF(<35%)andarereceivingstandardtherapy,includingdiuretics,ACEinhibitors,andbetablockers.Thedoseofaldosterone
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antagonistshouldbeincreaseduntilthedosesusedaresimilartothosewhichhavebeenshowntobeeffectiveinclinicaltrials(Table234-5).
AdverseEffects
Themajorproblemwiththeuseofaldosteroneantagonistsisthedevelopmentoflife-threateninghyperkalemia,whichismorepronetooccurin patientswhoarereceivingpotassiumsupplementsorwhohaveunderlyingrenalinsufficiency.Aldosteroneantagonistsarenotrecommended whentheserumcreatinineis>2.5mg/dL(orcreatinineclearanceis<30mL/min)orwhentheserumpotassiumis>5mmol/L.Painful gynecomastiamaydevelopin1015%ofpatientswhousespironolactone,inwhichcaseeplerenonemaybesubstituted.
SPECIALPOPULATIONS
Thecombinationofhydralazineandisosorbidedinitrate(Table234-5)isrecommendedaspartofstandardtherapyinadditiontobetablockers andACEinhibitorsforAfricanAmericanswithNYHAclassIIIVHF.Althoughtheexactmechanismfortheeffectsofthiscombinationisnot known,itisbelievedtobesecondarytothebeneficialeffectsofNOontheperipheralcirculation.
MANAGEMENTOFPATIENTSWHOREMAINSYMPTOMATIC
Additionalpharmacologictherapyshouldbeconsideredinpatientswhohavepersistentsymptomsorprogressiveworseningdespiteoptimized therapywithanACEinhibitorandabetablocker.AgentsthatmaybeconsideredaspartofadditionaltherapyincludeanARB,spironolactone, thecombinationofhydralazineandisosorbidedinitrate,anddigitalis.Theoptimalchoiceofadditionaldrugtherapytoimprovetheoutcome furtherhasnotbeenfirmlyestablished.Thus,thechoiceofaspecificagentwillbeinfluencedbyclinicalconsiderations,includingrenalfunction, serumpotassiumconcentration,bloodpressure,andrace.ThetriplecombinationofanACEinhibitor,anARB,andanaldosteroneantagonist shouldnotbeusedbecauseofthehighriskofhyperkalemia. DigoxinisrecommendedforpatientswithsymptomaticLVsystolicdysfunctionwhohaveconcomitantatrialfibrillation,anditshouldbe consideredforpatientswhohavesignsorsymptomsofHFwhilereceivingstandardtherapy,includingACEinhibitorsandbetablockers.Therapy withdigoxiniscommonlyinitiatedandmaintainedatadoseof0.1250.25mgdaily.Forthegreatmajorityofpatients,thedoseshouldbe0.125 mgdaily,andtheserumdigoxinlevelshouldbe<1ng/mL,especiallyinelderlypatients,patientswithimpairedrenalfunction,andpatientswith alowleanbodymass.Higherdoses(andserumconcentrations)appeartobelessbeneficial.Thereisnoindicationforusingloadingdosesof digoxintoinitiatetherapyinpatientswithHF.
ANTICOAGULATIONANDANTIPLATELETTHERAPY
PatientswithHFhaveanincreasedriskforarterialorvenousthromboembolicevents.InclinicalHFtrials,therateofstrokerangesfrom1.3to 2.4%peryear.DepressedLVfunctionisbelievedtopromoterelativestasisofbloodindilatedcardiacchamberswithincreasedriskofthrombus formation.Treatmentwithwarfarin[goalinternationalnormalizedratio(INR)23]isrecommendedforpatientswithHFandchronicor paroxysmalatrialfibrillationorwithahistoryofsystemicorpulmonaryemboli,includingstrokeortransientischemicattack.Patientswith symptomaticorasymptomaticischemiccardiomyopathyanddocumentedrecentlargeanteriorMIorrecentMIwithdocumentedLVthrombus shouldbetreatedwithwarfarin(goalINR23)fortheinitial3monthsaftertheMIunlesstherearecontraindicationstoitsuse. AspirinisrecommendedinHFpatientswithischemicheartdiseaseforthepreventionofMIanddeath.However,lowerdosesofaspirin(75or81 mg)maybepreferablebecauseoftheconcernofworseningofHFathigherdoses.
MANAGEMENTOFCARDIACARRHYTHMIAS
(SeealsoChap.233)Atrialfibrillationoccursin1530%ofpatientswithHFandisacommoncauseofcardiacdecompensation.Most antiarrhythmicagents,withtheexceptionofamiodaroneanddofetilide,havenegativeinotropiceffectsandareproarrhythmic.Amiodaroneisa classIIIantiarrhythmicthathasfewornonegativeinotropicand/orproarrhythmiceffectsandiseffectiveagainstmostsupraventricular arrhythmias.Amiodaroneisthepreferreddrugforrestoringandmaintainingsinusrhythm,anditmayimprovethesuccessofelectrical cardioversioninpatientswithHF.AmiodaroneincreasesthelevelofphenytoinanddigoxinandprolongstheINRinpatientstakingwarfarin. Therefore,itisoftennecessarytoreducethedoseofthesedrugsbyasmuchas50%wheninitiatingtherapywithamiodarone.Theriskof adverseeventssuchashyperthyroidism,hypothyroidism,pulmonaryfibrosis,andhepatitisisrelativelylow,particularlywhenlowerdosesof amiodaroneareused(100200mg/d). Implantablecardiacdefibrillators(ICDs;seebelow)arehighlyeffectiveintreatingrecurrencesofsustainedventriculartachycardiaand/or ventricularfibrillationinHFpatientswithrecurrentarrhythmiasand/orcardiacsyncope,andtheymaybeusedasstand-alonetherapyorin combinationwithamiodaroneand/orabetablocker(Chap.233).Thereisnorolefortreatingventriculararrhythmiaswithanantiarrhythmic agentwithoutanICD.
DEVICETHERAPY CardiacResynchronization
Approximatelyone-thirdofpatientswithadepressedEFandsymptomaticHF(NYHAclassIIIIV)manifestaQRSduration>120ms.ThisECG findingofabnormalinter-orintraventricularconductionhasbeenusedtoidentifypatientswithdyssynchronousventricularcontraction.The
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mechanicalconsequencesofventriculardyssynchronyincludesuboptimalventricularfilling,areductioninLVcontractility,prolongedduration (andthereforegreaterseverity)ofmitralregurgitation,andparadoxicalseptalwallmotion.Biventricular pacing,alsotermedcardiac resynchronization therapy(CRT),stimulatesbothventriclesnearlysimultaneously,therebyimprovingthecoordinationofventricularcontraction andreducingtheseverityofmitralregurgitation.WhenCRTisaddedtooptimalmedicaltherapyinpatientsinsinusrhythm,thereisasignificant decreaseinpatientmortalityratesandhospitalizationandareversalofLVremodeling,aswellasimprovedqualityoflifeandexercisecapacity. Accordingly,CRTisrecommendedforpatientsinsinusrhythmwithanEF<35%andaQRS>120msandthosewhoremainsymptomatic(NYHA IIIIV)despiteoptimalmedicaltherapy.ThebenefitsofCRTinpatientswithatrialfibrillationhavenotbeenclearlyestablished.
ImplantableCardiacDefibrillators
(SeealsoChap.233)TheprophylacticimplantationofICDsinpatientswithmildtomoderateHF(NYHAclassIIIII)hasbeenshowntoreduce theincidenceofsuddencardiacdeathinpatientswithischemicornonischemiccardiomyopathy.Accordingly,implantationofanICDshouldbe consideredforpatientsinNYHAclassIIIIIHFwithadepressedEFof<35%whoarealreadyonoptimalbackgroundtherapy,includinganACE inhibitor(orARB),abetablocker,andanaldosteroneantagonist.AnICDmayalsobecombinedwithabiventricularpacemakerinpatientswith NYHAclassIIIIVHF.
MANAGEMENTOFHFWITHAPRESERVEDEJECTIONFRACTION(>4050%)
DespitethewealthofinformationwithrespecttotheevaluationandmanagementofHFwithadepressedEF,therearenoprovenand/or approvedpharmacologicordevicetherapiesforthemanagementofpatientswithHFandapreservedEF.Therefore,itisrecommendedthat initialtreatmenteffortsshouldbefocused,whereverpossible,ontheunderlyingdiseaseprocess(e.g.,myocardialischemia,hypertension) associatedwithHFwithpreservedEF.Precipitatingfactorssuchastachycardiaandatrialfibrillationshouldbetreatedasquicklyaspossible throughratecontrolandrestorationofsinusrhythmwhenappropriate.Dyspneamaybetreatedbyreducingtotalbloodvolume(dietarysodium restrictionanddiuretics),decreasingcentralbloodvolume(nitrates),orbluntingneurohormonalactivationwithACEinhibitors,ARBs,and/or betablockers.Treatmentwithdiureticsandnitratesshouldbeinitiatedatlowdosestoavoidhypotensionandfatigue.
ACUTEDECOMPENSATEDHF DefininganAppropriateTherapeuticStrategy
ThetherapeuticgoalsforthemanagementofacutedecompensatedHF(ADHF)therapyareto(1)stabilizethehemodynamicderangementsthat provokedthesymptomsresponsibleforthehospitalization,(2)identifyandtreatthereversiblefactorsthatprecipitateddecompensation,and(3) reestablishaneffectiveoutpatientmedicalregimenthatwillpreventdiseaseprogressionandrelapse.Inmostinstancesthiswillrequire hospitalization,ofteninanintensivecareunit(ICU)setting.Everyeffortshouldbemadetoidentifytheprecipitatingcauses,suchasinfection, arrhythmias,dietaryindiscretion,pulmonaryembolism,infectiveendocarditis,occultmyocardialischemia/infarction,andenvironmentaland/or emotionalstress(Table234-4),sinceremovaloftheseprecipitatingeventsiscriticaltothesuccessoftreatment. ThetwoprimaryhemodynamicdeterminantsofADHFareelevatedLVfillingpressuresandadepressedcardiacoutput.Frequentlythedepressed cardiacoutputisaccompaniedbyanincreaseinsystemicvascularresistance(SVR)asaresultofexcessiveneurohormonalactivation.Because thesehemodynamicderangementsmayoccursinglyortogether,patientswithacuteHFgenerallypresentwithoneoffourbasichemodynamic profiles(Fig.234-6):normalLVfillingpressurewithnormalperfusion(ProfileA),elevatedLVfillingpressurewithnormalperfusion(ProfileB), elevatedLVfillingpressureswithdecreasedperfusion(ProfileC),andnormalorlowLVfillingpressurewithdecreasedtissueperfusion(Profile L).
Figure234-6
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Hemodynamicprofilesinpatientswithacuteheartfailure.Mostpatientscanbecategorizedintooneofthefourhemodynamicprofilesbyperforming abriefbedsideexaminationthatincludesexaminationoftheneckveins,lungs,andperipheralextremities.Moredefinitivehemodynamicinformationmay beobtainedbyperforminginvasivehemodynamicmonitoring,particularlyifthepatientisgravelyilloriftheclinicalpresentationisunclear.This hemodynamicclassificationprovidesausefulguideforselectingtheinitialoptimaltherapiesforthemanagementofacuteHF.LV,leftventricular;CO, cardiacoutput;SVR,systemicvascularresistance.(Modified from Grady et al: Circulation 102:2443, 2000.)
Accordingly,thetherapeuticapproachtotreatingpatientswithacuteHFshouldbetailoredtoreflectthepatient'shemodynamicpresentation. Thegoalshouldbe,wheneverpossible,torestorethepatienttoanormalhemodynamicprofile(ProfileA).Inmanyinstancesthepatient's hemodynamicpresentationcanbeapproximatedfromtheclinicalexamination.Forexample,patientswithelevatedLVfillingpressuresmayhave signsoffluidretention(rales,elevatedneckveins,peripheraledema)andarereferredtoasbeing"wet,"whereaspatientswithadepressed cardiacoutputandanelevatedSVRgenerallyhavepoortissueperfusionmanifestedbycooldistalextremitiesandarereferredtoasbeing "cold."Nonetheless,itshouldbeemphasizedthatpatientswithchronicheartfailuremaynothaveralesorevidenceofperipheraledemaatthe timeoftheinitialpresentationwithacutedecompensation,andthismayleadtotheunderrecognitionofelevatedfillingpressures.Inthese patients,itmaybeappropriatetoperforminvasivehemodynamicmonitoring. Patientswhoarenotcongestedandhavenormaltissueperfusionarereferredtoasbeing"dry"and"warm,"respectively.WhenacuteHF patientspresenttothehospitalwithProfileA,theirsymptomsareoftenduetoconditionsotherthanHF(e.g.,pulmonaryorhepaticdiseaseor transientmyocardialischemia).Morecommonly,however,acuteHFpatientspresentwithcongestivesymptoms["warmandwet"(ProfileB)],in whichcasetreatmentoftheelevatedfillingpressureswithdiureticsandvasodilatorsiswarrantedtoreduceLVfillingpressures.ProfileB includesmostpatientswithacutepulmonaryedema.Thetreatmentofthislife-threateningconditionisdescribedinChap.272. PatientsalsomaypresentwithcongestionandasignificantlyelevatedSVRandreductionofcardiacoutput["coldandwet"(ProfileC)].Inthese patients,cardiacoutputcanbeincreasedandLVfillingpressuresreducedbyusingintravenousvasodilators.Intravenousinotropicagentswith vasodilatingaction[dobutamine,low-dosedopamine,milrinone(Table234-6)]augmentcardiacoutputbystimulatingmyocardialcontractility aswellasbyfunctionallyunloadingtheheart.
Table234-6DrugsfortheTreatmentforAcuteHeartFailure
Vasodilators Nitroglycerin Nitroprusside Nesiritide
InitiatingDose
MaximalDose
20 g/min 10 g/min Bolus2 g/kg
40400 g/min 30350 g/min 0.010.03 g/kgpermina
Inotropes Dobutamine 12 g/kgpermin 210 g/kgperminb Milrinone Bolus50 g/kg 0.10.75 g/kgpermin b Dopamine 12 g/kgpermin 24 g/kgpermin b Levosimendan Bolus12 g/kg 0.10.2 g/kgpermin c Vasoconstrictors Dopamineforhypotension Epinephrine Phenylephrine Vasopressin
5 g/kgpermin 0.5 g/kgpermin 0.3 g/kgpermin 0.05units/min
515 g/kgpermin 50 g/kgpermin 3 g/kgpermin 0.10.4units/min
Notes: aUsually<4 g/kg/min.

b
Inotropeswillalsohavevasodilatoryproperties.
cApprovedoutsidetheUnitedStatesformanagementofacuteheartfailure.
PatientswhopresentwithProfileL("coldanddry")shouldbecarefullyevaluatedbyright-heartcatheterizationforthepresenceofanoccult elevationofLVfillingpressures.IfLVfillingpressuresarelow[pulmonarycapillarywedgepressure(PCWP)<12mmHg],acautioustrialoffluid repletionmaybeconsidered.Thegoalsoffurthertherapydependontheclinicalsituation.Therapytoreachtheaforementionedgoalsmaynot
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bepossibleinsomepatients,particularlyiftheyhavedisproportionateRVdysfunctionoriftheydevelopcardiorenalsyndrome,inwhichrenal functiondeterioratesduringaggressivediuresis.Worseningrenaldysfunctionoccursinapproximately25%ofpatientshospitalizedwithHFandis associatedwithprolongedhospitalstaysandhighermortalityratesafterdischarge.
PharmacologicManagementofAcuteHF
(Table234-6)
Vasodilators
Afterdiuretics,intravenousvasodilatorsarethemostusefulmedicationsforthemanagementofacuteHF.Bystimulatingguanylylcyclasewithin smooth-musclecells,nitroglycerin,nitroprusside,andnesiritideexertdilatingeffectsonarterialresistanceandvenouscapacitancevessels, whichresultsinaloweringofLVfillingpressure,areductioninmitralregurgitation,andimprovedforwardcardiacoutputwithoutincreasing heartrateorcausingarrhythmias.Hypotensionisthemostcommonsideeffectofallvasodilatingagents. Intravenousnitroglyceringenerallyisbegunat20 g/minandisincreasedin20- gincrementsuntilpatientsymptomsareimprovedorPCWPis decreasedto16mmHgwithoutreducingsystolicbloodpressurebelow80mmHg.ThemostcommonsideeffectofIVororalnitratesis headache,which,ifmild,canbetreatedwithanalgesicsandoftenresolvesduringcontinuedtherapy.Nitroprussidegenerallyisinitiatedat10 g/minandincreasedby1020 gevery1020minastolerated,withthesamehemodynamicgoalsasdescribedabove.Therapidityofonset andoffset,withahalf-lifeofapproximately2min,facilitatesearlyestablishmentofanindividualpatient'soptimallevelofvasodilationinthe ICU.Themajorlimitationofnitroprussideissideeffectsfromcyanidetoxicity,whichmanifestspredominantlyasgastrointestinalandcentral nervoussystemmanifestationsandismostlikelytooccurinpatientsreceiving>250 g/minforover48h. Nesiritide,thenewestvasodilator,isarecombinantformofbrain-typenatriureticpeptide,whichisanendogenouspeptidesecretedprimarily fromtheLVinresponsetoanincreaseinwallstress.Nesiritideisgivenasabolus(2 g/kg)followedbyafixed-doseinfusion(0.010.03 g/kg permin).NesiritideeffectivelylowersLVfillingpressuresandimprovessymptomsduringthetreatmentofacuteHF.Headacheislesscommon withnesiritidethanwithnitroglycerin.Althoughtermedanatriuretic peptide,nesiritidehasnotbeenassociatedwithmajordiuresiswhenused aloneinclinicaltrials.Itdoes,however,appeartopotentiatetheeffectofconcomitantdiureticssuchthatthetotalrequireddiureticdosemaybe slightlylower.Therehave,however,beenrecentconcernsabouttheadverseeffectsofneseritideonrenalfunctioninacutedecompensatedHF whichmayberelatedtotheinitialbolus.
Inotropic Agents
Positiveinotropicagentsproducedirecthemodynamicbenefitsbystimulatingcardiaccontractilityaswellasbyproducingperipheralvasodilation. Collectively,thesehemodynamiceffectsresultinanimprovementincardiacoutputandafallinLVfillingpressures. Dobutamine,whichisthemostcommonlyusedinotropicagentforthetreatmentofacuteHF,exertsitseffectsbystimulating 1and 2 receptors,withlittleeffecton 1receptors.Dobutamineisgivenasacontinuousinfusionataninitialinfusionrateof12 g/kgpermin.Higher doses(>5 g/kgpermin)arefrequentlynecessaryforseverehypoperfusion;however,thereislittleaddedbenefittoincreasingthedoseabove 10 g/kgpermin.Patientsmaintainedonchronicinfusionsfor>72hgenerallydeveloptachyphylaxisandrequireincreasingdoses. MilrinoneisaphosphodiesteraseIIIinhibitorthatleadstoincreasedcyclicAMPbyinhibitingitsbreakdown.Milrinonemayactsynergisticallywith -adrenergicagoniststoachieveagreaterincreaseincardiacoutputthanisachievedwitheitheragentalone,anditmayalsobemoreeffective thandobutamineinincreasingcardiacoutputinthepresenceofbetablockers.Milrinonemaybeadministeredasabolusdoseof50 g/kgper min,followedbyacontinuousinfusionrateof0.10.75 g/kgpermin.Ifthepatienthasalowbloodpressure,manyclinicianswillomitthe bolusdose.Becausemilrinoneisamoreeffectivevasodilatorthandobutamine,itproducesagreaterreductioninLVfillingpressures,albeitwith agreaterriskofhypotension. Althoughshort-termuseofinotropesprovideshemodynamicbenefits,theseagentsaremorepronetocausetachyarrhythmiasandischemic eventsthanvasodilatorsare.Therefore,inotropesaremostappropriatelyusedinclinicalsettingsinwhichvasodilatorsanddiureticsarenot helpful,suchasinpatientswithpoorsystemicperfusionand/orcardiogenicshock,patientsrequiringshort-termhemodynamicsupportafteran MIorsurgery,andpatientsawaitingcardiactransplantation,oraspalliativecareinpatientswithadvancedHF.Ifpatientsrequiresustaineduse ofintravenousinotropes,strongconsiderationshouldbegiventotheuseofanICDtosafeguardagainsttheproarrhythmiceffectsofthese agents.
Vasoconstrictors
VasoconstrictorsareusedtosupportsystemicbloodpressureinpatientswithHF.Ofthethreeagentsthatarecommonlyused(Table234-6), dopamineisgenerallythefirstchoicefortherapyinsituationsinwhichmodestinotropyandpressorsupportarerequired.Dopamineisan endogenouscatecholaminethatstimulates 1and 1receptorsanddopaminergicreceptors(DA1andDA2)intheheartandcirculation.The effectsofdopaminearedose-dependent.Lowdosesofdopamine(<2 g/kgpermin)stimulatetheDA1andDA2receptorsandcause vasodilationofthesplanchnicandrenalvasculature.Moderatedoses(24 g/kgpermin)stimulatethe 1receptorsandcauseanincreasein cardiacoutputwithlittleornochangeinheartrateorSVR.Athigherdoses( 5 g/kgpermin)theeffectsofdopamineonthe 1receptors overwhelmthedopaminergicreceptors,andvasoconstrictionensues,leadingtoanincreaseinSVR,LVfillingpressures,andheartrate. Significantadditionalinotropicandbloodpressuresupportcanbeprovidedbyepinephrine,phenylephrine,andvasopressin(Table234-6); however,prolongeduseoftheseagentscanleadtorenalandhepaticfailureandcancausegangreneofthelimbs.Therefore,theseagents shouldnotbeadministeredexceptintrueemergencysituations.
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VasopressinAntagonists
VasopressinlevelsareoftenelevatedinpatientswithHFandLVdysfunctionandmaycontributetothehyponatremiathatdevelopsinHF patients.Vasopressinantagonistsreducebodyweightandedemaandnormalizeserumsodiuminpatientswithhyponatremiabuthavenotbeen associatedwithimprovedpatientoutcomesinclinicaltrials.Tolvaptan(oral)andconivaptan(IV)arecurrentlyapprovedforthetreatmentof hyponatremiabutarenotapprovedforthetreatmentofHF.
MechanicalandSurgicalInterventions
IfpharmacologicinterventionsfailtostabilizeapatientwithrefractoryHF,mechanicalandsurgicalinterventionsmayprovideeffective circulatorysupport.Theseinterventionsincludeintraaorticballooncounterpulsation,percutaneousandsurgicallyimplantedLVassistdevices, andcardiactransplantation(Chap.235).
PlanningforHospitalDischarge
Patienteducationshouldtakeplaceduringtheentirehospitalization,withaspecificfocusonsaltandfluidstatusandobtainingdailyweights,in additiontomedicationschedules.AlthoughthemajorityofpatientshospitalizedwithHFcanbestabilizedandreturnedtoagoodleveloffunction onanoralregimendesignedtomaintainstability,3050%ofpatientsdischargedwithadiagnosisofHFarerehospitalizedwithin36months. Althoughtherearemultiplereasonsforrehospitalization,failuretomeetcriteriafordischargeisperhapsthemostcommon.Criteriafor dischargeshouldincludeatleast24hofstablefluidstatus,bloodpressure,andrenalfunctionontheoralregimenplannedforhome.Before discharge,patientsshouldbefreeofdyspneaorsymptomatichypotensionwhileatrest,washing,andwalkingontheward.
CORPULMONALE Definition
Corpulmonale,oftenreferredtoaspulmonary heart disease,isdefinedasdilationandhypertrophyoftherightventricleinresponsetodiseases ofthepulmonaryvasculatureand/orlungparenchyma.Historically,thisdefinitionhasexcludedcongenitalheartdiseaseandthosediseasesin whichtherightheartfailssecondarytodysfunctionoftheleftsideoftheheart.
EtiologyandEpidemiology
Corpulmonaledevelopsinresponsetoacuteorchronicchangesinthepulmonaryvasculatureand/orthelungparenchymathataresufficientto causepulmonaryhypertension.Thetrueprevalenceofcorpulmonaleisdifficulttoascertainfortworeasons.First,notallpatientswithchronic lungdiseasewilldevelopcorpulmonale,andsecond,ourabilitytodiagnosepulmonaryhypertensionandcorpulmonalebyroutinephysical examinationandlaboratorytestingisrelativelyinsensitive.However,advancesin2-Decho/Dopplerimagingandbiomarkers(BNP)makeit easiertoscreenforanddetectcorpulmonale. Oncepatientswithchronicpulmonaryorpulmonaryvasculardiseasedevelopcorpulmonale,theprognosisworsens.Althoughchronic obstructivepulmonarydisease(COPD)andchronicbronchitisareresponsibleforapproximately50%ofthecasesofcorpulmonaleinNorth America(Chap.260),anydiseasethataffectsthepulmonaryvasculature(Chap.250)orparenchymacanleadtocorpulmonale.Table234-7 providesalistofcommondiseasesthatmayleadtocorpulmonale.IncontrasttoCOPD,theelevationinpulmonaryarterypressureappearsto besubstantiallyhigherintheinterstitiallungdiseases(Chap.261),inwhichthereisaninversecorrelationbetweenpulmonaryarterypressure andthediffusioncapacityforcarbonmonoxide,aswellaspatientsurvival.Whencorpulmonaleoccursinconjunctionwithobstructivesleep apnea,typicallyCOPDorahypoventilationsyndrome[e.g.,obesityhypoventilationsyndrome(OHS)]ispresentconcurrently(Chap.265).
Table234-7EtiologyofChronicCorPulmonale
DiseasesLeadingtoHypoxemicVasoconstriction Chronicbronchitis Chronicobstructivepulmonarydisease Cysticfibrosis Chronichypoventilation Obesity Neuromusculardisease Chestwalldysfunction Livingathighaltitudes DiseasesthatCauseOcclusionofthePulmonaryVascularBed Thromboembolicdisease,acuteorchronic
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Pulmonaryarterialhypertension Pulmonaryveno-occlusivedisease DiseasesthatLeadtoParenchymalDisease Chronicbronchitis Chronicobstructivepulmonarydisease Bronchiectasis Cysticfibrosis Pneumoconiosis Sarcoidosis Interstitiallungdisease
PathophysiologyandBasicMechanisms
Althoughmanyconditionscanleadtocorpulmonale,thecommonpathophysiologicmechanismineachcaseispulmonaryhypertensionthatis sufficienttoleadtoRVdilation,withorwithoutthedevelopmentofconcomitantRVhypertrophy.Thesystemicconsequencesofcorpulmonale relatetoalterationsincardiacoutputaswellassaltandwaterhomeostasis.Anatomically,theRVisathin-walled,compliantchamberthatis bettersuitedtohandlevolumeoverloadthanpressureoverload.Thus,thesustainedpressureoverloadimposedbypulmonaryhypertensionand increasedpulmonaryvascularresistanceeventuallycausestheRVtofail. TheresponseoftheRVtopulmonaryhypertensiondependsontheacutenessandseverityofthepressureoverload.Acutecorpulmonaleoccurs afterasuddenandseverestimulus(e.g.,massivepulmonaryembolus),withRVdilatationandfailurebutnoRVhypertrophy(Chap.262). Chroniccorpulmonale,however,isassociatedwithamoreslowlyevolvingandprogressivepulmonaryhypertensionthatleadstoinitialmodest RVhypertrophyandsubsequentRVdilation. DecompensationofchroniccorpulmonalecanbeaggravatedbyintermittenteventsthatinducepulmonaryvasoconstrictionandRVafterload, suchashypoxemiaandespeciallyhypercarbia-inducedrespiratoryacidosis(e.g.,OHS),aswellassustainedevents,includingCOPD exacerbations,acutepulmonaryemboli,andpositive-pressure(mechanical)ventilation.RVfailurealsocanbeprecipitatedbyalterationsinRV volumethatoccurinvarioussettings,includingincreasedsaltandfluidretention,atrialarrhythmias,polycythemia,sepsis,andalargeleft-toright(extracardiac)shunt.Themostcommonmechanismsthatleadtopulmonaryhypertension,includingvasoconstriction, activationoftheclottingcascade,andobliterationofpulmonaryarterialvessels,arediscussedinChap.250.
ClinicalManifestations
SYMPTOMS
Thesymptomsofchroniccorpulmonalegenerallyarerelatedtotheunderlyingpulmonarydisorder.Dyspnea,themostcommonsymptom,is usuallytheresultoftheincreasedworkofbreathingsecondarytochangesinelasticrecoilofthelung(fibrosinglungdiseases),altered respiratorymechanics(e.g.,overinflationwithCOPD),orinefficientventilation(e.g.,primarypulmonaryvasculardisease).Orthopneaand paroxysmalnocturnaldyspneaarerarelysymptomsofisolatedrightHFandusuallypointtowardconcurrentleftheartdysfunction.Rarely,these symptomsreflectincreasedworkofbreathinginthesupinepositionresultingfromcompromiseddiaphragmaticexcursion.TussiveoreffortrelatedsyncopemayoccurbecauseoftheinabilityoftheRVtodeliverbloodadequatelytotheleftsideoftheheart.Abdominalpainandascites thatoccurwithcorpulmonalearesimilartotheright-heartfailurethatensuesinchronicHF.Lower-extremityedemamayoccursecondaryto neurohormonalactivation,elevatedRVfillingpressures,orincreasedlevelsofcarbondioxideandhypoxemia,whichcanleadtoperipheral vasodilationandedemaformation.ThesymptomsofacutecorpulmonalewithpulmonaryembolusarereviewedinChap.262.
SIGNS
ManyofthesignsencounteredincorpulmonalearealsopresentinHFpatientswithadepressedEF,includingtachypnea,elevatedjugular venouspressures,hepatomegaly,andlower-extremityedema.Patientsmayhaveprominentvwavesinthejugularvenouspulseasaresultof tricuspidregurgitation.OthercardiovascularsignsincludeanRVheavepalpablealongtheleftsternalborderorintheepigastrium.Theincrease inintensityoftheholosystolicmurmuroftricuspidregurgitationwithinspiration("Carvallo'ssign")maybelosteventuallyasRVfailureworsens. Cyanosisisalatefindingincorpulmonaleandissecondarytoalowcardiacoutputwithsystemicvasoconstrictionandventilation-perfusion mismatchesinthelung.
Diagnosis
Themostcommoncauseofright-heartfailureisnotpulmonaryparenchymalorvasculardiseasebutleftheartfailure.Therefore,itisimportant toevaluatethepatientforLVsystolicanddiastolicdysfunction.TheECGinseverepulmonaryhypertensionshowsPpulmonale,rightaxis deviation,andRVhypertrophy.Radiographicexaminationofthechestmayshowenlargementofthemainpulmonaryartery,thehilarvessels,
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andthedescendingrightpulmonaryartery.Spirometryandlungvolumescanidentifyobstructiveand/orrestrictivedefectsindicativeof parenchymallungdiseases;arterialbloodgasescandemonstratehypoxemiaand/orhypercapnia.Spiralcomputedtomography(CT)scansofthe chestareusefulindiagnosingacutethromboembolicdisease;however,ventilation-perfusionlungscanningremainsbestsuitedfordiagnosing chronic thromboembolic disease(Chap.262).Ahigh-resolutionCTscanofthechestcanidentifyinterstitiallungdisease. Two-dimensionalechocardiographyisusefulformeasuringRVthicknessandchamberdimensionsaswellastheanatomyofthepulmonaryand tricuspidvalves.LocationoftheRVbehindthesternumanditscrescentshapechallengeassessmentofRVfunctionbyechocardiography, especiallywhenparenchymallungdiseaseispresent.CalculatedmeasuresofRVfunction[e.g.,tricuspidannularplanesystolicexcursion (TAPSE)ortheTeiIndex]supplementmoresubjectiveassessmentsofRVfunction.Theinterventricularseptummaymoveparadoxicallyduring systoleinthepresenceofpulmonaryhypertension.Asnoted,Dopplerechocardiographycanbeusedtoassesspulmonaryarterypressures.MRI isalsousefulforassessingRVstructureandfunction,particularlyinpatientswhoaredifficulttoimagewith2-Dechocardiographybecauseof severelungdisease.Right-heartcatheterizationisusefulforconfirmingthediagnosisofpulmonaryhypertensionandforexcludingelevatedleftheartpressures(measuredasthePCWP)asacauseforright-heartfailure.BNPandN-terminalBNPlevelsareelevatedinpatientswithcor pulmonalesecondarytoRVstretchandmaybedramaticallyelevatedinacutepulmonaryembolism.
Treatment:CorPulmonale
Theprimarytreatmentgoalofcorpulmonaleistotargettheunderlyingpulmonarydisease,sincethiswilldecreasepulmonaryvascular resistanceandlessenRVafterload.Mostpulmonarydiseasesthatleadtochroniccorpulmonaleareadvancedandthereforearelessamenableto treatment.Generalprinciplesoftreatmentincludedecreasingworkofbreathingbyusingnoninvasivemechanicalventilationandbronchodilation, aswellastreatinganyunderlyinginfection(Chaps.260and261).Adequateoxygenation(oxygensaturation 9092%)andcorrecting respiratoryacidosisarevitalfordecreasingpulmonaryvascularresistanceandreducingdemandsontheRV.Patientsshouldbetransfusedif theyareanemic,andphlebotomymaybeconsideredinextremecasesofpolycythemia. DiureticsareeffectiveinRVfailure,andindicationsaresimilartothoseforchronicHF.Onecaveatofchronicdiureticuseistoavoidinducing contractionalkalosisandworseninghypercapnia.Digoxinisofuncertainbenefitinthetreatmentofcorpulmonaleandmayleadtoarrhythmias inthesettingoftissuehypoxemiaandacidosis.Therefore,ifdigoxinisadministered,itshouldbegivenatlowdosesandmonitoredcarefully. PulmonaryvasodilatorscaneffectivelyimprovesymptomsthroughmodestreductionofpulmonarypressuresandRVafterloadwhenisolated pulmonaryarterialhypertensionispresent.Vasodilatorsareunprovenincasesofpulmonaryhypertensionandcorpulmonaledueto parenchymallungdiseasesorhypoventilationsyndromes.Thetreatmentoftheacutecorpulmonalethatoccurswithpulmonary embolusisdescribedinChap.262.ThetreatmentofpulmonaryhypertensionisdiscussedinChap.250.
FURTHERREADINGS
AshrafianHetal:Metabolicmechanismsinheartfailure.Circulation116:434,2007[PMID:17646594]
BardyGHetal:Amiodaroneoranimplantablecardioverter-defibrillatorforcongestiveheartfailure.NEnglJMed352:225,2005[PMID: 15659722]
ChapmanHA:Disordersoflungmatrixremodeling.JClinInvest113:148,2004[PMID:14722604]
ClelandJGetal:Theeffectofcardiacresynchronizationonmorbidityandmortalityinheartfailure.NEnglJMed352:1539,2005[PMID: 15753115]
FriedrichEB,BohmM:Managementofendstageheartfailure.Heart93:626,2007[PMID:17435073]
HuntSAetal:2009focusedupdateincorporatedintotheACC/AHA2005GuidelinesfortheDiagnosisandManagementofHeartFailurein Adults:AreportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines:developedin collaborationwiththeInternationalSocietyforHeartandLungTransplantation.Circulation119:e391,2009
KesslerRetal:"Naturalhistory"ofpulmonaryhypertensioninaseriesof131patientswithchronicobstructivelungdisease.AmJRespirCrit CareMed164:219,2001[PMID:11463591]
MannDL,BristowMR:Mechanismsandmodelsinheartfailure:Thebiomechanicalmodelandbeyond.Circulation111:2837,2005[PMID: 15927992]
MosterdA,HoesAW:Clinicalepidemiologyofheartfailure.Heart93:1137,2007[PMID:17699180]
PengoVetal:Incidenceofchronicthromboembolicpulmonaryhypertensionafterpulmonaryembolism.NEnglJMed350:2257,2004[PMID: 15163775]
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Heart Failure and Cor Pulmonale

Infiltrativedisordersa Toxic/drug-induceddamage Metabolicdisordera Viral

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Secondary(hypertension) Aging PulmonaryHeartDisease Corpulmonale Pulmonaryvasculardisorders High-OutputStates Metabolicdisorders Thyrotoxicosis Nutritionaldisorders(beriberi)

Storagediseases(hemochromatosis) Fibrosis Endomyocardialdisorders

Excessiveblood-flowrequirements Systemicarteriovenousshunting Chronicanemia

Functional Capacity ClassI

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ambulatorypatients.Inbedriddenpatients,edemamaybefoundinthesacralarea(presacral edema)andthescrotum.Long-standingedema maybeassociatedwithinduratedandpigmentedskin.

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Dietaryindiscretion Myocardialischemia/infarction Arrhythmias(tachycardiaorbradycardia) DiscontinuationofHFtherapy

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Combinationofhydralazine/isosorbidedinitrate 1025mg/10mgtid Fixeddoseofhydralazine/isosorbidedinitrate Digoxin

37.5mg/20mg(onetablet)tid 75mg/40mg(twotablets)tid 0.125mgqd 0.375mg/db

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trials). B.TheKaplan-Meiercurvesformortalityfor12,763HFpatientswithadepressedEFtreatedwithanACEinhibitorinfiveclinicaltrials,including postinfarctiontrials.ThebenefitsofACEinhibitorswereobservedearlyandpersistedlong-term.(Modified from MD Flather et al: Lancet 355:1575, 2000.)

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activationaremediatedbythe 1receptor.WhengiveninconcertwithACEinhibitors,betablockersreversetheprocessofLVremodeling, improvepatientsymptoms,preventhospitalization,andprolonglife.Therefore,betablockersareindicatedforpatientswithsymptomaticor asymptomaticHFandadepressedEF<40%.

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

Vasodilators Nitroglycerin Nitroprusside Nesiritide

20 g/min 10 g/min Bolus2 g/kg

40400 g/min 30350 g/min 0.010.03 g/kgpermina

5 g/kgpermin 0.5 g/kgpermin 0.3 g/kgpermin 0.05units/min

515 g/kgpermin 50 g/kgpermin 3 g/kgpermin 0.10.4units/min

Notes: aUsually<4 g/kg/min.

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

AccessMedicine | Print: Chapter 234. Heart Failure and Cor Pulmonale

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