病理生理學(xué)課件：心功能不全

心功能不全LearningObjectivesDiscussthedefinitionDiscusstheetiologyDiscusstheclassificationDiscussmainmechanismsDiscusstheresponseofbodytoheartfailureDiscusstheclinicalmanifestationsDiscussthetreatprinciplesQ:心臟泵功能有哪些？舒張期的充盈和收縮期的射血充盈和射血都是耗能的過程心臟的解剖特點Indepolarization,fastsodiumchannelsopen,allowingarapidinfluxofsodium(positivelycharged)ionsintothecell.Asthecellvoltagepeaks,thefastsodiumchannelclosesandthecellmovesintotheearlystageofrepolarization.Thisearlyrepolarizationisfollowedbyaplateauphase,inwhichcalciumandsodiumionsslowlyenterthecellthroughslowcalcium-sodiumchannels.Thiscalciuminfluxfacilitatestheprolongedcontractionofcardiacmusclefibers.Thecellthenmovesintorapidrepolarization.Repolarizationisbasicallyaregroupingphase,inwhichthecellmembranebecomespolarizedagainwithapositivechargeontheouterandanegativechargeontheinnersurfaceofthecellmembrane.Inthecaseofcardiacmyocytes,thesodiumandcalciumchannelscloseandsodiumandcalciumnolongermoveintothecell.Toreestablishthepolaritywithinthecell,thecellmembranebecomesmorepermeabletopotassium.Thispositivelychargedion(K)exitsthecell.Thisprocessisrepeatedagainandagaintoproducecardiaccontractionandrelaxationthatischaracteristicoftheheart.Pwavethedepolarizationoftheatriaviathesinoatrialnode

?P-QintervalthedepolarizationoftheAVnodeandbundlefibers

?QRSdepolarizationoftheventricles

?Trepolarizationoftheventricles

?UrepolarizationofPurkinjefibersCardiacOutput

Measurementoftheheart’sefficiencytopumpoptimalamountsofbloodisreferredtoascardiacoutput.Cardiacoutput(CO)dependsonstrokevolume(SV)andheartrate(HR)andisexpressedas:CO=SVXHR.Strokevolumeistheamountofbloodpumpedoutofoneventricleoftheheartinasinglebeat.Heartrateisthenumberofheartbeatsthatoccurinoneminute.Cardiacoutputvarieswithage,bodysize,andmetabolicneedsofbodytissues.Theaveragecardiacoutputinadultsisabout3.5to8.0L/min.Thismeansthateveryminute,upto8Lofbloodmovesthroughtheheart.BloodPressure

Bloodpressureisthepressureortensionofthebloodwithinthesystemicarteries.Bloodpressureisneededtocontinuouslyperfusevitalorgans.Pressureinthearteriesismaintainedby:1.Contractionoftheleftventricle2.Peripheralvascularresistance3.Elasticityofthearterialwalls4.Viscosityandvolumeoftheblood影響心肌輸出量的五個因素前負(fù)荷心肌收縮力后負(fù)荷心率血容量正常心肌的功能代謝特點冠脈血流量大：靜息狀態(tài)60-80ml/(min.100g)毛細(xì)血管密度大：充足的氧氣和營養(yǎng)豐富的肌紅蛋白：心肌供氧心肌代謝的適應(yīng)性強(qiáng)：脂肪酸、葡萄糖和乳酸主要功能物質(zhì)，分別為67%、17%和16%。豐富的線粒體：ATP，適應(yīng)能量消耗的機(jī)制心肌氧的供應(yīng)來自冠脈血流，受心肌攝氧率、動脈血氧含量及冠脈血流量（小動脈口徑）心肌缺血的原因冠脈流量絕對不足：冠狀動脈阻塞：動脈粥樣硬化、附壁血栓冠狀動脈痙攣：激烈運(yùn)動、過量飲酒、煙；植物神經(jīng)功能紊亂，交感神經(jīng)異常興奮，冠脈血管收縮；內(nèi)皮損傷、血小板聚集，釋放有強(qiáng)烈縮血管物質(zhì)TXA2，引起冠脈痙攣。冠脈流量相對不足：冠脈流量沒有變化心肌收縮力增加，收縮性增強(qiáng)，心率加快是心肌耗氧量增加的主要因素。心肌功能性缺氧，動脈血氧含量減少如貧血、一氧化碳中毒等心肌供養(yǎng)減少。缺血對心肌的影響缺血對心肌代謝的影響缺血對心肌功能的影響心肌缺血的形態(tài)學(xué)變化缺血對心肌代謝的影響

心肌缺血，心肌氧張力下降，脂肪酸、葡糖糖、丙酮酸、乳酸的氧化代謝嚴(yán)重受阻線粒體呼吸鏈的運(yùn)轉(zhuǎn)減速或停止，ATP生成減少主要變化是高能磷酸化合物生成減少，引起心肌損傷的代謝產(chǎn)物在心肌堆積（乳酸、長鏈脂酰CoA,脂酰肉毒堿等）缺血對心肌功能的影響

心肌收縮性減弱心肌舒張功能障礙心肌舒縮的不協(xié)調(diào)性心肌電活動異常心肌收縮性減弱

心肌收縮成份破壞：收縮蛋白肌動蛋白和肌球蛋白，調(diào)節(jié)蛋白肌鈣蛋白和向肌球蛋白大量分解，心泵功能減弱心肌能量不足：心肌粗細(xì)肌纖維的滑行消耗ATP，缺氧氧化產(chǎn)能過程受阻，ATP和CP生成減少，不能提供能量支持酸中毒，酸性代謝產(chǎn)物增加，不能及時清除，pH下降，H+干擾Ca++與肌鈣蛋白結(jié)合，抑制糖酵解減少能量生成心肌舒張功能障礙

心肌收縮后張力迅速下降，有利于心肌再次充盈。舒張性減弱，直接后果導(dǎo)致心室充盈量下降，心輸出量隨之減少左室舒張性下降，左室舒張末期壓力上升，肺靜脈回流受阻，肺發(fā)生淤血、水腫。缺血ATP減少，Ca++與肌鈣蛋白仍處于結(jié)合狀態(tài)，不能完全舒張；收縮力減小，舒張勢能減??；心肌水腫，壞死和纖維化心肌的順應(yīng)性減低。心肌舒縮的不協(xié)調(diào)性

心肌收縮和舒張以及電活動異常等，心臟各部分在時間和空間上出現(xiàn)不協(xié)調(diào)，心泵功能減弱，心輸出量減少。心肌電活動異常

心肌的興奮性、自律性和傳導(dǎo)性改變導(dǎo)致心肌電活動異常。能量不足、酸中毒細(xì)胞內(nèi)K+外流，破壞了細(xì)胞內(nèi)外的離子分布；極化程度比周圍程度減少，缺血區(qū)域和正常區(qū)域之間造成“損失電流”，ST段偏高。細(xì)胞內(nèi)K+外流，Na+內(nèi)流，除極化過程N(yùn)a+內(nèi)流受阻，除極變慢，心肌興奮性、自律性和傳導(dǎo)性異常，表現(xiàn)為心律失常或傳導(dǎo)阻滯心肌缺血的形態(tài)學(xué)變化

與缺血時間、快慢以及缺血的程度有關(guān)冠脈血流阻斷5-15分鐘：糖原減少，水腫，染色質(zhì)聚積。冠脈血流阻斷15-18分鐘：心肌停跳，再灌注可以恢復(fù)，心肌細(xì)胞損傷可逆。冠脈血流阻斷30分鐘：糖原消失線粒體腫脹，漿膜破裂。心肌缺血的形態(tài)學(xué)變化：

3種基本病變

嚴(yán)重的急性缺血可發(fā)生心肌細(xì)胞和間質(zhì)細(xì)胞的凝固性壞死，壞死的肌纖維變細(xì)長，嗜伊紅染色，核破壞。缺血發(fā)生急但程度輕，心肌發(fā)生凝固性肌溶解，主要是心肌，間質(zhì)細(xì)胞相對完好。心肌缺血發(fā)生較輕而緩，發(fā)生液化性肌溶解。從空泡到液體的網(wǎng)狀空架，最后病灶纖維化形成瘢痕。心肌缺血損傷的類型隱匿性心肌缺血心絞痛心肌梗死缺血/再灌注損傷胸痛、頭暈和氣急由于心肌缺氧，代謝產(chǎn)物如H+，K+，緩激肽，ADP等刺激心肌內(nèi)的神經(jīng)末梢，通過胸1-5交感神經(jīng)節(jié)，經(jīng)脊髓傳入到大腦中樞引起痛覺。除了胸骨壓榨痛外，還放射到上臂、頸部、肩部，主要交感神經(jīng)節(jié)與體神經(jīng)較接近，疼痛牽涉到體表。能量不足、酸中毒使心肌收縮和舒張功能受影響，心輸出量下降，左心室舒張末期壓力增大，肺循環(huán)受阻，造成頭暈、氣急等癥狀。心梗冠脈缺血和痙攣引起心肌梗死，缺血后冠脈的失去內(nèi)皮依賴性舒張功能，對各種縮血管物質(zhì)很敏感，加上血小板聚集，釋放各種縮血管活性物質(zhì)，發(fā)生持久的冠脈痙攣可引起血流中斷，導(dǎo)致心肌梗死。缺血與再灌注損傷

發(fā)生的條件

缺血時間再灌注的壓力和溫度再灌注液中Ca++濃度線粒體的能量物質(zhì)缺血前的心臟疾患缺血與再灌注損傷

表現(xiàn)

心功能下降心律失常：室速和室顫心肌出血心肌水腫心肌酶的漏出細(xì)胞內(nèi)Ca++增加心肌超微結(jié)構(gòu)改變心肌氧的攝取利用障礙心肌細(xì)胞的凋亡缺血與再灌注損傷

發(fā)生的機(jī)制

心肌能量耗竭膜損傷中性粒細(xì)胞積聚無復(fù)流現(xiàn)象氧自由基損傷鈣超載五、心肌缺血的損傷機(jī)制自由基的作用鈣超載中性粒細(xì)胞能量缺乏酸中毒：酸性產(chǎn)物、乳酸、鈣離子和磷酸根結(jié)合、游離脂肪酸（酯化產(chǎn)生6個氫離子）、CO2其他：contractilityafterloadpreloadStrokeVolumeCardiacoutputHeartrateDeterminantsofcardiacfunctionHeartfailureistheinabilityofthehearttosupplyadequatebloodflowandgenerateacardiacoutputsufficienttomeetthemetabolicdemandsofthebody.ShockPericarditis

DefinitionPrevalence2to3million400,000newcases1996WHOsurvey:Incidencerate1.9%men>women2-yearmortalityrate37%6-yearmortalityrate82%American:EtiologyPrimarymyocardialdysfunctiondirectimpairmentofmyocardialcontractilityanddiastolicfunctionischemicheartdisease,myocarditis,cardiomyopathyVentricularoverloadresultofexcesspressure,volumeorhigh-outputstateshypertension,aorticstenosis,pulmonaryembolismaorticormitralregurgitationthyrotoxicosis,anemia,pregnancyorinfectionPredisposing

causeSystemicInfectionAcid-base&ElectrolyteDisturbanceArrhythmiaPregnancy&LabourLeftvsRightVentricularLowvsHighOutputSystolicvsDiastolicClassificationDegreeofcardiacfunctionClassPatientSymptomsClassI(Mild)Nolimitationofphysicalactivity.Ordinaryphysicalactivitydoesnotcauseunduefatigue,palpitation,ordyspnea(shortnessofbreath).ClassII(Mild)Slightlimitationofphysicalactivity.Comfortableatrest,butordinaryphysicalactivityresultsinfatigue,palpitation,ordyspnea.ClassIII(Moderate)Markedlimitationofphysicalactivity.Comfortableatrest,butlessthanordinaryactivitycausesfatigue,palpitation,ordyspnea.ClassIV(Severe)Unabletocarryoutanyphysicalactivitywithoutdiscomfort.Symptomsofcardiacinsufficiencyatrest.Ifanyphysicalactivityisundertaken,discomfortisincreased.NYHAClassification

MostAbnormally

elevateddemands

CO<4L/min,cardiacindex<2.5L/min/m2COmaybenormalatrestbutmaysimplyfailtorisesufficientlyonexertioncardiacoutputmaybewithinnormalrangeorevenelevated,suchashyperthyroidism,anemia,Paget'sdisease,AVfistulaorberiberi.

LowvsHighOutputLeftventricular

rightventricular

pulmonarycongestionshortnessofbreath,fatigueandcoughing

Partinitiallyinvolvedinthepathologicalchanges

Intheearlystages

Asheartfailureprogresses

bothventriclesfailurefluidbuild-upintheveinsandswellinginthelegsandankleswholeheartfailure

Rheumaticmyocarditis

Veryseriousanemia

Inabilityofthehearttorelaxproperlyandfillwithbloodasaresultofstiffeningoftheheartmuscle.Diastolicheartfailure-

Systolicheartfailure-

Inabilityofthehearttocontractwithenoughforcetopumpadequateamountsofbloodthroughthebody.Cardiac

MuscleMolecularBasisofContraction

WeakenofcontractilityAbnormityof

diastolicpropertiesofventricleAsynergia

ofventricularcontractionandrelaxationMechanismsforheartfailureweakenofcontractilityForceVelocity(1)Damageofmyocardialcells(2)Myocardialmetabolicdysfunction(3)DysfunctionofECcoupling(4)Hypertrophy

WeakenofcardiaccontractilityCellswellsandruptures.Cellcontentsspillout.

NecrosisMyocardialInfarctionMyocardialischemiaHypoxiaVirusorbacterialinfectionAtherosclerosisofthelargercoronaryarteries

Itoncewasthoughtthatmostheartattackswerecausedfromtheclosureofanartery.Itisnowclearthatthisprocesscanoccurineven

minorblockages.Thereisruptureofthecholesterolplaque.Theheartmusclethatisinjuredinthiswaycancauseirregularrhythmsthatcanbefatal,evenwhenthereisenoughmusclelefttopumpplentyofblood.TherelationshipbetweenventriculardysfunctionandprognosisMyocardialinfarctedsizeCardiacindexMortality5-10%Normal2%10-20%Slightlydecreased10%20-40%Decreased22%>40%Markedlydecreased60%ActiveSignal-dependentGene-directedEnergy-requiring

ApoptosisCellular

self-destruction

processDNA'ladder'

DetectionofDNAfragmentationApoptosisindex35.5%Moreandmorestudieshaveproposedthatapoptosishasbeenshowntocontributetolossofcardiomyocytesincardiomyopathy,progressivedeclineinventricularfunction,andcongestiveheartfailure.

MechanismsOxidativestressCytokinesImbalanceincellularcalciumDysfunctionofmitochondriaEnergymetabolismofcardiacmyocyteliberation

storingutilizationpumpFreeCa2+CombinedCa2+Actin-myosineH2Ocitricacidα-ketoglutaricacid

oxaloaceticacid

succinicacid

acetyl

DisordersinliberationofenergyOccursin

ischemicheartdisease,shock,severeanemiaandhypoxia.ThereducedcontractilityismainlybecauseofthedecreasedlevelofATP.

MechanicalenergydecreaseCalciumimbalancemitochondriaDysfunctionProteinsynthesisdecreaseTheactomyosin-ATPaseintheheadofmyosinhydrolyzesATPandgeneratesenergyneededbyfilamentssliding.WhenATPleveldecreased,thereisnotenoughsubstrateforATPasesothemechanicalenergyforcontractionisreduced.NormaltransportanddistributionofcalciumdependonthechannelandcalciumpumpThepumpneedsenergytotransportcalciumoutofthecellagainsttheconcentrationgradient.Thecalciumoverloadwilldirectlyleadcontractureandruptureofmyocardiumandsodamagethecontractility.

DisordersinutilizationofenergyKeyproblemishowmuchtheefficiencyofactomyosin-ATPaseis.

Thisenzymereducesitsactivityinheartfailure.MyosinisozymeV3isincreasedespeciallyduringhypertrophy.

Excitation-contractioncouplingIntracellularcalciumconcentrationsofcardiacmusclecellsrangefrom10-7to10-5M.

Extracellularconcentrationofcalciumisabout2×10-3M.Thereisachemicalgradientforcalciumtodiffuseintothecell.Becausecellshaveanegativerestingmembranepotential,thereisalsoanelectricalforcedrivingcalciumintothecell.

Thechangeofintracellularcalciumconcentrationandthereactionofcontractileproteintothischangedeterminethecontractilityofcardiacmyocyte.

Dysfunctionofexcitation-contractioncouplingDysfunctionofCalcium

handlingbySR

Ca2+bindingtotroponin

CalciuminfluxHowistheprocessofcalciuminfluxchangedinheartfailure?

TwomainpathwaysCalciumchannelNa+-Ca2+exchangerCalciumChannel

Thedensityofbeta-adrenoceptorisrelativelydecreased.Generationofnorepinephrineisdecreasedwhileconsumingisfasted.Acidosiscausedbyhypoxiaorischemiawillbluntthesensitivityofmyocytetobeta-adrenoceptor.Hyperkalemiawillinhibitthecalciuminfluxbecauseextracellularpotassiumandcalciumcompetewitheachotherinentryintocells.

Whathappenedtothechannelinheartfailure?MolecularComponents:Electrogenicexchangeof3Nafor1CaForwardmode=Caremoval,inwardcurrentReversemode=Cainflux,outwardcurrentModulatedbyCa,PIP2,ATPThreeisoforms(NCX1,NCX2,NCX3)+splicevariantn970AAs,~120kDNa+-Ca2+exchangerIncreasedexpressionandfunctionoftheexchangerinhumanheartfailureaswellasinanimalmodels.ThisincreaseistheconsequenceofdefectiveSRCa2+uptakeanddependson[Ca2+]iinthefailingheart.

Itmayplayakeyroleforalteredcontractilefunctionandarrhythmogenesisinhypertrophyandheartfailure.CardiovascularResearch

Volume:57,Issue:4

March15,2003

Dysfunctionofexcitation-contractioncouplingDysfunctionofCalcium

handlingbySR

Ca2+bindingtoTroponin

CalciuminfluxRe-uptakeStoringReleaseMSR

HandlingofcalciumbySRATP-dependentpump

Phospholamban

brakeInheartfailureExpressionofpumpBeta-adrenoceptoractivationATPsupplyCa2+-inducedCa2+releaseRyanodinereceptor

SRCa2+contentdecreasemRNAandproteinlevelarebothfoundtoreduceinheartfailureHydrogenincreasesaffinityofcalciumanditsbindingprotein,sothecalciumisdifficulttobereleased.

ConcentrationofcytosoliccalciumNormalaffinityoftroponintocalcium

Dysfunctionofexcitation-contractioncouplingDysfunctionofHandlingthecalciumbySR

Ca2+bindingtotroponin

Calciuminflux1.Ca2+entryviaL-typeCa2+

channels.2.Ca2+-induced-Ca2+-release(CICR)fromSRthroughRyanodinereceptors.3.ReuptakeintoSRviaATPdependentpump(stimulatedbyphosphorylationofphospholamban).BoundintheSRtocalsequestrin4.Extrusionfromthemyocyte?–Na+/Ca2+exchange3:1?Ca2+pumpofsarcolemmaHowdoesthemyocytemaintainthecalciumhomeostasis?

Myocardialrelaxationisanactive

process,notmerelyanintermittentrestperiodbetweensystolicperiods.Upto15%ofmyocardialenergymaybeexpendedforthatrelaxation.Diastolicstageisimportanttobloodsupplyforheartitselfanditisalsonecessaryforthevenousreturn.Diastolicpropertiesofventricle(1)Delayedcalciumdecrease(2)Impaireddissociationoftheactin-myosincomplex(3)Decreaseddiastolicpotentialenergy

ofventricles(4)ReducedcomplianceofmyocardiumAbnormityofdiastolicpropertiesofventricleAftereachsystole,theconcentrationofmyoplasmicCa2+

needtodecreasefrom10-5mol/Lto10-7mol/L,allowingdecouplingoftheactin-myosincross-bridges.WithoutadequateATPseeninmyocardialischemiaandsevereanemia,Ca2+isdelayeduptakedbysarcoplasmicreticulumanddelayedeffluxfromthemyocyte.Thus,Ca2+stillcombines

withtroponinandmyocardiumcannotrelaxfully.

DelayedcalciumdecreaseMyocardialrelaxationisnotapassive,butratherisanenergy-requiringactivity.ATPisneededfortheactin-myosincomplextodissociate,soinadequateATPsupplymayleadtoimpairmentofactin-myosindecoupling.Obviously,anypathologicfactorwithdisordersinenergymetabolismmayresultinheartfailurethroughdiastolicdysfunction.

Impaireddissociationoftheactin-myosinEarlydiastolicrecoiloftheventricularwallsinconjunctionwithreleaseofelasticpotentialenergystoredduringsystoledeformation,generatingsuctionandthuscontributingtodiastolicfilling.

DecreaseddiastolicpotentialenergyofventriclesManypathologicfactorsaccountedfordepressedmyocardialcontractilitymayleadalimitedloadingofventricleaswellasdiastolicpotentialenergy.Inaddition,ventricularrelaxationmaybedepressedwhencoronarybloodflowreducesduetocoronaryarterydisease,systemichypertension,andcardiomyopathy.

ReducedcomplianceofmyocardiumTheabilityofabloodvesseloracardiacchambertochangeitsvolumeinresponsetochangesinpressurehasimportantphysiologicalimplications.C=V/P

Complianceisdeterminedby:PhysicalpropertiesofthetissuesmakinguptheventricularwallStateofventricularrelaxationventricularhypertrophy

lowcardiacoutput,pulmonaryvenoushypertension,andpulmonaryedema.AsynergiaofventricularcontractionandrelaxationTheheartcannotcontractsimultaneously.

Hypokinesis

(impairedwallwithdiminishedorabsentcontraction);Dyskinesis(impairedwalldemonstratingparadoxicaloutwardmotionduringsystole);Contractionasynchronism

or

dysynchrony.Dysynchronyoccurswhentheelectricalimpulsesthatcoordinatetheventriclesmisfiresuchasarrhythmia,sothatthedifferentpartsoftheheartcannotcontractatthesametime.ReducestheforwardflowofbloodthroughtheheartAbnormalinterventricularseptalwallmotionReduceddiastolicfillingtimeProlongedmitralregurgitationdurationNormalHypokinesisDyskinesisDysynchronyTheProgressiveDevelopmentofCardiovascularDiseaseThisprogressionofheartfailurefollowsthedevelopmentalrulewhichisfromslighttosevere,fromcompensationtodecompensation.Thereactionstotheinitiatingevent,suchasincreasedpreload,afterload,donotchangethroughthewholeperiodfromearlystagetolatestage.

vasoconstriction

ResponseofthebodyCardiaccompensationSystemiccompensationNeurohormonalcompensationCardiaccompensationIncreaseofheartrateExpansionoftheheartHypertrophyFrank-StarlingLawoftheHeartCardiacOutputincreasesasLVEnd-DiastolicVolumeincreasesWhenvenousreturnisincreasedtotheheartorheartcannotejectenoughbloodtoartery,ventricularfillingandpreloadincrease.Thisstretchingofthemyocytescausesanincreaseinforcegenerationwhichenablesthehearttoejecttheadditionalvenousreturn,therebyincreasingSV.

ExpansionoftheheartWhatisthebasisforthismechanism?

1.Length-tensionrelationshipsforcardiacmyocytes.2.Length-dependentactivationSystemiccompensationIncreaseinbloodvolumeRedistributionofbloodflowIncreaseoferythrocyteIncreasedabilityoftissuestoutilizeoxygenNeurohormonalcompensationArterialbaroreceptorsCardiopulmonarybaroreceptorsSympatheticnervesRenin-angiotensinsystemAntidiuretichormoneAtrialnatriureticpeptideArterialconstrictionVenousconstrictionIncreasedbloodvolumeMaintainarterialpressureIncreasedvenouspressureCatecholaminesDownregulationofadrenergicRVasoconstrictionofperipheralvasculatureRASsystemRetainsNa/water,↑preloadStimulatesfibrosisPotentvasoconstrictor,↑afterloadAntidiuretichormoneWaterretentionVasoconstrictionEndothelin–1VasoconstrictionStimluatescardiacfibrosisOverloadofheartOxygenconsumingincreaseArrhythmiaInjurybycytokinesMyocardialremodelingRetentionofwaterandsodium

DeleteriouseffectsMyocardialremodeling-Changesinshapeandsizeofthechamberinvolveschangesinthestructure,function,andgeneexpressionofthemyocardialcellProcessesOccurringinventricularremodelingCardiomyocytelengtheningVentricularwallstressincreasesInfarctexpansionratherthanextensionoccursInflammationandreabsorptionofnecrotictissueScarformationContinuedexpansionofinfarctzoneDilationandreshapingoftheleftventricleMyocytehypertrophyOngoingmyocytelossExcessiveaccumulationofcollagenininterstitiumGenemakeupHemodynamicSympatheticnervoussystemHormonalalterationsWhyventricularremodelingoccurs?BetablockersandACEIhaveadirectantagonisticeffectontheremodelingprocess.TheheartiscomposedofCardiacmyocytesNonmyocytecellsExtracellularmatrixECM

isdefinedasanetworksurroundingandsupportingthecellswhichmakeupthemyocardium.

Structuralproteins

Adhesiveproteins

Anti-adhesiveproteins

Enzymes

collagentypesIandIIIandelastinlaminin,fibronectinandcollagentypesIVandVItenascin,thrombospondinandosteopontinmetalloproteinases–

Reductionintheearlyfillingoftheventricle–Systolicfunctionisalteredbyboththealterationsintheventricularfillingandbyfibrosisdisturbingthemechanicalcouplingbetweenthesarcomeres–fibrosiscausesmyocardialelectricaldysfunctionandleadstotheoccurrenceofventriculararrhythmiasThemainconsequencesoffibrosis:Matrixmetalloproteinases

Responsibleforextracellularcollagendegradationandremodelingisthematrixmetalloproteinases.MMPhashighselectivityandaffinityforcomponentsoftheextracellularmatrix.MMPactivityisinhibitedinprogressivechronicheartfailure.

Thisinhibitionleadstothecollagenaggradationsinthecell.

HypertrophyItmeanstheenlargementorovergrowthofheartduetoanincreaseinsizeofitsconstituentcells.

Dependingonthetypeofhemodynamicloadproducingthefailure,sarcomeresdevelopeitherinparallel

orinseries.overload

chamberradius

wallthickness

ConcentrichypertrophyEccentrichypertrophyMechanismsunderlyingtheinductionofmyocardialhypertrophyinresponsetohaemodynamicstress-Increasethecontractileforceofheart

-ReduceventricularwalltensiontowardsnormalandthenreduceoxygenconsumingofheartWhatistheeffectofhypertrophy?-Physiological-PathologicalAssociatedwithahighriskofcardiacmortality

Howhypertrophyturnsintodecompensation?

Intrinsicdefect

ChangeofphenotypeRemodelingofextracellularmatrix

LopsidedgrowthClinicalManifestations

CongestionofPulmonaryCirculationCongestionofSystemicCirculationLowCardiacOutputstate

PulmonaryedemaDyspnea

venouscongestionEdemaHepatomegaly

PalenessFatiguelimbweaknessurinereducesshockPulmonaryedemaisaconditionassociatedwithincreasedlossoffluidfromthepulmonarycapillariesintothepulmonaryinterstitiumandalveoli.

PulmonaryedemaPlasmaoncoticpressure

higher

than

pulmonarycapillarypressureConnectivetissueandcellularbarriersarerelativelyimpermeabletoplasmaproteinsExtensivelymphaticsystem

DyspneaExertionaldyspnea

OrthopneaParoxysmalnocturnaldyspneaParoxysmalnocturnaldyspneaisasuddenonsetofsevereshortnessofbreathandcoughing,awakeningthepatient.1Depressionofrespiratorycenterduringsleep2Decreaseofventricularfunctionduetodecreasedsympathetictone3RedistributionoffluidtothechestCardiacasthma

ischaracterizedbywheezingduetobronchospasm.TreatmentprinciplesTre