病理生理学课件：心力衰竭

Cardiac

insufficiency

§1Generaldescription

心脏是机体重要的生命器官之一，它的主要功能是为血液循环提供动力。2023/10/14体积：握住左拳大小重量：不超过500g做功：

70ml/搏×70次/min

×60min×24h

＝7056L/d10.08万次/天2023/10/14Prevalance5to6million550,000newcasesWHOsurvey:Incidencerate1.9%men>women2-yearmortalityrate37%6-yearmortalityrate82%American:2023/10/14

冠心病

(CHD)

高血压

(Hypertension)

心肌病

(Cardiomyopathy)

瓣膜疾病(Valvularheartdisease)HeartfailureWhatcausesheartfailure?2023/10/14Inadditiontothosecausesabove,thefollowingfactorsalsocanplayaroleindeterminingifheartfailurewillaffectyou:familyhistoryofheartdisease(家族史）diabetes（糖尿病）markedobesity（肥胖）.heavyconsumptionoftobaccoandalcohol(吸烟、酗酒）5.largesaltintakeindiet(高盐饮食）6.failuretotakemedications（治疗不及时）7.sustainedrapidheartrhythms（心律失常）Otherfactors2023/10/142023/10/14墨西哥超级胖子因心力衰竭去世47岁的墨西哥超级胖子何塞·路易斯·加尔萨因心力衰竭去世，死前体重达到453公斤。2023/10/14Conceptofheartfailureheartfailureindicatestheinabilityofthehearttopumpenoughbloodtomeetthemetabolicrequirementsduetoimpairedsystolicand/ordiastolicfunctionoftheheart

2023/10/14thesystolicor/anddiastolic(filling)functionoftheheartimpairedcardiacoutputdecreaseunabletomeetthemetabolicdemandsofbodyheartfailure2023/10/14

Cardiacinsufficiency

completelycompensation

decompensation

mildsevereHeartfailure★

heartfailure

&Cardiacinsufficiency2023/10/14Congestiveheartfailure:

Heartfailurewithincreasedvolumeandfluidaccumulatedinthelungs,abdominalorgans(especiallytheliver),andperipheraltissuesiscalledcongestiveheartfailureconcept充血性心力衰竭

(congestiveheartfailure,CHF)是指在各种原因所致的心脏疾病后期，由于心输出量与静脉回流量不相适应，导致肺循环和（或）体循环静脉淤血，机体常有钠、水潴留，和血容量增多，出现心腔扩大，静脉淤血及组织水肿的表现。

2023/10/14

§2Causes、

PrecipitatingfactorsandClassification

ofheartfailure

EssentialfunctionsoftheheartaresecuredbyintegrationofelectricalandmechanicalfunctionsoftheheartCardiacoutput(CO)=heartrate(HR)xstrokevol.(SV)-changesoftheheartrate-changesofstrokevolumeControlofHR:-autonomicnervoussystem-hormonal(humoral)control

ControlofSV:

-preload-contractility-afterload2023/10/14ContractilityandfillingpreloadStrokeVolumeCardiacoutputHeartrateDeterminantsofcardiacfunction一Causesafterload2023/10/14

Causesofheartfailure

systolicdysfunctionofmyocardiumMyocardialimpairmentCardiomyopathies、Myocarditis、Toxicity、Myocardialinfarction

MetabolicabnormalitiesIschemia、Hypoxia、DeficiencyofVitB1

2023/10/14

Overloadformyocardiumpressureoverload(afterload)

Systemichypertention;aorticvalvularstenosis;Pulmonaryhypertention;PulmonaryvalvularstenosisVentricularejection

Causesofheartfailure2023/10/14Mitraloraorticregurgitation;Tricuspidandpulmonaryregurgitation;Highcardiacoutput(hyperthyroidism、arterivenousfistula、anemia)Loadingconditionoftheheartattheendofdiastole↑volumeoverload（preload）

Causesofheartfailure2023/10/14

DiastolicdysfunctionandRestrictionoffillingMitralor/andtricuspidstenosis;Pericardialdisease:constrictivepericarditis,endomyocardialfibrosis;Ventricularfilling2023/10/14

infection(pulmonaryinfection)

precipitatingfactors二Precipitatingfactors2023/10/14infection

heartrate

diastolicphaseshortenfeverendotoxinrespiratoryinfection2023/10/14

cardiacdysrhythmia

precipitatingfactors2023/10/14尤其是快速型心律失常心率↑

舒张期缩短心肌耗氧量↑冠脉血流↓

心肌缺血、缺氧

心室充盈↓心泵功能↓

心输出量↓房室活动协调性紊乱2023/10/14

water-electrolytesandacid-basedisturbance

precipitatingfactors

Ca2+inflow↓,SRreleased↓Ca2+

bindingtotroponin↓activityofATPenzyme↓sensitivityofCaptoCA↓

acidosis(H+)Hyperpotassaemia(Hyperkalemia)myocardialconductibilityautorhythmicitycardiaccontractilitymyocardialexcitability↑→↓2023/10/14

妊娠期血容量↑（临产期↑）→分娩时疼痛、精神紧张、↓↓稀释性贫血交感一肾上腺髓质系统兴奋高动力循环状态↓静脉回流↑小血管收缩

心脏前负荷↑（左室）后负荷↑心肌耗氧量↑和冠脉流量↓

↓心输出量↓pregnancyanddelivery2023/10/14Excessivelylaborandspiritualburden;infusion

precipitatingfactors2023/10/14severity

mildheartfailure

moderateheartfailure

severeheartfailure

三、Classificationofheartfailure2023/10/14Ⅰ级：一般体力活动不出现心衰相关症状Ⅱ级：休息时不出现症状但一般体力活动受限Ⅲ级：轻体力活动受限Ⅳ级：休息时仍有症状

分期

心功能分级2023/10/14output

low-outputheartfailure

high-outputheartfailure(*comparedwithbeforeheartfailure)2023/10/14LowoutputheartfailurebeforehighoutputheartfailurehighoutputheartfailureNormaloutput

healthadult2023/10/14High-outputheartfailure:isanuncommontypeofheartfailurethatiscausedbyanexcessiveneedforcardiacoutput.Withit,thefunctionoftheheartmaybesupra-normalbutinadequateowingtoexcessivemetabolicneeds.Causesofhigh-outputfailureincludesevereanemia,fever,hyperthyroidismandpregnancy.concept2023/10/14onset

acuteheartfailure

chronicheartfailure2023/10/14Locationleft-sideheartfailureright-sideheartfailure.

wholeheartfailure2023/10/14法洛氏四联症2023/10/14functionimpairedsystolicheartfailurediastolicheartfailure2023/10/14§3Compensatoryresponsestoheartfailure2023/10/14一、neurohumoralcompensation交感－肾上腺髓质系统激活

(activationof

sympathetic-adrenalmedullasystem)

肾素-血管紧张素-醛固酮系统激活

(activationofrenin-angiotensin-aldosteronesystem,RAAS)

2023/10/14血流重新分布心衰心输出量压力感受器交感迷走心缩力↑血管收缩

缺血缺氧化学感受器呼吸深快回心血量↑血压sympathetic-adrenalmedullasystem肾血管收缩肾血流量RAASAngⅡ钠水重吸收

ET↑心缩力↑血管收缩RAAS血容量↑血压↑醛固酮

心肌重塑2023/10/14Renin-angiotensinsystemandconceptofitsinhibitoryactionAngiotensinogenLiverKid-neyLungAngiotensinⅠAngiotensinⅡVascularcontractionAngiotensionIIReceptorantangonistsACEInhibitorsAngiotensinconvertingenzyme(ACE)ReninRenininhibitorsetc.etc.etc.Receptor钠尿肽ANPBNP2023/10/14二、cardiaccompensationincreasedheartratecardiacdilationenhancementofcardiaccontractilityventricularremodeling2023/10/14(一)Increasedheartrate

MechanismpressurereceptorvolumereceptorsympatheticnerveexcitedHR↑2023/10/14利在一定范围内，心输出量↑提高心脑的灌流弊心率过快(>180次/分)对机体不利:增加心肌耗氧量心室充盈不足

心搏出量

心脏舒张期过短冠脉血流过少2023/10/14(二)

cardiacdilatationFrank-Starling

lawnormalcondition

1.72.02.23.6

mstrengthofcontractinitiallengthofmusle2023/10/14Frank-Starlinglaw:

Themoreamyocyteorventricularchamberisstretched,themoreitwillcontract2023/10/14紧张源性扩张(tonicitydilatation)

心室容量加大并伴有收缩力增强的心脏扩张肌源性扩张(myocardiogenicdilatation)心肌拉长不伴有收缩力增强的心脏扩张2023/10/14basedonSNS(EP,NEandβ-receptor).EP,NEb-receptorMembraneCa2+channelprotein→inflowofCa2+↑→Ca2+insarcoplasmreleased↑

phosphorylationPhospholamban(PLB)→inhibitiononCa2+pumpofSR↓→uptake

ofCa2+bySR↑

PositiveMyodynamicsEffect①②③(三)

enhancementofcardiaccontractility2023/10/14

––structural,metabolicorfunctionalmodereconstructionbasedonthealterationofgeneexpression

Theremodelinginvolving：Myocardialcells(hypertrophy)，Non-myocardialcells(proliferation)andExtracellularmatrix(rebuilding)(1)

Myocardialhypertrophy(2)

Phenotypealteration(3)Non-myocardialcellsproliferationand

ECMrebuilding(四)Ventricularremodeling2023/10/14

(1)

Myocardialhypertrophy

Conceptionsizeweight

OverloadhypertrophyclassificationReactivehypertrophyOverloadinghypertrophy2023/10/14心肌肥大的种类

离心性肥大(eccentrichypertrophy)

在长期容量负荷作用下，心肌纤维呈串联性(serieshyperplasia)增生，心室腔明显扩大。

向心性肥大(concentrichypertrophy)

在长期压力负荷作用下，心肌纤维呈并联性(parallelhyperplasia)增生,心室壁明显增厚。Overloadinghypertrophy2023/10/14concentrichypertrophyeccentrichypertrophy2023/10/14EccentrichypertrophyConcentrichypertrophyCausesPreload↑Afterload↑ReplicationformsofsarcomereInseriesParellelconnectionMorphologicchangeChambersofheartenlargeobviouslyHeartwallincreasesobviously

Wallthickness/radiusofchambers↓/N↑SignificanceAlleviatingpreloadOvercomingtheafterload2023/10/14Concentrichypertrophy:istheresponsetopressureoverload.Itisassociatedwithincreasednumberofsarcomerearrangedin

parallel.Theincreaseinwallthicknessreduceswalltensionandcardiaccompliancewithoutincreasingtheinternalchambersize.Eeccentrichypertrophy:theresponsetovolumeoverloadischaracterizedbydilationofchambersize,aswellasrelativedecreasedwallthickness.Itisthoughttoresultfromincreasednumberofsarcomerearrangedinseries.

concept2023/10/14Effects

1.Compensatoryeffects

MyocardialcontractilityCOWalltension↓consumptionofO2↓2.HarmfuleffectsMyocardialischemiaSecondarydysfunctionofconstrictionandrelaxation2023/10/14(2)

Phenotypealteration

Thephenotypeofcelldependsontheproteinsexpressed.Alterationofgeneexpression(isoformswitches,over-expression,deletion,mutation)

fetaltype

Phenotypealteration(remodelingofmyocardiumonthemolecularlevel)

Myocardialabnormalityinstructureandfunction

2023/10/14(3)Non-myocardialcellsproliferationandECMrebuilding

mechanicalloadexpression(TGF-b,FGF,a-SMA)Fibroblast

proliferation

chemicalsignalsecretion(collagen,MMP1(基质金属蛋白酶-1)

ECMremodelingcollagennetworkbiochemistricremodeling(typeI/typeIII)structuralremodeling(stiffness↑infusionofcoronaryartery↓)2023/10/14三、extracardialcompensationIncreasedabilityofcellstouseoxygen

Redistributionofbloodflow

Increaseinerythrocyte

Increasedbloodvolume2023/10/14(一)Increasedbloodvolume

机制意义:增加回心血量,但可致前负荷增加

1.

sympathetic-adrenalmedullasystem肾小球滤过率

（CA，AGII,PGE2,肾血流)2.RAAS--肾小管对水钠的重吸收3.促进水钠重吸收的激素（醛固酮

ADH）4.抑制水钠重吸收的激素（PGE2利钠素）(二)

Redistributionofbloodflowreducedcardiacoutput↓increasedactivityofsympatheticnervoussystem↓

increasedsecretionofcatecholamine↓contractionoftherenal,muscular,skinarteries(moreα-receptor)↓morebloodsupplytoheartandbrain↓

increasethecontractilityofmyocardium

？（三)Increaseoferythrocytesdecreasedcardiacoutput↓Hypoxia↓StimulatethesynthesisandreleaseofEPO↓Stimulatethebonemarrowandregulatetheproductionoferythrocytes↓Increasesoxygensupplytothetissues

？（四)IncreasedabilityoftissuestoutilizeoxygenHF→chronichypoxia→Thequantityofmitochondriaandtheirsurfacearea↑

Theamountandtheactivitiesofmanyenzymesintherespiratorychain↑phosphofructokinaseisactivated→anaerobicglycolysis↑→ATP↑myoglobin↑→acompensatorymechanismofoxygenstorage2023/10/142023/10/14§4MechanismsofheartfailureContractionprotein:thinfilament--肌动蛋白(actin)sarcomerethickfilament---肌球蛋白(myosin)regulationprotein:Tropomyosin向肌球蛋白Troponin肌钙蛋白excitation-contractioncouplingThemolecularbasisformyocardialcontraction:2023/10/142023/10/142023/10/14SRdepolarizationmitochondrionCa2+［Ca2+］10-7mol/L

［Ca2+］10-5mol/L

2023/10/14tropomyosincontraction（粗）myosin（细）actintroponinInteractionpointCa2+ATPase2023/10/14

［Ca2+］10-5mol/LrepolarizationSRmitochondrionCa2+［Ca2+］10-7mol/L2023/10/14relaxationtropomyosin（粗）myosin（细）actintroponinInteractionpointCa2+ATPaseMolecular

Basis

of

Contraction

2023/10/14▲收缩●结构●能量●Ca2+的转运▲舒张●Ca2+的复位●能量●粗细肌丝解离

2023/10/14一、Decreasedmyocardialcontractility(一)Injuriesofmyocardialcontractileprotein(二)Disorderofmyocardialenergymetabolism(三)Impairedexcitation-contractioncoupling2023/10/14(一)InjuriesofmyocardialcontractileproteinDecreasedmyocardialcontractilitymyocardialcell

necrosis

myocardialcell

apoptosiscontractilitydecreased1.Lossofcardiomyocyte2023/10/14myocardialcellnecrosis

Myocardialinfarction;Myocardialischemia

(myocardialinfarction);Hypoxia;infectionAtherosclerosisofthelargercoronaryarteriesMyocardialInfarctionThequantitativerelationship----------------------------------------------------------sizeofmyocardialcardiacprognosisinfarctionoutput(mortality)-----------------------------------------------------------5~10%normal2%10~20%slightlydecreased10%20~40%decreased22%>40%markedlydecreased60%----------------------------------------------------------oxidativestressCytokinescalciumhomeostasisDisequilibriummitochondriadisfunction

病理生理学Pathophysiologyapoptoticindex

35.5％

(N:0.2~0.4%）myocardialcellapoptosis2023/10/142023/10/142.StructuralalterationcelldeathhypertrophyandatrophyfibrosisHeterogeneity[hetərəudʒi'ni:əti]Inmolecularlevel:

overexpressionoffetalgeneproductionoffunctionalprotein↓Incellularlevel:2023/10/142023/10/14cellnumber↓

myofilamentrearrangementcollagendegradation↑enlargedchambersandthinwallInorganlevel:2023/10/14(二)Disorderofmyocardialenergymetabolism

impairedenergyproduction

reducedenergyreserve

impairedenergyutilization

Decreasedmyocardialcontractility2023/10/141.impairedenergyproduction

CHDshockanemiacardiachypertrophy

Disorderofmyocardialenergymetabolism2023/10/142.

reducedenergyreservephosphocreatinekinaseATPcreatineCPMyocardialhypertrophyactivityofphosphocreatinekinase↓

CP↓Disorderofmyocardialenergymetabolism2023/10/143.

impairedenergyutilizationActivityofmyosin–ATPaseV1(αα):

V2(αβ):

V3(ββ):Myocardialhypertrophy

activityofATPasedecreaseDisorderofmyocardialenergymetabolism能量生成能量利用脂肪酸乳酸丙酮酸葡萄糖氨基酸三羧酸循环氧化磷酸化ATPADP+PiCa2+与肌钙

蛋白结合心肌收缩心衰时的能量代谢障碍CP能量储存冠脉阻塞休克严重贫血VitB1缺乏ATPase心肌肥大乙酰CoA心肌肥大2023/10/14(三)Impairedexcitation-contractioncoupling.Decreasedmyocardialcontractility1.Sarcoplasmicreticulum(SR)mishandlingCa2+.2.ReducedinfluxofextracellularCa2+3.DysfunctionofCa2+bindingtotroponin

2023/10/142023/10/141.Sarcoplasmicreticulum(SR)mishandlingCa2+Impairedexcitation-contractioncouplingReducedCa2+uptakebySR

myocardialischemiaCa2+pump↓

β-R↓→PLB↓

Ca2+pump↓ATP-dependentpump

Phospholamban(PLB)

2023/10/14ReducedCa2+releasedbySR

Ryanodinereceptor(Ry-R)orRy-R

mRNAdecreased

Acidosis

reducedreleaseofCa2+bySRSRmishandlingCa2+2023/10/142.ReducedinfluxofextracellularCa2+Ca2+inflowvoltagedependence

β-receptordependenceNa+/Ca2+

exchangeImpairedexcitation-contractioncoupling2023/10/14L型通道亚单位2023/10/14G蛋白ATPcAMP肌膜激活钙备用通道腺苷酸环化酶（AC）β受体蛋白NE胞外Ca2+内流障碍2023/10/14

K+impairedinfluxofCa2+(Hyperkalemia)Reductionofβ1-receptordensity

NorepinephrinedepletionH+depressthesensitivityofβreceptorCausesofCa2+influxdecreasedinheartfailure:Reducedinfluxofextracellular

Ca2+

Acidosisdecreasethe△Ψ，L-Ca2+cannel↓2023/10/143.DysfunctionofCa2+bindingtotroponin

troponinH+Ca2+Impairedexcitation-contractioncoupling2023/10/14王世强研究发现，心衰细胞的L型钙通道活动没有明显异常，但其L型钙通道触发产生的钙瞬变幅度显著下降，时程显著延长。他对单个耦联位点进行的测定表明，L型钙通道触发ryanodine受体产生钙火花的潜伏期显著延长。由于L型钙通道开放时间有限，潜伏期延长就意味着两分子间耦联概率下降，其中触发失败的耦联单位仍可为后继的L型钙通道开放所触发，从而产生钙释放的去同步化2023/10/14心肌收缩性下降的机制小结心肌收缩性减弱能量代谢异常生成障碍利用障碍心肌细胞的坏死和凋亡兴奋-收缩藕联障碍钙离子与肌钙蛋白结合障碍钙离子内流障碍钙离子摄取储存释放储存障碍2023/10/142023/10/14二、Impairedmyocardialdiastolicproperties

DelayedrepositionofCa2+

[Ca2+]10-5mol/L→10-7mol/LATP

Ca++－ATP酶Ca++Ca++Ca++肌浆网Initiativediastolicfunctiondecrease2023/10/142023/10/14

Impaireddissociationoftheactin-myosincomplexImpairedmyocardialdiastolicpropertiesATP↓2023/10/142023/10/14

Reducedventricularcompliance

myocardialhypertrophy;

fibrosis;edema

dv/dpImpairedmyocardialdiastolicpropertiespassivediastolicfunctiondecrease心室顺应性(ventricularcompliance)：心室在单位压力变化下所引起的容积改变(dv/dp),其倒数(dp/dv)即为心室僵硬度（ventricularstiffness）正常降低升高P—V曲线VP100110（ml）30181310（mmHg）V稍有增加P增加很多正常V100P10

V110P13心梗（顺↓）

V100P18V110P

302023/10/142023/10/14三、Inconsistentbehaviorinsystolicanddiastolicfunctionoftheheart心衰发生机制小结心衰收缩性

心肌细胞坏死\凋亡能量生成

利用障碍兴奋收缩耦联障碍肌浆网处理Ca+能力

胞外Ca+内流障碍Ca+与肌钙蛋白结合障碍舒张性

Ca+复位延缓肌球-肌动蛋白解离障碍心室舒张势能

心室顺应性

各部舒缩不协调2023/10/14Questions:严重心肌缺血通过哪些机制使心肌收缩力减弱？酸中毒引起心肌兴奋收缩偶联障碍的机制？心肌过度肥大引起心力衰竭的机制？*2023/10/14ReducedconcentrationofNE;decreaseddensityandsensitivityofβ1-adrenergicreceptorDecreasedoxygenandbloodsupplyAlteredofenergymetabolism(production/reserve/utilization)Dysfunctionofexcitation-contractioncouplingExcessivecardiachypertrophyDecreasedcompliance&5Consequencesoftheheartfailureinmetabolismandfunction2023/10/14(一)肺循环淤血(Pulmonarycongestion)

当PCWP>18mmHg时，即出现肺循环淤血征，见于左心衰竭。2023/10/14

左心衰竭能导致肺淤血、肺水肿；因此主要的临床表现是呼吸困难肺水肿心力衰竭细胞2023/10/14Mechanismofdyspnea:

1)肺淤血水肿→肺顺应性下降2)

支气管粘膜充血水肿→气道阻力增加

3)肺毛细血管压增高，间质水肿→肺间质压增高刺激J感受器→呼吸浅快

1、呼吸困难(dyspnea)2023/10/14表现形式:劳力性呼吸困难:

活动时发生,休息减轻

(dyspneaonexertio