病理生理學課件：心力衰竭

Cardiac

insufficiency

§1Generaldescription

心臟是機體重要的生命器官之一，它的主要功能是為血液循環(huán)提供動力。2023/10/14體積：握住左拳大小重量：不超過500g做功：

70ml/搏×70次/min

×60min×24h

＝7056L/d10.08萬次/天2023/10/14Prevalance5to6million550,000newcasesWHOsurvey:Incidencerate1.9%men>women2-yearmortalityrate37%6-yearmortalityrate82%American:2023/10/14

冠心病

(CHD)

高血壓

(Hypertension)

心肌病

(Cardiomyopathy)

瓣膜疾病(Valvularheartdisease)HeartfailureWhatcausesheartfailure?2023/10/14Inadditiontothosecausesabove,thefollowingfactorsalsocanplayaroleindeterminingifheartfailurewillaffectyou:familyhistoryofheartdisease(家族史）diabetes（糖尿?。﹎arkedobesity（肥胖）.heavyconsumptionoftobaccoandalcohol(吸煙、酗酒）5.largesaltintakeindiet(高鹽飲食）6.failuretotakemedications（治療不及時）7.sustainedrapidheartrhythms（心律失常）Otherfactors2023/10/142023/10/14墨西哥超級胖子因心力衰竭去世47歲的墨西哥超級胖子何塞·路易斯·加爾薩因心力衰竭去世，死前體重達到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)是指在各種原因所致的心臟疾病后期，由于心輸出量與靜脈回流量不相適應(yīng)，導致肺循環(huán)和（或）體循環(huán)靜脈淤血，機體常有鈉、水潴留，和血容量增多，出現(xiàn)心腔擴大，靜脈淤血及組織水腫的表現(xiàn)。

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↑

舒張期縮短心肌耗氧量↑冠脈血流↓

心肌缺血、缺氧

心室充盈↓心泵功能↓

心輸出量↓房室活動協(xié)調(diào)性紊亂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↑（臨產(chǎn)期↑）→分娩時疼痛、精神緊張、↓↓稀釋性貧血交感一腎上腺髓質(zhì)系統(tǒng)興奮高動力循環(huán)狀態(tài)↓靜脈回流↑小血管收縮

心臟前負荷↑（左室）后負荷↑心肌耗氧量↑和冠脈流量↓

↓心輸出量↓pregnancyanddelivery2023/10/14Excessivelylaborandspiritualburden;infusion

precipitatingfactors2023/10/14severity

mildheartfailure

moderateheartfailure

severeheartfailure

三、Classificationofheartfailure2023/10/14Ⅰ級：一般體力活動不出現(xiàn)心衰相關(guān)癥狀Ⅱ級：休息時不出現(xiàn)癥狀但一般體力活動受限Ⅲ級：輕體力活動受限Ⅳ級：休息時仍有癥狀

分期

心功能分級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法洛氏四聯(lián)癥2023/10/14functionimpairedsystolicheartfailurediastolicheartfailure2023/10/14§3Compensatoryresponsestoheartfailure2023/10/14一、neurohumoralcompensation交感－腎上腺髓質(zhì)系統(tǒng)激活

(activationof

sympathetic-adrenalmedullasystem)

腎素-血管緊張素-醛固酮系統(tǒng)激活

(activationofrenin-angiotensin-aldosteronesystem,RAAS)

2023/10/14血流重新分布心衰心輸出量壓力感受器交感迷走心縮力↑血管收縮

缺血缺氧化學感受器呼吸深快回心血量↑血壓sympathetic-adrenalmedullasystem腎血管收縮腎血流量RAASAngⅡ鈉水重吸收

ET↑心縮力↑血管收縮RAAS血容量↑血壓↑醛固酮

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

MechanismpressurereceptorvolumereceptorsympatheticnerveexcitedHR↑2023/10/14利在一定范圍內(nèi)，心輸出量↑提高心腦的灌流弊心率過快(>180次/分)對機體不利:增加心肌耗氧量心室充盈不足

心搏出量

心臟舒張期過短冠脈血流過少2023/10/14(二)

cardiacdilatationFrank-Starling

lawnormalcondition

1.72.02.23.6

mstrengthofcontractinitiallengthofmusle2023/10/14Frank-Starlinglaw:

Themoreamyocyteorventricularchamberisstretched,themoreitwillcontract2023/10/14緊張源性擴張(tonicitydilatation)

心室容量加大并伴有收縮力增強的心臟擴張肌源性擴張(myocardiogenicdilatation)心肌拉長不伴有收縮力增強的心臟擴張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心肌肥大的種類

離心性肥大(eccentrichypertrophy)

在長期容量負荷作用下，心肌纖維呈串聯(lián)性(serieshyperplasia)增生，心室腔明顯擴大。

向心性肥大(concentrichypertrophy)

在長期壓力負荷作用下，心肌纖維呈并聯(lián)性(parallelhyperplasia)增生,心室壁明顯增厚。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(基質(zhì)金屬蛋白酶-1)

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

Redistributionofbloodflow

Increaseinerythrocyte

Increasedbloodvolume2023/10/14(一)Increasedbloodvolume

機制意義:增加回心血量,但可致前負荷增加

1.

sympathetic-adrenalmedullasystem腎小球濾過率

（CA，AGII,PGE2,腎血流)2.RAAS--腎小管對水鈉的重吸收3.促進水鈉重吸收的激素（醛固酮

ADH）4.抑制水鈉重吸收的激素（PGE2利鈉素）(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--肌動蛋白(actin)sarcomerethickfilament---肌球蛋白(myosin)regulationprotein:Tropomyosin向肌球蛋白Troponin肌鈣蛋白excitation-contractioncouplingThemolecularbasisformyocardialcontraction:2023/10/142023/10/142023/10/14SRdepolarizationmitochondrionCa2+［Ca2+］10-7mol/L

［Ca2+］10-5mol/L

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

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

Basis

of

Contraction

2023/10/14▲收縮●結(jié)構(gòu)●能量●Ca2+的轉(zhuǎn)運▲舒張●Ca2+的復(fù)位●能量●粗細肌絲解離

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

病理生理學Pathophysiologyapoptoticindex

35.5％

(N:0.2~0.4%）myocardialcellapoptosis2023/10/142023/10/142.StructuralalterationcelldeathhypertrophyandatrophyfibrosisHeterogeneity[het?r?ud?i'ni:?ti]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環(huán)氧化磷酸化ATPADP+PiCa2+與肌鈣

蛋白結(jié)合心肌收縮心衰時的能量代謝障礙CP能量儲存冠脈阻塞休克嚴重貧血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型通道亞單位2023/10/14G蛋白ATPcAMP肌膜激活鈣備用通道腺苷酸環(huán)化酶（AC）β受體蛋白NE胞外Ca2+內(nèi)流障礙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王世強研究發(fā)現(xiàn)，心衰細胞的L型鈣通道活動沒有明顯異常，但其L型鈣通道觸發(fā)產(chǎn)生的鈣瞬變幅度顯著下降，時程顯著延長。他對單個耦聯(lián)位點進行的測定表明，L型鈣通道觸發(fā)ryanodine受體產(chǎn)生鈣火花的潛伏期顯著延長。由于L型鈣通道開放時間有限，潛伏期延長就意味著兩分子間耦聯(lián)概率下降，其中觸發(fā)失敗的耦聯(lián)單位仍可為后繼的L型鈣通道開放所觸發(fā)，從而產(chǎn)生鈣釋放的去同步化2023/10/14心肌收縮性下降的機制小結(jié)心肌收縮性減弱能量代謝異常生成障礙利用障礙心肌細胞的壞死和凋亡興奮-收縮藕聯(lián)障礙鈣離子與肌鈣蛋白結(jié)合障礙鈣離子內(nèi)流障礙鈣離子攝取儲存釋放儲存障礙2023/10/142023/10/14二、Impairedmyocardialdiastolicproperties

DelayedrepositionofCa2+

[Ca2+]10-5mol/L→10-7mol/LATP

Ca++－ATP酶Ca++Ca++Ca++肌漿網(wǎng)Initiativediastolicfunctiondecrease2023/10/142023/10/14

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

Reducedventricularcompliance

myocardialhypertrophy;

fibrosis;edema

dv/dpImpairedmyocardialdiastolicpropertiespassivediastolicfunctiondecrease心室順應(yīng)性(ventricularcompliance)：心室在單位壓力變化下所引起的容積改變(dv/dp),其倒數(shù)(dp/dv)即為心室僵硬度（ventricularstiffness）正常降低升高P—V曲線VP100110（ml）30181310（mmHg）V稍有增加P增加很多正常V100P10

V110P13心梗（順↓）

V100P18V110P

302023/10/142023/10/14三、Inconsistentbehaviorinsystolicanddiastolicfunctionoftheheart心衰發(fā)生機制小結(jié)心衰收縮性

心肌細胞壞死\凋亡能量生成

利用障礙興奮收縮耦聯(lián)障礙肌漿網(wǎng)處理Ca+能力

胞外Ca+內(nèi)流障礙Ca+與肌鈣蛋白結(jié)合障礙舒張性

Ca+復(fù)位延緩肌球-肌動蛋白解離障礙心室舒張勢能

心室順應(yīng)性

各部舒縮不協(xié)調(diào)2023/10/14Questions:嚴重心肌缺血通過哪些機制使心肌收縮力減弱？酸中毒引起心肌興奮收縮偶聯(lián)障礙的機制？心肌過度肥大引起心力衰竭的機制？*2023/10/14ReducedconcentrationofNE;decreaseddensityandsensitivityofβ1-adrenergicreceptorDecreasedoxygenandbloodsupplyAlteredofenergymetabolism(production/reserve/utilization)Dysfunctionofexcitation-contractioncouplingExcessivecardiachypertrophyDecreasedcompliance&5Consequencesoftheheartfailureinmetabolismandfunction2023/10/14(一)肺循環(huán)淤血(Pulmonarycongestion)

當PCWP>18mmHg時，即出現(xiàn)肺循環(huán)淤血征，見于左心衰竭。2023/10/14

左心衰竭能導致肺淤血、肺水腫；因此主要的臨床表現(xiàn)是呼吸困難肺水腫心力衰竭細胞2023/10/14Mechanismofdyspnea:

1)肺淤血水腫→肺順應(yīng)性下降2)

支氣管粘膜充血水腫→氣道阻力增加

3)肺毛細血管壓增高，間質(zhì)水腫→肺間質(zhì)壓增高刺激J感受器→呼吸淺快

1、呼吸困難(dyspnea)2023/10/14表現(xiàn)形式:勞力性呼吸困難:

活動時發(fā)生,休息減輕

(dyspneaonexertio