慢性血栓栓塞性肺动脉高压的病理生理学研究进展课件.ppt

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关键词：: 慢性血栓栓塞肺动脉高压病理生理学研究进展课件

资源描述：: 1、1 12 225.Pulmonary hypertension with unclear multifactorial mechanisms1.Pulmonary Arterial Hypertension Idiopathic PAH Heritable Drug-and toxin-induced Associated with:Connective tissue diseases HIV infection Portal hypertension Anorexigens Congenital Heart Diseases PPHN PAH with venulae/cap inv(PVO
2、D)3.PH owing to Lung Diseases/Hypoxemia COPD Interstitial Lung Diseases Sleep-disordered breathing Developmental Abnormalities etc2.PH with owing to Left Heart Disease Systolic dysfunction Diastolic dysfunction ValvularSimonneau et al;JACC 20094.Chronic thromboembolic pulmonary hypertension(CTEPH)Up
3、dated Clinical Classification of PH(Dana Point,2008)Recurrent,unresolved pulmonary thromboembolism in the central pulmonary arteries Sustained pulmonary vascular bed obstruction,PVR&PAP increased Right heart failure death 5-year mortality rate 90%3 34 42004;350:2257-64.VTE incidence5 5Post-opPre-opO
4、peration6 6仅中远端肺血管病变仅中远端肺血管病变未见明显血栓未见明显血栓近端肺动脉血栓机化近端肺动脉血栓机化:继发于肺血栓栓塞症继发于肺血栓栓塞症近端肺血栓与中远近端肺血栓与中远端肺血管病变并存端肺血管病变并存7 7 50-60%Pulmonary endarterectomy 15-20%8 8Pathophysiology of CTEPH9 9 PAP=CO PVRPAP,Pulmonary Artery PressureCO,Cardiac OutputPVR,Pulmonary Vascular Resistance101010rPV R8L1r4 111111Semin
5、Thorac Cardiovasc Surg 18:265-276,20061212Limitations of the embolic hypothesis for CTEPH1313Media hypertrophyIntimal thickeningPlexiform lesionsNormalRevised from Proc Am Thorac Soc Vol 3.pp 571576,2006141411515Fibrinogen level in Chinese CTEPHcontrolPTECTEPH0100200300400*#fibriongen(mg/dl)p=0.014
6、normal vs PTE;p=0.09 normal vs CTEPH;p=0.0012 PTE vs CTEPHNormal:n=72PTE:n=70CTEPH:n=51Results from our own lab(unpublished)1616Control CTEPHfrequencyp valueFibrinogen candidate geneB-455G/A G/G 67%(46/69)68%(23/34)G/A 25%(17/69)32%(11/34)A/A 9%(6/69)0(0/31)G 79%84%A 21%16%B-148 C/T C/C 65%(30/46)68
7、%(23/34)C/T 24%(11/46)32%(11/34)T/T 11%(5/46)0(0/34)C 77%84%T 23%16%genotype/Allelep=0.34p=0.62p=0.1p=0.581717Fibrin function1818Fibrinogen structureBCB.Lim et al.Lancet 2003;361:1424-1431 TA.Morris et al.Thromb Res 2007;119:257-259 R.Ajjan et al.Blood 2008;111:643-650 1919Control PTE CTEPHfrequency
8、p valueFibrinogen candidate geneBArg448Lys(G/A)G/G 69%(45/65)65%(46/71)63%(19/30)G/A 22%(14/65)34%(24/71)33%(10/30)A/A 9%(6/65)1%(1/71)3%(1/30)G 80%82%80%A 20%18%20%AThr312Ala(A/G)A/A 35%(24/68)17%(12/69)14%(4/29)A/G 40%(27/68)51%(35/69)72%(21/29)G/G 25%(17/68)32%(22/69)14%(4/29)A 55%57%50%G 45%43%5
9、0%genotype/Allelep=0.16p=0.93p=0.011p=0.12p=0.059 normal vs PTE，p=0.012 normal vs CTEPH，p=0.011 PTE vs CTEPH2020J.Suntharalingam et al.Eur Respir J 2008;31:736-741212122222Jason X.-J.Yuan，et al.Circulation,2005;111;534-538The Need for Multiple Hits2323Cells isolated from PTE specimen2424HPASMC-N0HPA
10、SMC-N1CTEPH-1CTEPH-2CTEPH-3HPASMC-N2CTEPH-4HPASMC-N0HPASMC-N1CTEPH-1CTEPH-2HPASMC-N2CTEPH-3CTEPH-4Phase contrast microscopy detection of morphology of cultured HPASMCs.Immunofluorescence stainingby-smooth muscle actin(SMA)-SMA(red),nucleus(blue).2525Vimentin+DAPIVimentin+SM a a-actinSM a a-actinSM a
11、 a-actin+DAPI2626normal vs CTEPH0123456789100123456normalCTEPHtime(d)cell viability(ratio to 0 d)n=3,p=0.018 by two way ANOVA2727control-CTEPH SKF group012345678910012345normalCTEPHtime(d)cell viability(ratio to 0d)normal vs CTEPH Nif group012345678910012345normalCTEPHtime(d)cell viability(ratio to
12、0d)n=3,p0.01 by two way ANOVAn=3,p0.05 by two way ANOVA2828 normal vs CTEPH024681012140.60.81.01.20 mM Ca2+1.8 mM Ca2+CTEPHnormaltime(min)ratio(340 nm/380 nm)normal vs CTEPH EDTA group012345678910012345normalCTEPHtime(d)cell viability(ratio to 0d)normal：n=11 CTEPH：n=7n=3,p0.001 by two way ANOVA2929n
13、=15n=50.00.40.81.2n=5T(ms)V(mV)-60060120 CTEPHPASMCp0.05 by T test-3030K is insensitive to 4-AP in PASMC with CTEPH-3131Dysfunctional of Kv channels in PASMC with CTEPHKv1.5-actinCTEPH patientNormal subjectKv1.5 mRNAnormalCTEPH0.000.250.500.751.00*Kv1.5 mRNA(arbitary unit)-3232ROCSOCCa2+Ca2+Ca2+Ca2+
14、LigandLigandPKCVDCKvEmCa2+Ca2+K+DAGIP3Ca2+Ca2+Store DepletionGPCRRTKGPIP2PLCPLCSRCa2+Ca 2+cytContractionProliferationMigrationROCSOCCa2+Ca2+Ca2+Ca2+LigandLigandPKCVDCKvEmCa2+Ca2+K+DAGIP3Ca2+Ca2+Store DepletionGPCRRTKGPIP2PLCPLCSRCa2+Ca 2+cytContractionProliferationMigrationVDC,voltage-dependent Ca2+
15、channels-3333ROCSOCCa2+Ca2+Ca2+Ca2+LigandLigandPKCVDCKvEmCa2+Ca2+K+DAGIP3Ca2+Ca2+Store DepletionGPCRRTKGPIP2PLCPLCSRCa2+Ca 2+cytContractionProliferationMigration-3434Enhancement of CCE in PASMC with CTEPH061218240.61.21.82.40 mM Ca2+10 M CPA1.8 mM Ca2+CPA peakCCE peakRes tingtim e(m in)ratio(340 nm/
16、380 nm)CTEPH patientsNormal subjectsCCE peakNormalCTEPH0.00.40.81.2*groupratio(340 nm/380 nm)Normal n=43,CTEPH n=37*represents p0.001-3535TRPV1TRPV2TRPV3TRPV4TRPM1TRPM2TRPM3TRPM4TRPM7TRPM8TRPC1TRPC2TRPC3TRPC4TRPC5TRPC6TRPC7mRNA Level(arbitrary unit)0.00.20.40.60.81.0TRPVsTRPMsTRPCsPTE CellsNormal PASMC-3636-3737-3838

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