1、慢性血栓栓塞性肺动脉高压的病理生理学研究进展25.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 ven
2、ulae/cap inv(PVOD)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 hyper
3、tension(CTEPH)Updated 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%2004;350:2257-64.VTE incidenceCCE pea
4、kNormalCTEPH0.00.40.81.2*groupratio(340 nm/380 nm)Post-opPre-opOperation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 50-60%Pulmonary endarterectomy 15-20%Pathophysiology of CTEPH PAP=CO PVRPAP,Pulmonary Artery PressureCO,Cardiac OutputPVR,Pulmon
5、ary Vascular Resistance10Kv1.5 mRNAnormalCTEPH0.000.250.500.751.00*r11Semin Thorac Cardiovasc Surg 18:265-276,2006Limitations of the embolic hypothesis for CTEPHMedia hypertrophyIntimal thickeningPlexiform lesionsNormal0.00.40.81.2n=5T (m s)V (m V)-6 006 01 2 0 C T E P HP A S M CRevised from Proc Am
6、 Thorac Soc Vol 3.pp 571576,20061Fibrinogen level in Chinese CTEPHcontrolPTECTEPH0100200300400*#fibriongen(mg/dl)p=0.014 normal vs PTE;p=0.09 normal vs CTEPH;p=0.0012 PTE vs CTEPHcontrolPTECTEPHp valuefibriongen mg/dl(s)287.970.8339.6136.3272.5750.01Normal:n=72PTE:n=70CTEPH:n=51Results from our own
7、lab(unpublished)Control CTEPHfrequencyp valueFibrinogen candidate geneB-455G/A G/G 67%(46/69)68%(23/34)G/A 25%(17/69)32%(11/34)A/A 9%(6/69)0(0/31)G 79%84%A 21%16%B-148 C/T C/C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%(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=0.58Fibrin
8、 functionFibrinogen 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 Control PTE CTEPHfrequencyp 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/
9、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%50%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 CTEPHJ.Suntharalingam
10、 et al.Eur Respir J 2008;31:736-7412Jason X.-J.Yuan，et al.Circulation,2005;111;534-538The Need for Multiple HitsCells isolated from PTE specimenHPASMC-N0HPASMC-N1CTEPH-1CTEPH-2CTEPH-3HPASMC-N2CTEPH-4HPASMC-N0HPASMC-N1CTEPH-1CTEPH-2HPASMC-N2CTEPH-3CTEPH-4Phase contrast microscopy detection of morphol
11、ogy of cultured HPASMCs.Immunofluorescence stainingby-smooth muscle actin(SMA)-SMA(red),nucleus(blue).Vimentin+DAPIVimentin+SM a a-actinSM a a-actinSM a a-actin+DAPIcontrol-CTEPH SKF group012345678910012345normalCTEPHtime(d)cell viability(ratio to 0d)n=3,p=0.018 by two way ANOVAnormal vs CTEPH Nif g
12、roup012345678910012345normalCTEPHtime(d)cell viability(ratio to 0d)n=3,p0.01 by two way ANOVAn=3,p0.05 by two way ANOVAnormal vs CTEPH EDTA group012345678910012345normalCTEPHtime(d)cell viability(ratio to 0d)normal vs CTEPH024681012140.60.81.01.20 mM Ca2+1.8 mM Ca2+CTEPHnormaltime(min)ratio(340 nm/3
13、80 nm)normal：n=11 CTEPH：n=7n=3,p0.001 by two way ANOVAnormal vs CTEPH0123456789100123456normalCTEPHtime(d)cell viability(ratio to 0 d)n=15n=5p0.05 by T test-2929K is insensitive to 4-AP in PASMC with CTEPH-Dysfunctional of Kv channels in PASMC with CTEPHKv1.5-actinCTEPH patientNormal subjectP V R8 L 1r4 -VDC,voltage-dependent Ca2+channels-Enhancement of CCE in PASMC with CTEPHCTEPH patientsNormal subjectsNormal n=43,CTEPH n=37*represents p0.001-NoImage-061218240.61.21.82.40 mM Ca2+10 M CPA1.8 mM Ca2+CPA peakCCE peakRestingtime(min)ratio(340 nm/380 nm)
