慢性血栓栓塞性肺动脉高压的病理生理学研究进展

1、慢性血栓栓塞性肺动脉高压的病理生理学研究进展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 mechanisms 1. Pulmonary Arterial Hypertension Idiopathic PAH Heritable Drug- and toxin-induced Associated with: Connective tissue diseases HIV infection Portal hypertension Anorexigens Congenital Heart

2、 Diseases PPHN PAH with venulae/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. Chron

3、ic thromboembolic pulmonary hypertension (CTEPH)Updated Clinical Classification of PH (Dana Point, 2008) CTEPH Recurrent, unresolved pulmonary thromboembolism in the central pulmonary arteries Sustained pulmonary vascular bed obstruction , PVR& PAP increased Right heart failure death 5-year mortalit

4、y rate 90% 245. Pulmonary hypertension witDVT-PE and CTEPH3DVT-PE and CTEPH52004;350:2257-64.VTE incidence USSymptomatic VTE 600,000/yearPE, n=237,058 /year EuropeSymptomatic VTE 1.50million/yFatal PE 435,000/year China PE 3.1 million /yearEpidemiology42004;350:2257-64.VTE incidencePresent treatment

5、 (PTE)Post-opPre-opOperation5Present treatment (PTE)Post-opCTEPH： Specimen of PTE仅中远端肺血管病变未见明显血栓近端肺动脉血栓机化:继发于肺血栓栓塞症近端肺血栓与中远端肺血管病变并存6CTEPH： Specimen of PTE仅中远端肺血管病 Postoperative results of the 400 CTEPH patients in Beijing ChaoYang hospital and UCSDOperation doesnt mean everything 50-60%PAP NormalPul

6、monary endarterectomyPAP higher 15-20%7 Postoperative results of tPathophysiology of CTEPH8Pathophysiology of CTEPH10 PAP = CO PVRPAP, Pulmonary Artery PressureCO, Cardiac OutputPVR, Pulmonary Vascular ResistanceHumanPA tree10PVRPAPPhysiology of Pulmonary Circulation9 PAP = CO PVRHuman10PVRPAPVR 1/r

7、4 (inversely proportional to the fourth power of the radius, r, of pulmonary artery lumen)r11Physiology of Pulmonary Circulation10PVR 1/r4r11Physiology of Pul PE and unresolved clot formation Pulmonary vascular remodeling“Dual-compartment hypothesis”rPAPPVRSacks, et al. Semin Thorac Cardiovasc Surg

8、18:265-276 , 200611 PE and unresolved clot formatHigh PAP after PTEAbsence of recurrent VTE or PELack of correlation between PAP and angiographic pulmonary vascular bed obstruction Higher PVR than in acute PE patientsPathology evidenceLimitations of the embolic hypothesis for CTEPH12High PAP after P

9、TELimitations Media hypertrophyIntimal thickeningPlexiform lesionsNormalRevised from Proc Am Thorac Soc Vol 3. pp 571576, 2006“Dual-compartment hypothesis”13Media hypertrophyIntimal thick1Thrombosis Non-resolutionKey point of“Dual-compartment hypothesis”141Thrombosis Non-resolutionKey Fibrinogen lev

10、el in Chinese CTEPHp=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 lab (unpublished)Thrombosis Nonresolution15Fibrinogen level in Chinese CControl CTEPHfreq

11、uencyp 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=0.58Thrombosis Nonresolu

12、tion16Control CTEPHfrequencypFibrin functionThrombosis Non-resolution17Fibrin functionThrombosis Non-Fibrinogen 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 Thrombosis Non-resolution18Fibrinogen structureBC

13、B. Lim eControl 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%(6/65) 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%(21/2

14、9) 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 CTEPHThrombosis Non-resolution19Control PTE J. Suntharalingam et al. Eur Respir J 2008; 31:736-741Thrombosis Non-resolution20J. Sunth

15、aralingam et al. Eur Pathophysiology of CTEPH2Pulmonary vascular remodelingRole of ion channel and Ca2+ 21Pathophysiology of CTEPH2PulmoJason X.-J. Yuan，et al. Circulation, 2005;111;534-538The Need for Multiple Hits 22Jason X.-J. Yuan，et al. CirculPulmonary vascular remodeling Cells isolated from PT

16、E specimen23Pulmonary vascular remodeling HPASMC-N0HPASMC-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 (b

17、lue).Pulmonary vascular remodeling 24HPASMC-N0HPASMC-N1CTEPH-1CTEPHVimentin+DAPIVimentin+SM a-actinSM a-actinSM a-actin+DAPIPulmonary vascular remodeling 25Vimentin+DAPIVimentin+SM a-actn=3, p=0.018 by two way ANOVAPulmonary vascular remodeling 26n=3, p=0.018 by two way ANOVAPn=3, p0.01 by two way A

18、NOVAn=3, p0.05 by two way ANOVAPulmonary vascular remodeling ion channel and Ca 2+27n=3, p0.01 by two way ANOVAn=normal：n=11 CTEPH：n=7n=3, p0.001 by two way ANOVAPulmonary vascular remodeling ion channel and Ca 2+28normal：n=11 CTEPH：n=7n=3, p0NormalCTEPHn=15n=5p0.05 by T testPulmonary vascular remod

19、eling-ion channel and Ca2+29NormalCTEPHn=15n=5p0.05 by T K is insensitive to 4-AP in PASMC with CTEPHPulmonary vascular remodeling-ion channel and Ca2+30K is insensitive to 4-AP in PADysfunctional of Kv channels in PASMC with CTEPHKv1.5-actinCTEPH patientNormal subjectPulmonary vascular remodeling-i

20、on channel and Ca2+31Dysfunctional of Kv channels i K+ channel activity causes membrane depolarizationVDC, voltage-dependent Ca2+ channelsCa2+Pulmonary vascular remodeling-ion channel and Ca2+32 K+ channel activityVDC, voltTransient Receptor Potential (TRP) ChannelsParticipate in Forming Functional SOC and ROCin Human Pulmonary Vascular SMC and EC.Three Major Families of TRP Channels:TRPC FamilyTRPV FamilyTRPM FamilyCa2+Pulmonary vascular remodeling-ion channel and Ca2+33Ca2+Pulmonary vascular remodEnhancement of CCE in PASMC with CTEPHCTEPH patient