高血壓與血管損傷高平進(jìn)

1、高血壓與血管損傷高平進(jìn)Vascular injury is defined by functional and structural alteration of large and small vascular induced by high blood pressure.Definition of vascular injury The common pathophysiology of target organ complication is vascular injury Hypertension is a vascular diseaseTHE VASCULAR TREEVascula

2、r injuries in Hypertension高血壓時(shí)，大動(dòng)脈發(fā)生外向型肥厚，小動(dòng)脈發(fā)生內(nèi)向型肥厚，更小的動(dòng)脈變稀疏。Our approach高血壓時(shí)是否存在血管結(jié)構(gòu)與功能異常?血管結(jié)構(gòu)與功能異常的機(jī)制?降壓藥物能否改善異常的血管結(jié)構(gòu)?用于臨床的無創(chuàng)性血管功能檢測指標(biāo)有哪些?怎樣尋找血管損傷的生物標(biāo)志?Part IThe change of Vascular structure and function in hypertensionThe mechanism of abnormal structureThe effect of losartan and spironolactone o

3、n collagen and elastin of thoracic aorta. The change of Vascular structure and function in hypertensionVascular structure: Mass collagen elastinVascular function : PWVStressstrain relationship of the aorta膠原和彈性蛋白在血管的分布膠原蛋白主要分布在中膜.彈性蛋白主要分布在外膜Han wq CEPP 2009 receipt膠原和彈性蛋白變化aortic mass，collagen, elas

4、tin: SHR WKY； aortic mass，collagen, elastin: increased with age advancingHan wq CEPP 2009 receipt質(zhì)量膠原彈性蛋白相關(guān)性分析:血管結(jié)構(gòu)與脈壓的關(guān)系PP和中膜干重、膠原和彈性蛋白含量正相關(guān)MAP和彈性蛋白/膠原比值負(fù)相關(guān)Han wq CEPP 2009 receiptVascular function in hypertensive ratsDetection in of PWV in DOCA rats脈搏波在動(dòng)脈中的傳導(dǎo)速度稱脈搏波傳導(dǎo)速度（PWV）,測量兩個(gè)動(dòng)脈記錄部位之間的脈搏波傳導(dǎo)時(shí)間和距離

5、，可以計(jì)算出PWV。 SBP 與PWV：R=0.777, p0.001 DBP 與PWV ，R=0.777, p0.001PWV與血壓的相關(guān)性The mechanism of abnormal structure in vascular wall Angiotensin II Reactive oxygen species (ROS) CTGF InflammationEffect of Ang II on collagen synthesis and expressionCollagen I-actin3H proline incorporation was used to study th

6、e effects of Ang II on collagen synthesis. The AT1-R antagonist Losartan (10-5 mol/L) inhibited the Ang II- induced 3H proline incorporation, Effect of PPAR- agonists on Ang II-induced collagen type I expressionEffect of the Ang II on collagen type I expressionZhang J et al. CEPP 2007Collagen IAng I

7、I-induced ROS formationAng II-induced ROS formationShen WL et al. BBRC 2006,;339:337-43. ROS in aorta vesselsEffect of ROS on AngII-induced collagen expressionZhangjia 2008 Hypertens ResCTGF involved in AngII-induced collagen synthesisChe ZQ et al. 2008 Hypertens ResInflammatory mediators mRNA expre

8、ssion confirmed by Real-time PCRIL-6 (n=4)MCP-1 (n=4)ICAM-1 (n=4)P-selectin (n=3)Inflammatory mediators protein expression or secretion IL-6 secretion from AF ICAM-1 expression in AF ELISA (n=4) Western blot (n=4) Effect of treatment on vascular structure and function Angiotensin II receptor blocker

9、s (ARB)Aldosterone antagonist (spironolactone)Antioxidant (apocynine)improved vascular structure and functionLosartan和 Spironolactone 血管壁組織干重1Losartan： 1632周處理組降低2. Spironolactone: 兩種處理組降低 Losartan和 Spironolactone - 膠原含量416周(幼年組):SPIR處理16-32周(成年組):LOS處理Han wq CEPP 2009 receiptLosartan和 Spironolacton

10、e -彈性蛋白Losartan和 Spironolactone對彈性蛋白沒有影響Han wq CEPP 2009 receiptPWV抗氧化劑對血管功能的影響 (PWV)PWVLosartan對血管功能的影響 (PWV)Part IIEvaluation of vascular injury in the patients with hypertensionIs there an earlier marker to predict the hypertension complications ?Non- invasive examination of vascular structure an

11、d function 血管結(jié)構(gòu)檢查： 動(dòng)脈內(nèi)中膜厚度 ( IMT ) 判斷有無斑塊 踝臂血壓指數(shù) ( ABI ) 判斷有無下肢動(dòng)脈閉塞血管功能檢查：動(dòng)脈脈搏波傳導(dǎo)速度（PWV） 判斷血管僵硬度 中心動(dòng)脈反射波增強(qiáng)指數(shù)（CAI） 判斷中心動(dòng)脈僵硬度中心動(dòng)脈脈搏壓（CPP） 判斷中心動(dòng)脈僵硬度動(dòng)態(tài)動(dòng)脈硬化指數(shù)（AASI）判斷整體動(dòng)脈硬化情況大小動(dòng)脈彈性指數(shù)（C1/C2） 判斷全身大小動(dòng)脈彈性血流介導(dǎo)的血管舒張功能（FMD） 判斷內(nèi)皮功能 SBPDBPAASI is based on the slope of DBP on SBP in 24-h ambulatory BP recordings.A

12、ASI的定義是1減去舒張壓與收縮壓之間的回歸斜率。 動(dòng)態(tài)的動(dòng)脈硬化指數(shù) (AASI)Correlation between PWV and AASIr = 0.51p 0.9mm定義為增厚，IMT1.3mm定義為斑塊形成。圖a為正常頸總動(dòng)脈IMT；圖b為頸總動(dòng)脈IMT增厚；圖c為頸總動(dòng)脈粥樣硬化斑塊形成（箭頭所示）。動(dòng)脈中內(nèi)膜厚度(IMT)基礎(chǔ)狀態(tài)下肱動(dòng)脈直徑圖反應(yīng)性充血后肱動(dòng)脈直徑圖FMD=(反應(yīng)性充血后直徑- 基礎(chǔ)狀態(tài)下直徑)/基礎(chǔ)狀態(tài)下直徑血流介導(dǎo)的血管舒張(FMD) rP valueAge(years)-0.2350.001BMI(kg/m2)-0.2270.001Waist(cm)-

13、0.2440.001Waist-Hip ratio-0.2000.001 hs-CRP(mg/L)0.0630.298TC(mmol/L)-0.0430.475TG (mmol/L)-0.0830.164HDL-C (mmol/L)0.1860.002 LDL-C (mmol/L)-0.0340.572Blood-fasting glucose(mmol/L) -0.0590.314SBP(mmHg)-0.1250.036 DBP(mmHg)0.0550.355PP(mmHg)-0.1870.002History of hypertension(years)-0.2020.001Correla

14、tion of FMD with cardiovascular risk factorsXu JZ，et al J human hypertension 2009Correlation of FMD with target organ damage (TOD)Xu JZ，et al J human hypertension 2009CharacteristicsNo TOD(n=61)One TOD(n=113)Two TOD(n=59)ThreeTOD (n=47)Age (years)5310598*639*649*Gender, F/M28/3355/5818/4117/30BMI (k

15、g/m2)24.492.5725.502.97*26.163.45*26.482.54*Waist (cm)85.988.1587.388.3190.109.92*92.558.22*WHR (cm/cm)0.890.050.890.050.910.05*0.930.06*Smoking, n(%)19(35.85)28(24.78)21(35.59)22(46.81) *DM, n(%)3(4.92)13(11.50)5(8.47)5(10.64)SBP (mm Hg)129.8716.63139.2014.50*147.2517.27*158.8719.50*&DBP (mm Hg)84.

16、4111.4484.3910.6786.0212.4988.4912.06PP (mm Hg)45.4611.8354.8114.20*61.2413.49*70.3816.76*&Hypertension (years)10.788.4116.5810.85*18.0710.83*22.4911.90*&Hs-CRP (mg/L)1.913.601.902.531.641.232.022.23TG (mmol/L)2.051.332.301.762.151.172.341.61TC (mmol/L)4.951.065.021.015.110.825.230.81HDL-C (mmol/L)1

17、.440.351.430.361.390.341.420.37LDL-C (mmol/L)2.780.742.750.782.930.692.970.68Glucose (mmol/L)5.320.615.540.955.460.845.661.20Glucose 2 h (mmol/l)6.722.277.602.997.713.228.062.72*Characteristics of the Study Population Xu JZ，et al J human hypertension 2009Number of target organ damage (TOD) and the s

18、everity of FMD Xu JZ，et al J human hypertension 2009The severity of FMD and TODTo find the Bio-markers for predictor vascular injury in hypertensionGenetic markerFunctional/structure markerBio-marker定義：與疾病相關(guān)的生物學(xué)信息稱之為醫(yī)學(xué)生物標(biāo)志TGF-b1 ANGII Cellular models of vascular injury To find interesting genes Func

19、tional study in vivo and in vitro Clinical evaluation (detection and follow up)CTGFOsteopontinRho A / ROKInflarmation factors CRPThe strategic plan for discovering Bio-markers高血壓組與正常對照組一般資料的比較( s )一般指標(biāo)高血壓組(n=218)正常對照組(n=206)P年齡 (歲)55.774.6254.638.240.091性別 (男/女)100/11884 /1220.327*體重指數(shù)(kg/m2)26.203.

20、3422.722.500.001收縮壓 (mmHg)143.1121.13114.8013.170.001舒張壓 (mmHg)87.6511.2776.476.870.001空腹血糖 (mmol/L)5.580.904.900.710.001膽固醇 (mmol/L)5.220.925.290.910.430HDL-C(mmol/L)1.430.351.580.340.001LDL-C(mmol/L)2.890.742.950.690.395甘油三酯 (mmol/L)2.341.871.340.830.001血尿素氮(mmol/L)5.561.425.161.200.002血尿酸 (mol/L)

21、340.9286.93285.7568.650.001Unpublished data高血壓組與正常對照組血清OPN與hs-CRP濃度的比較(s )因子高血壓組(n=218)正常對照組(n=206)POPN (ng/ml)56.9326.2151.4819.660.016CRP (mg/l)2.032.960.130.220.001Unpublished data血清hs-CRP與OPN的相關(guān)性 Unpublished dataLn(hs-CRP)、OPN與多種危險(xiǎn)因素的相關(guān)性分析 變量AGEBMIBUNUAHDL-CLDL-CFGTGOPNr0.2170.1930.2950.238-0.16

22、40.1060.0750.048P0.0010.0010.0010.0010.0010.0290.1230.329Ln(hs-CRP)r0.1560.5510.1580.385-0.3170.0220.3200.317P0.0010.0010.0010.0010.0010.6560.0010.001Unpublished data各種相關(guān)因素的工作特征(ROC)曲線下面積比較 Unpublished data相關(guān)因素的Logistic逐步回歸分析 變量BSEExp(B)95%可信區(qū)間Phs-CRP, +1 SD/101.410.184.082.87-5.790.001體重指數(shù), +1 SD0.

23、650.271.921.12-3.280.017空腹血糖, +1 SD0.910.222.481.62-3.800.001甘油三酯, +1 SD1.020.322.781.48-5.220.001Unpublished dataMMP-2、MMP-9、TIMP-1 levels between hypertensives and normotensivesVariablesNormotensives (n=168)Hypertensives (n=378)PMMP-252.354.3888.7911.420.01MMP-9110.693.90112.605.16NSTIMP-1306.089.53342.186.1790(n=162)CKD260-90(n=170)CKD360(n=46)MMP-2(ng/ml)82.0111.3077.8814.05*152.9967.32MMP-9(ng/ml)110.048.08117.047.46105.2015.31TIMP-1(ng/ml)316.977.97*345.179.71#419.9118.16OPN (n