高血压与血管损伤高平进

1、高血压与血管损伤高平进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高血压时，大动脉发生外向型肥厚，小动脉发生内向型肥厚，更小的动脉变稀疏。Our approach高血压时是否存在血管结构与功能异常?血管结构与功能异常的机制?降压药物能否改善异常的血管结构?用于临床的无创性血管功能检测指标有哪些?怎样寻找血管损伤的生物标志?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胶原和弹性蛋白在血管的分布胶原蛋白主要分布在中膜.弹性蛋白主要分布在外膜Han wq CEPP 2009 receipt胶原和弹性蛋白变化aortic mass，collagen, elas

4、tin: SHR WKY； aortic mass，collagen, elastin: increased with age advancingHan wq CEPP 2009 receipt质量胶原弹性蛋白相关性分析:血管结构与脉压的关系PP和中膜干重、胶原和弹性蛋白含量正相关MAP和弹性蛋白/胶原比值负相关Han wq CEPP 2009 receiptVascular function in hypertensive ratsDetection in of PWV in DOCA rats脉搏波在动脉中的传导速度称脉搏波传导速度（PWV）,测量两个动脉记录部位之间的脉搏波传导时间和距离

5、，可以计算出PWV。 SBP 与PWV：R=0.777, p0.001 DBP 与PWV ，R=0.777, p0.001PWV与血压的相关性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 血管壁组织干重1Losartan： 1632周处理组降低2. Spironolactone: 两种处理组降低 Losartan和 Spironolactone - 胶原含量416周(幼年组):SPIR处理16-32周(成年组):LOS处理Han wq CEPP 2009 receiptLosartan和 Spironolacton

10、e -弹性蛋白Losartan和 Spironolactone对弹性蛋白没有影响Han wq CEPP 2009 receiptPWV抗氧化剂对血管功能的影响 (PWV)PWVLosartan对血管功能的影响 (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 血管结构检查： 动脉内中膜厚度 ( IMT ) 判断有无斑块 踝臂血压指数 ( ABI ) 判断有无下肢动脉闭塞血管功能检查：动脉脉搏波传导速度（PWV） 判断血管僵硬度 中心动脉反射波增强指数（CAI） 判断中心动脉僵硬度中心动脉脉搏压（CPP） 判断中心动脉僵硬度动态动脉硬化指数（AASI）判断整体动脉硬化情况大小动脉弹性指数（C1/C2） 判断全身大小动脉弹性血流介导的血管舒张功能（FMD） 判断内皮功能 SBPDBPAASI is based on the slope of DBP on SBP in 24-h ambulatory BP recordings.A

12、ASI的定义是1减去舒张压与收缩压之间的回归斜率。 动态的动脉硬化指数 (AASI)Correlation between PWV and AASIr = 0.51p 0.9mm定义为增厚，IMT1.3mm定义为斑块形成。图a为正常颈总动脉IMT；图b为颈总动脉IMT增厚；图c为颈总动脉粥样硬化斑块形成（箭头所示）。动脉中内膜厚度(IMT)基础状态下肱动脉直径图反应性充血后肱动脉直径图FMD=(反应性充血后直径- 基础状态下直径)/基础状态下直径血流介导的血管舒张(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定义：与疾病相关的生物学信息称之为医学生物标志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高血压组与正常对照组一般资料的比较( s )一般指标高血压组(n=218)正常对照组(n=206)P年龄 (岁)55.774.6254.638.240.091性别 (男/女)100/11884 /1220.327*体重指数(kg/m2)26.203.

20、3422.722.500.001收缩压 (mmHg)143.1121.13114.8013.170.001舒张压 (mmHg)87.6511.2776.476.870.001空腹血糖 (mmol/L)5.580.904.900.710.001胆固醇 (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高血压组与正常对照组血清OPN与hs-CRP浓度的比较(s )因子高血压组(n=218)正常对照组(n=206)POPN (ng/ml)56.9326.2151.4819.660.016CRP (mg/l)2.032.960.130.220.001Unpublished data血清hs-CRP与OPN的相关性 Unpublished dataLn(hs-CRP)、OPN与多种危险因素的相关性分析 变量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各种相关因素的工作特征(ROC)曲线下面积比较 Unpublished data相关因素的Logistic逐步回归分析 变量BSEExp(B)95%可信区间Phs-CRP, +1 SD/101.410.184.082.87-5.790.001体重指数, +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