1、Hypertension and vascular injury高血压与血管损伤高血压与血管损伤Pingjin Gao（高（高平进）平进）Shanghai Institute of HypertensionDivision of Hypertension,Shanghai Jiaotong University School of Medicine上海市高血压研究所上海市高血压研究所上海交通大学医学院附属瑞金医院高血压科上海交通大学医学院附属瑞金医院高血压科Vascular injury is defined by functional and structural alteration of
2、 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 TREEVascular 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，更小的动脉变稀疏高血压时，大动脉发生外向型肥厚，小动脉
3、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 I The change of Vascular structure and function in hypertension The mechanism of abnormal structure The effect of losartan and spironolactone on collagen and elastin of thoracic aorta.
4、The change of Vascular structure and function in hypertension Vascular structure:Mass collagen elastin Vascular function:PWVStressstrain relationship of the aorta胶原和弹性蛋白在血管的分布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胶原和弹性蛋白胶原和弹性蛋白变变化化aortic mass，collagen,elastin:SHR WKY；aortic mas
5、s，collagen,elastin:increased with age advancingHan wq CEPP 2009 receipt质量胶原弹性蛋白相关性分析相关性分析:血管结构与脉压的关系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脉搏脉搏波在波在动动脉中的脉中的传导传导速度称速度称脉搏脉搏波波传传导导速度（速度（PWV）,测量两个测量两个动脉记录部
6、位之间的脉搏波传导时间和距离，可以计算出动脉记录部位之间的脉搏波传导时间和距离，可以计算出PWV。PWV(m/s)800700600500400SBP(mmHg)200180160140120100SBP 与与PWV：R=0.777,p0.001 PWV(m/s)800700600500400DBP(mmHg)1601501401301201101009080DBP 与与PWV，R=0.777,p0.001PWV与血压的相关性与血压的相关性The mechanism of abnormal structure in vascular wall Angiotensin II Reactive o
7、xygen species(ROS)CTGF InflammationEffect of Ang II on collagen synthesis and expressionCollagen I-actin3H proline incorporation was used to study the 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
8、-agonists on Ang II-induced collagen type I expressionEffect of the Ang II on collagen type I expressionZhang J et al.CEPP 2019Collagen IAng II-induced ROS formationAng II-induced ROS formationShen WL et al.BBRC 2019,;339:337-43.ROS in aorta vesselsEffect of ROS on AngII-induced collagen expressionZ
9、hangjia 2019 Hypertens ResCTGF involved in AngII-induced collagen synthesisChe ZQ et al.2019 Hypertens ResInflammatory mediators mRNA expression 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
10、 expression in AF ELISA(n=4)Western blot(n=4)Effect of treatment on vascular structure and function Angiotensin II receptor blockers(ARB)Aldosterone antagonist(spironolactone)Antioxidant(apocynine)improved vascular structure and functionLosartan和 Spironolactone 血管壁组织干重血管壁组织干重1Losartan：1632周处理组降低2.Sp
11、ironolactone:两种处理组降低 Losartan和 Spironolactone-胶原含量胶原含量416周(幼年组):SPIR处理16-32周(成年组):LOS处理Han wq CEPP 2009 receiptLosartan和 Spironolactone-弹性蛋白弹性蛋白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 II Evaluation of vascular injury in the patients w
12、ith hypertension Is there an earlier marker to predict the hypertension complications?Non-invasive examination of vascular structure and function 血管结构检查：血管结构检查：动脉内中膜厚度动脉内中膜厚度(IMT)判断有无斑块判断有无斑块 踝臂血压指数踝臂血压指数(ABI)判断有无下肢动脉闭塞判断有无下肢动脉闭塞血管功能检查：血管功能检查：动脉脉搏波传导速度（动脉脉搏波传导速度（PWV）判断血管僵硬度判断血管僵硬度 中心动脉反射波增强指数（中心动脉反射
13、波增强指数（CAI）判断中心动脉僵硬度判断中心动脉僵硬度中心动脉脉搏压（中心动脉脉搏压（CPP）判断中心动脉僵硬度判断中心动脉僵硬度动态动脉硬化指数（动态动脉硬化指数（AASI）判断整体动脉硬化情况判断整体动脉硬化情况大小动脉弹性指数（大小动脉弹性指数（C1/C2）判断全身大小动脉弹性判断全身大小动脉弹性血流介导的血管舒张功能（血流介导的血管舒张功能（FMD）判断内皮功能判断内皮功能 SBPDBPAASI is based on the slope of DBP on SBP in 24-h ambulatory BP recordings.AASI的定义是1减去舒张压与收缩压之间的回归斜率。
14、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血流介导的血管舒张(FMD)rP valueAge(years)-0.2350.001BMI(kg/m2)-0.2270.001Waist(cm)-0.2440.001Waist
15、-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)-0.2020.001Correlation of FMD with ca
16、rdiovascular 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(kg/m2)24.492.5725.502.97*
17、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)84.4111.4484.3910.6786.0212.4988.4
18、912.06PP(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)1.440.351.430.361.390.341.420.37LDL-C(
19、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 severity of FMD Xu JZ，et al J human hyperte
20、nsion 2009The severity of FMD and TODTo find the Bio-markers for predictor vascular injury in hypertensionGenetic markerGenetic markerFunctional/structure markerFunctional/structure markerBio-markerBio-marker定义：与疾病相关的生物学信息称之为医学生物标志定义：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 injur
21、y To find interesting genes Functional 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高血压组与正常对照组一般资料的比较(s)一般指标一般指标高血压组高血压组(n=218)正常对照组正常对照组(n=206)P年龄年龄(岁岁)55.774.625
22、4.638.240.091性别性别(男男/女女)100/11884/1220.327*体重指数体重指数(kg/m2)26.203.3422.722.500.001收缩压收缩压(mmHg)143.1121.13114.8013.170.001舒张压舒张压(mmHg)87.6511.2776.476.870.001空腹血糖空腹血糖(mmol/L)5.580.904.900.710.001胆固醇胆固醇(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
23、甘油三酯(mmol/L)2.341.871.340.830.001血尿素氮血尿素氮(mmol/L)5.561.425.161.200.002血尿酸血尿酸(mol/L)340.9286.93285.7568.650.001Unpublished data高血压组与正常对照组血清高血压组与正常对照组血清OPN与与hs-CRP浓度的比较浓度的比较(s)因子因子高血压组高血压组(n=218)正常对照组正常对照组(n=206)POPN(ng/ml)56.9326.2151.4819.660.016CRP(mg/l)2.032.960.130.220.001Unpublished data血清血清hs-C
24、RP与与OPN的相关性的相关性 Unpublished dataLn(hs-CRP)、OPN与多种危与多种危险险因素因素的相关性分析的相关性分析 变量变量AGEBMIBUNUAHDL-CLDL-CFGTGOPNr0.2170.1930.2950.238-0.1640.1060.0750.048P0.0010.001 0.001 0.0010.0010.0290.1230.329Ln(hs-CRP)r0.1560.5510.1580.385-0.3170.0220.3200.317P0.0010.0010.0010.001 0.0010.6560.001 0.001Unpublished dat
25、a各种相关因素的工作特征各种相关因素的工作特征(ROC)(ROC)曲线下面积比较曲线下面积比较 Unpublished data相关因素的相关因素的Logistic逐步回归分析逐步回归分析 变量变量BSEExp(B)95%可信区间可信区间Phs-CRP,+1 SD/101.410.184.082.87-5.790.001体重指数体重指数,+1 SD0.650.271.921.12-3.280.017空腹血糖空腹血糖,+1 SD0.910.222.481.62-3.800.001甘油三酯甘油三酯,+1 SD1.020.322.781.48-5.220.001Unpublished dataMMP
26、-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.
27、047.46105.2015.31TIMP-1(ng/ml)316.977.97*345.179.71#419.9118.16OPN(ng/ml)30.391.18*38.001.34#87.8613.33CRP(mg/l)5.330.428*5.920.4510.401.22高血高血压压血管血管损伤时损伤时表表现为现为血管血管结结构成分及功能改构成分及功能改变变,主主动动脉的脉的结结构改构改变变主主要要为为胶原胶原/弹弹性蛋白的含量性蛋白的含量/分布分布变变化化,功能功能变变化主要以化主要以PWV改改变为变为代表代表,血血管管结结构构/功能改功能改变变的机制十分复的机制十分复杂杂.涉及涉及A
28、ngII,ROS,CTGF等等.高血高血压压患者的血管功能改患者的血管功能改变变可以用非可以用非创伤创伤技技术检测术检测，AASI与收与收缩压缩压,脉脉压压及及PWV 有良好的相关性有良好的相关性;FMD检测检测内皮功能可能作内皮功能可能作为为一危一危险险因素因素,其程其程度与靶器官度与靶器官损伤损伤有一定关系。有一定关系。高血高血压压患者血患者血浆浆CRP、OPN、MMP-2、MMP-9、TIMP-1含量含量显显著高于著高于正常正常对对照照组组；且与慢性；且与慢性肾肾功能受功能受损损有关，但能否作有关，但能否作为为高血高血压压患者血管患者血管损损伤伤的生物的生物标标志待志待进进一步随一步随访
29、访研究。研究。Summary and ConclusionTo find the Bio-markers for predictor vascular injury in hypertensionFutureDingliang ZHU,PROF.Yi ZHANG,Associate PROF.Weiqing HAN,Ph.DWeili SHEN,MD,Ph.DJia Zhang,MD,Ph.DYanxiu LI,MDJianzhong XU,MD,Ph.DQizhi,CHEN,MD,Ph.DAcknowledgementsThis work was supported by grants from the National Natural Science Foundation of China(2019AA02Z179),National Basic Research program of China(2019CB503804)to PJ.GaoThe relationship of CRP with age,BMI,BUN and UAUnpublished data
