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1、Hypertension and vascular injury 高血压与血管损伤,Pingjin Gao（高平进） Shanghai Institute of Hypertension Division of Hypertension, Shanghai Jiaotong University School of Medicine,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,Vascular injury is defined by functional and structural alteration of large and small vascular induced
2、 by high blood pressure.,Definition of vascular injury,The common pathophysiology of target organ complication is vascular injury Hypertension is a vascular disease,THE VASCULAR TREE,Vascular 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?
3、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.,The change of Vascular structure and function in hyperten
4、sion,Vascular structure: Mass collagen elastin Vascular function : PWV,Stressstrain 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, elastin: SHR WKY； aortic mass，collagen, elastin: increased with age advancing,Han wq CEPP 2009
5、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 receipt,Vascular function in hypertensive rats,Detection 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，可以计算出PWV。,SBP 与PWV：R=0.777, p0.001,DBP 与PWV ，R=0.777, p0.001,PWV与血压的相关性,The mec
6、hanism of abnormal structure in vascular wall,Angiotensin II Reactive oxygen species (ROS) CTGF Inflammation,Effect of Ang II on collagen synthesis and expression,Collagen I,-actin,3H proline incorporation was used to study the effects of Ang II on collagen synthesis.,The AT1-R antagonist Losartan (
7、10-5 mol/L) inhibited the Ang II- induced 3H proline incorporation,Effect of PPAR- agonists on Ang II-induced collagen type I expression,Effect of the Ang II on collagen type I expression,Zhang J et al. CEPP 2007,Collagen I,Ang II-induced ROS formation,Ang II-induced ROS formation,Shen WL et al. BBR
8、C 2006,;339:337-43.,ROS in aorta vessels,Effect of ROS on AngII-induced collagen expression,Zhangjia 2008 Hypertens Res,CTGF involved in AngII-induced collagen synthesis,Che ZQ et al. 2008 Hypertens Res,Inflammatory mediators mRNA expression confirmed by Real-time PCR,IL-6 (n=4),MCP-1 (n=4),ICAM-1 (
9、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 blockers (ARB) Aldosterone antagonist (spironolactone) Antioxidant
10、 (apocynine),improved vascular structure and function,Losartan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 receipt,Losartan和 Spironolactone -弹性蛋白,Losartan和 Spironolactone对弹性蛋白没有影响,Han wq
11、CEPP 2009 receipt,PWV,抗氧化剂对血管功能的影响 (PWV),PWV,Losartan对血管功能的影响 (PWV),Part II,Evaluation of vascular injury in the patients with 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： 动脉内中膜厚度 ( IMT ) 判断有无
12、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,SBP,DBP,AASI 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。,动态的动
13、脉硬化指数,(AASI),Correlation between PWV and AASI,r = 0.51 p 0.0001 n = 166 97 women 69 men,The decrease of AASI (AASI) was significantly associated with the reduction of SBP(SBP ) and pulse pressure( PP), even after adjusting for age , gender, height, baseline 24-h BP ,PP, and heart rate (HR), nocturna
14、l BP fall.,2009 ESH post,0.44,0.45,0.46,0.47,0.48,0.49,0.50,0.51,0.52,0.53,unadjusted,adjusted,Non-stroke,Stroke,47,48,49,50,51,52,53,54,55,unadjusted,adjusted,Non-stroke,Stroke,Figure,AASI,24-h PP,AASI in hypertensives with and without stroke,2009 ESH post,颈总动脉IMT，本研究中应用PHILIPS HD11EX 超声仪提供的Qlab软件自
15、动测量，IMT0.9mm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),Correlation of FMD with cardiovascular risk factors,Xu JZ，et al J human hypertension 2009,Correlation of FMD with target organ damag
16、e (TOD),Xu JZ，et al J human hypertension 2009,Characteristics of the Study Population,Xu JZ，et al J human hypertension 2009,Number of target organ damage (TOD) and the severity of FMD,Xu JZ，et al J human hypertension 2009,The severity of FMD and TOD,To find the Bio-markers for predictor vascular inj
17、ury in hypertension,Genetic marker Functional/structure marker Bio-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 Functional study in vivo and in vitro Clinical evaluation (detection and follow up),CTGF Osteopontin Rho A / ROK Inflarmation fa
18、ctors CRP,The strategic plan for discovering Bio-markers,高血压组与正常对照组一般资料的比较( s ),Unpublished data,高血压组与正常对照组血清OPN与hs-CRP浓度的比较(s ),Unpublished data,血清hs-CRP与OPN的相关性,Unpublished data,Ln(hs-CRP)、OPN与多种危险因素的相关性分析,Unpublished 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,Unpublished da
19、ta,MMP-2、MMP-9、TIMP-1 levels between hypertensives and normotensives,MMP-2, MMP-9, TIMP-1, OPN and CRP between CKD groups in hypertensive patients,高血压血管损伤时表现为血管结构成分及功能改变, 主动脉的结构改变主要为胶原/弹性蛋白的含量/分布变化, 功能变化主要以PWV改变为代表,血管结构/功能改变的机制十分复杂. 涉及AngII, ROS,CTGF等. 高血压患者的血管功能改变可以用非创伤技术检测，AASI与收缩压,脉压及PWV 有良好的相关性;
20、 FMD检测内皮功能可能作为一危险因素, 其程度与靶器官损伤有一定关系。 高血压患者血浆CRP、OPN、 MMP-2、MMP-9、TIMP-1含量显著高于正常对照组；且与慢性肾功能受损有关，但能否作为高血压患者血管损伤的生物标志待进一步随访研究。,To find the Bio-markers for predictor vascular injury in hypertension,Future,Dingliang ZHU, PROF. Yi ZHANG, Associate PROF. Weiqing HAN, Ph.D Weili SHEN, MD, Ph.D Jia Zhang, MD
21、, Ph.D Yanxiu LI, MD Jianzhong XU, MD, Ph.D Qizhi, CHEN, MD, Ph.D,This work was supported by grants from the National Natural Science Foundation of China (2006AA02Z179), National Basic Research program of China (2006CB503804) to PJ. Gao,The relationship of CRP with age, BMI, BUN and UA,Unpublished data,