【作者】 谭红伟；

【导师】 张薇；

【作者基本信息】 山东大学 ， 内科学， 2008， 博士

【摘要】 背景代谢综合征（Metabolic syndrome,MS）是严重威胁人类健康的疾病。MS是指包括腹型肥胖、糖耐量异常、胰岛素抵抗、血脂异常及高血压等一组心血管疾病危险因素的症候群。MS的总体危险性并非其各组分的危险性简单相加,而可能是存在相互增强的作用。更好地理解MS的意义在于能帮助我们早期发现2型糖尿病及心血管疾病高危患者。临床研究表明,MS患者动脉粥样硬化性疾病发生率明显增高,即使在年轻人群中,MS依然是动脉粥样硬化的危险因素。上述研究提示,血管结构和功能异常可能是MS患者心血管疾病发生发展的基础。而关于MS大血管结构与功能的改变尚缺乏系统的研究。与正常人相比,MS患者血C-反应蛋白（CRP）、白介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、白介素-18（IL-18）等炎症因子水平升高。动物实验证实,MS大鼠血CRP水平升高,肾脏组织IL-6、单核细胞趋化蛋白-1（MCP-1）mRNA表达增加。这些研究结果提示可能炎症在MS的发生发展中起重要作用。但上述研究结果尚不足以帮助我们区分究竟炎症是MS的“标记物”还是“危险因素”。IL-18是调节免疫应答及炎症反应的重要炎症介质,IL-18在心血管疾病中的作用愈来愈受到重视。临床研究发现稳定性及不稳定性心绞痛患者颈动脉粥样斑块IL-18及IL-18受体表达上调,且IL-18mRNA表达与斑块不稳定性相关。IL-18能使ApoE基因缺陷小鼠动脉粥样硬化加重,而IL-18基因敲除能减轻小鼠动脉粥样硬化程度。肥胖者血IL-18水平升高;在MS人群的研究发现IL-18是代谢综合征的独立危险因素。上述研究提示IL-18可能在MS特别是在MS大血管结构与功能改变中发挥着重要作用。因此,我们假设大血管结构与功能异常,特别是血管炎症反应增强可能是MS患者心血管并发症的主要病理生理基础;炎症因子IL-18促进MS的发展,特别是能加重MS大血管炎症反应。本研究将对炎症是MS的“标记物”还是“危险因素”加以探讨,为更好的理解MS的发病机制提供理论依据。目的1.观察MS大鼠是否存在主动脉结构异常及血管炎症反应;2.明确IL-18能否促进MS的发展,特别是能否加重MS血管炎症反应;3.探讨IL-18在MS血管炎症反应中的作用机制。方法1.IL-18基因克隆及腺病毒表达载体的构建根据Genebank大鼠IL-18基因序列,设计引物,提取大鼠脾脏RNA,逆转录PCR（RT-PCR）扩增IL-18基因。回收目的基因并亚克隆至T载体,经测序鉴定正确后,应用Ad-Easy腺病毒载体构建系统,构建含大鼠IL-18基因的腺病毒质粒。经转染293-T细胞行病毒包装、扩增及纯化,得到大鼠IL-18腺病毒载体。2.代谢综合征大血管病变及IL-18在血管炎症反应中机制的研究雄性Wistar大鼠50只,随机分为对照组（12只）,MS组（38只）。对照组以标准大鼠饲料喂养,并给予普通饮水;MS组以标准大鼠饲料喂养,同时给予10%的高果糖饮水。喂养32周后再将MS组大鼠分为三组:MS组（9只）,继续给予高果糖饮水;空载体组（n=9只）,继续给予高果糖饮水的同时经尾静脉注射1×10¹⁰pfu含GFP腺病毒载体（溶于400ul无菌PBS）;IL-18载体组（n=13只）,继续给予高果糖饮水的同时经尾静脉注射1×10¹⁰pfu IL-18腺病毒载体（溶于400ul无菌PBS）;对照组及MS组给予等体积的无菌磷酸缓冲盐溶液（PBS）尾静脉注射。转染腺病毒载体后6周,处死动物,留取血管标本备用。实验过程中进行下述指标的测定:（1）所有大鼠开始果糖喂养前、喂养32周及转染载体后6周,抽取颈静脉窦血2ml,分离血清,常规法测定血脂、血糖、血胰岛素;（2）转染IL-18腺病毒载体后1、2、3、4、6周抽取各组大鼠颈静脉窦血2ml,分离血清,ELISA法测定血IL-18水平;（3）整个实验过程中,所有大鼠每两周测量体重及尾动脉血压一次;（4）实验结束前,所有大鼠均经颈动脉插管行心导管检查,测量收缩压及舒张压。实验结束时处死动物,留取血管标本,进行下列实验:（1）主动脉病理学检测;（2）Verhoeff弹力纤维染色;（3）实时定量RT-PCR检测IL-18、ICAM-1、VCAM-1mRNA表达;（4）免疫组织化学检测主动脉IL-18、ICAM-1、VCAM-1蛋白表达,并检测主动脉壁巨噬细胞含量;（5）Western Blot检测主动脉ICAM-1、VCAM-1、IRAK1蛋白含量;（6）EMSA法测定主动脉组织NF-κB活性。结果1.IL-18基因克隆及腺病毒载体构建我们根据大鼠IL-18基因序列,自行设计引物,成功克隆出了大鼠IL-18基因。经测序分析与已知大鼠IL-18序列完全相符。利用Ad-Easy腺病毒构建系统,成功构建了含大鼠IL-18基因的腺病毒载体（Ad-IL-18）。同时构建了不含目的基因的空载体（Ad-GFP）。2.代谢综合征大血管病变及IL-18在血管炎症反应中机制的研究2.1实验动物基本情况整个实验过程中共有7只大鼠死亡,均为代谢综合征组大鼠,正常对照组无大鼠死亡。共43只大鼠完成实验,其中对照组12只,MS组9只;空载体组9只;IL-18腺病毒载体组13只。2.2高果糖喂养32周两组大鼠代谢指标比较高果糖喂养前,两组大鼠体重、尾动脉收缩压、血糖、血脂、空腹胰岛素等均无差异。高果糖喂养32周后,与对照组比较,MS组大鼠体重、尾动脉收缩压、血甘油三酯、血胰岛素及HOMA升高,差异有显著性意义（P＜0.01～0.0001）;而两组大鼠血糖及血总胆固醇无显著差异。表明经32周高果糖喂养,已成功建立了大鼠MS模型。2.3 IL-18腺病毒载体转染后大鼠血IL-18水平变化转染前MS各组大鼠血IL-18水平较对照组明显升高,差异有统计学意义。IL-18腺病毒转染后1周,IL-18载体组大鼠血清IL-18显著升高,转染后2周达到最高水平,约为空载体组IL-18水平的4倍（256.53±25.32 vs.60.93±6.57 pg/ml,P＜0.0001）,于转染后3周开始降低,但仍高于空载体组IL-18水平（153.17±29.41vs.59.67±8.57 pg/ml,P＜0.0001）,4周时与空载体组IL-18水平相当（64.40±2.93vs.56.62±8.46 pg/ml,P=0.070）。2.4 IL-18对大鼠代谢指标的影响转染IL-18腺病毒载体后6周,与空载体组比较,IL-18载体组血胰岛素水平及HOMA升高,差异有显著性意义（P＜0.001及P＜0.05）;两组间其余指标比较无显著差异。与转染前比较,IL-18载体组血胰岛素水平及HOMA升高,差异有显著性意义（P＜0.001及P＜0.05）;与转染前比较其余指标无显著差异。2.5实验结束时各组大鼠有创血压比较实验结束时有创血压结果显示,与对照组比较,MS组、空载体组、IL-18载体组SBP、DBP均明显升高,差异有统计学意义,而脉压在各组间差异无统计学意义。与MS组及空载体组比较,IL-18载体组SBP、DBP差异无统计学意义。2.6各组大鼠主动脉形态学指标及超微结构比较HE染色显示,光镜观察正常对照组、MS组及空载体组大鼠主动脉内膜平坦,内皮细胞扁平、完整,紧贴于平滑的内弹力板上。IL-18载体组大鼠血管表面欠光滑,可见内皮细胞层断裂现象。与对照组相比,MS组大鼠主动脉血管管壁面积（MCSA）、中膜厚度（Mt）、管壁管腔比值（WLR）增加,差异均有统计学意义（P＜0.05～0.001）;而血管管腔面积（LCSA）、外弹力板面积（ECSA）、血管管腔直径（Ld）、血管直径（Vd）等指标无显著性差异。与空载体组比较,IL-18载体组大鼠Le、Mt、WLR增加,差异有统计学意义（P＜0.01～0.001）;与MS组比较,IL-18载体组大鼠Mt、WLR增加,差异有统计学意义（P＜0.01～0.001）;与对照组比较,IL-18载体组大鼠MCSA、Le、Mt、WLR增加,差异有统计学意义（P＜0.05～0.001）;而其他指标差异无显著性意义。2.7各组大鼠主动脉IL-18及粘附分子RT-PCR结果比较与对照组比较,MS组及空载体组大鼠主动脉IL-18 mRNA表达上调,差异有统计学意义（1.96±0.16 vs.1.03±0.26,P＜0.001;1.87±0.25 vs.1.03±0.26,P＜0.001）;与空载体组比较,IL-18载体组大鼠主动脉IL-18mRNA表达增强,差异有统计学意义（2.59±0.69 vs.1.87±0.25,P＜0.001）。与对照组比较,MS组及空载体组大鼠主动脉ICAM-1及VCAM-1mRNA表达升高,差异有统计学意义（P＜0.05～0.001）;与空载体组比较,IL-18载体组ICAM-1及VCAM-1mRNA表达进一步升高,差异有统计学意义（ICAM-1:2.85±0.89 vs.1.79±0.79,P＜0.01;VCAM-1:4.26±0.68 Vs.2.49±0.39,P＜0.001）。2.8免疫组织化学结果分析对照组大鼠主动脉IL-18蛋白表达很低;而MS组及空载体组IL-18表达明显增强;与其他三组比较,IL-18载体组IL-18表达进一步增强。IL-18蛋白主要分布于主动脉内膜,而中膜也有少量表达。对照组大鼠主动脉ICAM-1、VCAM-1蛋白表达很低;而MS组及空载体组IL-18表达明显增强;与其他三组比较,IL-18载体组ICAM-1、VCAM-1表达进一步增强。ICAM-1及VCAM-1蛋白主要分布于主动脉内膜,而中膜也有少量表达。正常对照组大鼠主动脉CD68阳性细胞很少,每高倍视野0-1个;与对照组比较,MS组及空载体组大鼠主动脉CD68阳性细胞数增加,差异有统计学意义（7.15±1.34 vs.0.59±0.28,P＜0.001;6.71±0.59 vs.0.59±0.28,P＜0.001）;而IL-18载体组CD68阳性细胞明显增多,和其他三组比较,差异有统计学意义（11.29±2.38vs.6.71±0.59,P＜0.001;11.29±2.38 vs.7.15±1.34,P＜0.001;11.29±2.38 Vs.0.59±0.28,P＜0.001）。2.9 Western Blot结果分析与对照组比较,MS组及空载体组IRAK-1、ICAM-1及VCAM-1蛋白含量升高,差异有统计学意义（P＜0.01～0.001）;与其他三组比较,IL-18载体组IRAK-1、ICAM-1及VCAM-1蛋白含量升高,差异有统计学意义（P＜0.01～0.001）。2.10 NF-κB活性比较以EMSA法检测各组大鼠主动脉NF-κB活性,结果显示与对照组比较,MS组及空载体组NF-κB活性增强;与空载体组相比,IL-18载体组NF-κB活性进一步增强。2.11相关分析结果相关分析结果显示,ICAM-1及VCAM-1与体重、尾动脉收缩压、胰岛素、HOMA、Mt及WLR等指标相关。结论1.我们成功构建了大鼠IL-18腺病毒载体,为更好的研究IL-18在心血管疾病中的作用奠定了基础。2.通过给予Wistar大鼠10%的高果糖饮水32周,能成功建立与人MS较为相似的MS大鼠模型。3.MS大鼠存在主动脉肥厚性重构,MS大鼠主动脉炎症反应增强,所有这些异常可能构成了MS心血管并发症高发的基础。4.IL-18能使MS大鼠血胰岛素水平升高,胰岛素抵抗加重。5.IL-18通过IRAK-1/NF-κB通路加重MS大鼠血管重构,并使MS大鼠血管炎症反应增强。背景随着人们生活水平的提高及生活方式的改变，MS在世界范围内发病率逐年增高。流行病学研究发现，我国成年人群男女合计年龄未标化的MS患病率为16．5％，年龄标化后的MS患病率男女分别为10．0％和23．3％；且我国MS患病率星北方高于南方，城市高于农村的特点。MS的基本特征为多重心血管危险因素在同一个体聚集，其主要后果为冠心病、糖尿病和动脉粥样硬化。近年来的研究表明，MS各组分之间并非简单的相加作用，可能存在相互增强的作用。因此对MS的发病机制及其组分之间的相互作用进行深入研究对于更好的预防、治疗MS患者具有重要意义。随着对MS认识的逐渐深入，MS的定义也不断发生变化。各诊断标准各有侧重，但大致都包括肥胖、高血压、血脂紊乱和血糖的异常。虽然MS的构成在不断发生变化，但高血压始终是MS的主要成分，这是由于在MS人群中高血压的发生率极高。超重或肥胖与MS关系密切，是MS发生、发展的关键因素和核心环节。超重和肥胖之所以在MS中占有重要地位，一方面是因为超重、肥胖与MS各个危险因素关系密切：另一方面肥大的脂肪细胞会分泌多种细胞因子，通过不同机制引起或加重MS的病情，这在中心性肥胖时尤为重要。目前，肥胖已被认为是代谢综合征的核心环节。临床研究表明，与正常人比较MS患者左室增大、室壁肥厚、左室重量增加，心脏收缩及舒张功能减低；与单纯高血压患者比较，伴有MS的高血压患者左室重量增加，舒张功能异常加重。上述研究提示，MS能引起心脏结构及功能异常，而MS患者心脏结构与功能异常可能是其心血管危险性增加的病理基础。心室功能的维持需要两个因素：心肌收缩力及心室各部位间运动的同步性。研究发现高血压患者左室收缩及舒张同步性受损；舒张性心力衰竭患者存在左室运动不同步。由于高血压及左室肥厚是舒张性心力衰竭的常见病因，因此，对伴有超重或肥胖、左室肥厚及室性心律失常的高血压患者左室功能及同步性进行研究是非常有意义的。综上所述，由于高血压和肥胖是MS的主要特征，也是导致左室功能障碍的常见原因，心室同步性对于维持正常的心脏功能至关重要。我们假设超重或肥胖的高血压患者左室功能及同步性受损。为了验证我们的假设，本研究选择临床就诊的高血压患者，采用组织多普勒测量左室不同部位组织运动速度及各部位组织运动同步性；并将患者按不同的标准分组，探讨肥胖、左室肥厚及室性心律失常对高血压患者左室功能及同步性的影响。目的1.研究高血压患者左室功能及同步性的改变；2．探讨超重及肥胖、左室肥厚、室性心律失常对高血压患者左室功能及同步性的影响。方法选择轻中度高血压患者125例，高血压伴室性心律失常患者30例，正常人32例，行二维、M型、脉冲多普勒及组织多普勒（TDI）超声心动图检查。应用12节段模式，以TDI收缩期心肌运动峰值速度（Sm）、舒张早期心肌运动峰值速度（Em）及Sin、Fan基底段6个节段平均值作为反应左室收缩及舒张功能的指标；以Sm达峰时间（TS）、Em达峰时间（Te）、12个节段中任意两个节段Ts最大差值Ts-max、12个节段中任意两个节段Te最大差值To-max及12个节段Ts、Te标准差（Ts-SD、Te-SD）作为反应同步性的指标。比较各组间上述各指标的差异。结果1．超重及肥胖高血压患者左室功能及同步性研究以BMI>24．0作为超重诊断标准，BMI>28．0作为肥胖诊断标准；剔除资料不全的患者，排除BMI>24．0的正常人：并使各组年龄匹配后，共有28例正常人及115例高血压患者最终入选。其中单纯高血压患者42例，超重高血压患者50例，肥胖高血压患者23例。由于超重与肥胖的高血压患者除了BMI外，其余指标两组间无差异，因而将两组患者合并，统称为超重及肥胖的高血压患者，共73例。1．1临床资料比较与对照组比较，单纯高血压组、超重及肥胖高血压组患者SBP、DBP、TG升高，HDL-C降低；与单纯高血压组比较，超重及肥胖高血压组BMI升高。三组间其他指标比较差异无显著性意义。‘1．2三组间二维及M型及脉冲多普勒超声指标比较与对照组比较，单纯高血压组、超重及肥胖高血压组患者LVPWd、LVMI、A波流速峰值增加，E／A减低；与对照组比较，超重及肥胖高血压组患者LVIDd增加。1．3三组间左室功能比较与对照组比较，超重及肥胖高血压组左室部分节段Sm、Em降低（P<0．05-⁰．01）。与对照组比较，单纯高血压组、超重及肥胖高血压组患者基底段6部位Em平均值（Mean Em）减低（5．81±1．98 vs．7．21±1．62 cm／s,P<0．01；5．19±2．03 vs．7．21±1．62cm／s，P<0．001），Era／Am减低（1．02±0．45 vs．1．45±0．67，P<0．01：0．87±0．46 vs．1．45±0．67，P<0．001）。与单纯高血压组比较，超重及肥胖高血压组Sin、Em降低（P<0．05-⁰．01），Mean Sm降低（5．16±1．07 vs．5．69±1．24 cm／s，P<0．05），Era／Am减低（0．87±0．46 vs．1．02±0．45，P<0．05）。1．4对照组、单纯高血压组、超重及肥胖高血压组左室同步性比较与对照组比较，单纯高血压患者、超重及肥胖高血压患者左室部分节段Ts延长，Ts-max增加，Ts-SD增加（P<0．05-⁰．001）。与单纯高血压组比较，超重及肥胖高血压患者左室侧壁中部、后壁基底段、后壁中部、下壁基底段TS延长（P<0．05--0．01），Ts-max增加（92±24vs．74±18ms，P<0．001）与对照组比较，单纯高血压组、超重及肥胖高血压组To-max增加（59±ll vs。46±14 ms，P<0．001；60士13 vs．46±14 ms，P<0．001）；与对照组比较，单纯高血压组Te-SD增加（44±3 vS．39±3 ms，P<0．001）。与单纯高血压组比较，超重及肥胖高血压患者Te-SD减小（41±2 vs．44±3 ms，P<0．01），To-max在两组间差异无统计学意义。1．5高血压组各指标相关性分析结果在高血压患者中，相关分析显示Mean Sm与体重指数、LVMI负相关；MeanEm与E正相关，与体重指数、年龄负相关：Ts-max与体重指数、LVMI正相关：To-max与高血压病程、LVMI正相关，与MeanEm负相关。2．伴左室肥厚的高血压患者左室功能及同步性比较以左室心肌重量指数（LVMI）男^&gt;150g／m2，女性>120 g，m2作为左室肥厚的诊断标准：剔除资料不全的患者；并使各组年龄匹配后，共有30例正常人及1 15例高血压患者最终入选。其中非左室肥厚高血压组（NLVH）84例，左室肥厚高血压组（LVH）3l例。2．1一般资料比较三组间年龄、性别、心率及QRS波宽度比较无显著性差异。与对照组比较，NLVH及LVH组SBP、DBP升高，BMI增加。其余指标无差异。2．2三组间二维、M型超声及脉冲多普勒指标比较与对照组比较，NLVH组、LVH组患者LVPWd、IVSd、LVMI、A波流速峰值增加，E／A降低，差异有统计学意义：与NLVH组比较，LVH组患者LVIDd、LVPWd、IVSd及LVMI增加。2．3三组间左室各部位组织多普勒速度比较与对照组比较，NLVH组及LVH组Sm、Em、Mean Em、Era／Am降低（P<0．05～0．001）。与NLVH组比较，LVH组患者Sm、Em降低（P<0．05～0．001）；Mean Sm降低（4．92±1．39vs．5．58±1．13 cuds，P<0．05），MeanEm降低（4．56±1．89vs．5．65±1．94cm／s，P<0．05）。2．4对照组、NLVH及LVH组左室运动同步性比较与对照组比较，NLVH患者及LVH患者Ts延长（P<0．05-0．001），Ts-max增加（97±26 vs．53±15 ms，P<0．001；79±25 vs．53±15 InS，P<0．001），Ts-SD增加（37±5 vs．24±3 ms，P<0．001；34+6 vs．24±3 ms，P<0．001）。与NLVH组比较，LVH组Ts延长（P<0．05～0．01），"Is-max增加（97±26 vs．79±25 ms，P<0．01）。与对照组比较，LVH患者Te延长，（P<0．05-4）．01)，Te-max增加（67±11 vs．47±13 ms，P<0．001）；与对照组比较，NLVH组患者Te-max增加（57±11 vs．47±13ms，P<0．001）。与NLVH组比较，LVH组Te延长（P<0．05-0．01），Te-max增加（67±11vs．57±11 ms，P<0．001）。2．5高血压组各指标相关性分析结果将NLVH及LVH组患者合并，相关分析发现Ts-max与LVMI正相关（r=0．26，P<0．01）、与左室基底段6部位Sm平均值负相关（r=：-0．23，P<0．05）。Te-max与E（r=．0．27，P<0．01）、Em（r=．0．26，P<0．01）及Era／Am（r=．0．27，P<0．01）负相关。其余指标间无相关性。2．6 NLVH及LVH患者左室不同步的发病率比较以Ts-max>84 ms为标准判断，71．0％的LVH患者表现出左室收缩不同步，37．2％的NLVH患者表现出左室收缩不同步（X2=10．45，P=0．001）。以Te-max>73 ms判断，29．0％的LVH患者存在舒张不同步，10．7％的NLVH患者存在舒张不同步（x2=5．76，P--O．02）。2．7 Ts-max及Te-max预测高血压患者左室肥厚的敏感性和特异性应用受试者特征曲线估测Ts-max及To-max对LVH的诊断价值，结果显示Ts-max受试者曲线下面积为0．691（95％可信区间为0．582-0．800），Ts-max>88 ms预测高血压左室肥厚的敏感性为68％，特异性为71％。Te-max．受试者曲线下面积为0．590（95％可信区间为0．477-0．704），其预测高血压左室肥厚的敏感性及特异性均较差。3.伴室性心律失常的高血压患者左室功能及同步性比较高血压组排除超声检查过程中发现有偶发心律失常及有心律失常家族史的患者；剔除资料不全者，并使各组年龄匹配后，共有32例正常人，74例单纯高血压患者及30例高血压伴室性心律失常患者入选。3．1临床资料比较三组间年龄、性别、心率及QRS波宽度比较无显著性差异。与对照组比较，单纯高血压组及高血压伴心律失常组SBP、DBP、BMI增加。伴室性心律失常患者心律失常病史平均为20±11月，24小时心律失常数目为4676±586次；4（13％）例服用抗心律失常药物。3．2二维、M型超声及脉冲多普勒指标比较与对照组比较，单纯高血压组及高血压伴室性心律失常组患者LVMI、A波流速峰值增加，E／A减低；与对照组比较，高血压伴室性心律失常组WSd增加。3．3三组间左室各部位组织多普勒速度比较与对照组比较，单纯高血压组及高血压伴室性心律失常组Sm降低（P<0．05-0．01）；Em降低（P<0．05-0．001）；Mean Em减低（5．24±2．15 vs．7．08±1．74 cm/s，P<0．001；4．81±1．60 vs．7,08±1．74 cm／s,P<0．001）；Em／Am减低（0．92±0．44 vs．1．41±0．68，P<0．001；0．87±0．45 vs．1．41±0．68，P<0．01）。与对照组比较，高血压伴室性心律失常组Mean Sm降低（5．02±1．07 vs．5．76±1．28 cm／s，P<0．05），差异有统计学意义。与单纯高血压组比较，高血压伴室性心律失常组患者左室室间隔中部、侧壁基底段、侧壁中部、后壁基底段Sm降低（P<0．05--O．01）；左室侧壁基底段、侧壁中部、后壁中部Em降低（P<0．05）。3．4三组间左室运动同步性比较与对照组比较，单纯高血压组及高血压伴室性心律失常患者TS延长，（P<0．05～0．001）；Ts-max增加（79±25 vs．54±15 ms，P<0．001；94±21 vs．54±15 ms，P<0．001），Ts-SD增加（33±6 vs．24±3 ms，P<0．001；38±6 vs．24±4 ms，P<0．001）。与单纯高血压组比较，高血压伴室性心律失常组左室侧壁基底段、侧壁中部、Ts延长（P<0．05），ls-max增加（94±2l vs．79±25 ms，P<0．01），Ts-SD增加（38±6vs．33±6ms．P<0.05 ）。反映左室舒张同步性的指标在三组间比较无统计学差异。3．5高血压伴室性心律失常组各指标相关性分析结果高血压伴室性心律失常亚组相关分析发现ls-max与心律失常时间正相关（r=0．43，P<0．05）、与LVMI正相关（r=0．37，P<0．05）。其余指标间无相关性。3．6 Ts-max对高血压伴室性心律失常患者的诊断价值我们应用受试者特征曲线估测了Ts-max对高血压伴室性心律失常患者盼诊断价值，结果显示Ts-max受试者曲线下面积为0．658（95％可信区间为0．543-0．772），Ts-max>70 ms预测高血压伴室性心律失常的敏感性为90％，特异性为33％。结论1．高血压患者存在左室收缩及舒张功能障碍及左室同步性异常；2．超重及肥胖高血压患者左室收缩及舒张功能障碍加重，左室收缩同步性受损；3．高血压LVH患者较NLVH患者左室功能受损，左室收缩及舒张存在明显不同步：4．高血压伴室性心律失常患者左室功能受损，左室收缩同步性障碍加重；5．组织多普勒（TDI） TS-max是评价伴有其他心血管危险因素的高血压患者左室收缩同步性的较好指标。背景代谢综合征（MS）是多种心血管疾病危险因素在同一个体内集结的状态。MS的主要组成成分是肥胖（尤其是内脏型肥胖）、糖尿病或糖调节受损、以高甘油三酯血症及低高密度脂蛋白胆固醇血症为特点的血脂紊乱以及高血压。此外，MS还包括组织胰岛素抵抗、高尿酸血症及微量蛋白尿。MS患者发生冠心病及中风的危险性增加3倍，心血管死亡率也显著增加，即使在无基础心血管疾病及糖尿病的患者中，MS也显著增加心血管疾病及全因死亡率。提示MS潜在的心血管损害可能是其心血管并发症高发的原因。因此，寻找能逆转或延缓MS患者心血管损害的药物对于更好的治疗MS患者至关重要。随着对MS发病机制研究的进一步深入，炎症在MS及胰岛素抵抗中的作用越来越受到重视。许多研究证实MS是一个低度的系统性炎症状态，MS的发生往往伴随着炎症因子水平的升高。临床研究显示炎症指标CRP与BMI、腰臀比、胰岛素敏感性、空腹胰岛素等密切相关，且CRP水平随着代谢紊乱数目的增多而升高，提示慢性亚临床炎症状态可能是MS的特征之一。动物实验研究表明，肥胖Zucker大鼠肾小球基质炎症因子IL-6、MCP-1表达升高。遗传性MS大鼠炎症因子CRP、氧化应激水平均明显升高。这些研究提示CRP、IL-6等炎症因子可能参与了MS的发生发展。钙通道阻滞剂（CCBs）是临床常用于治疗高血压、冠心病的药物之一。临床研究结果显示CCBs能降低冠心病血压正常者心血管事件发生率，且血管内超声提示CCBs能延缓AS进展。给予高血压患者CCBs治疗能显著改善患者心脏收缩及舒张功能。进一步研究表明，CCBs降低心血管事件的发生可能与其抗炎、抗氧化作用有关。本研究已经证实MS存在血管高炎症反应状态，因此我们假设CCBs能抑制MS血管炎症反应，并能改善高血压患者心功能。目的1．观察非洛地平对MS大鼠血管炎症反应的影响并探讨其可能的机制；2．评价西尼地平对高血压患者左室功能的影响。方法1．非洛地平抑制代谢综合征大鼠血管炎症反应的研究雄性Wistar大鼠33只，随机分为对照组（12只），MS组（21只）。对照组以标准大鼠饲料喂养，并给予普通饮水；MS组以标准大鼠饲料喂养，同时给予10％的高果糖饮水。喂养32周后再将MS组大鼠分为两组：MS组（9只），继续给予高果糖饮水；非洛地平组（n=9只），继续给予高果糖饮水的同时给予非洛地平5mg／kg．d灌胃；对照组及MS组给予等体积的双蒸水灌胃。给予非洛地平6周后，处死动物，留取血管标本备用。实验过程中进行下述指标的测定：（1）所有大鼠开始果糖喂养前、喂养32周及非洛地平干预后6周，抽取颈静脉窦血2ml。分离血清，常规法测定血脂、血糖、血胰岛素；（2）整个实验过程中，所有大鼠每两周测量体重及尾动脉血压一次。实验结束时处死动物，留取血管标本，进行下列实验：（1）主动脉病理学检测；（2）Verhoeff弹力纤维染色；（3）实时定量RT-PCR检测ICAM-1、VCAM-I mRNA表达：（4）免疫组织化学检测主动脉ICAM-1、VCAM-1蛋白表达，并检测主动脉壁巨噬细胞含量；（5）Western Blot检测主动脉ICAM-1、VCAM-I、IRAK-1蛋白含量：（6）EMSA法测定主动脉组织NF-κB活性。2．西尼地平对高血压患者左室功能影响的研究选择轻中度高血压患者40例，正常人16例。高血压患者给予西尼地平5-10mg／d治疗8周。高血压患者在西尼地平治疗前后行二维、M型、脉冲多普勒及组织多普勒（TDI）超声心动图检查，并以LVMI将其分为左室肥厚（LVH）组15例及非左室肥厚（NLVH）组25例；对照组在入选时行超声心动图检查。以脉冲多普勒E／A、TDI收缩期心肌运动峰值速度（Sm）、舒张早期心肌运动峰值速度（Em）、舒张晚期心肌运动峰值速度（Am）、Era／Am、及TDI Tei指数作为反应左室功能的指标。比较各组间及治疗前后上述各指标的差异。结果1．非洛地平对代谢综合征大鼠血管炎症反应影响的研究1．1实验动物基本情况整个实验过程中共有3只大鼠死亡，均为代谢综合征组大鼠，正常对照组无大鼠死亡。共30只大鼠完成实验，其中对照组12只，MS组9只；非洛地平组9只。1．2高果糖喂养32周两组大鼠代谢指标比较高果糖喂养前，两组大鼠体重、尾动脉收缩压、血糖、血脂、空腹胰岛素等均无差异。高果糖喂养32周后，与对照组比较MS组大鼠体重、尾动脉收缩压、血甘油三酯、血胰岛素及HOMA升高，差异有显著性意义（P<0．01^-0．0001）；而两组大鼠血糖及血总胆固醇无显著差异。表明经32周高果糖喂养，已成功建立了大鼠MS模型。1．3非洛地平对大鼠代谢指标的影响非洛地平治疗6周后，与MS组比较，非洛地平组尾动脉收缩压、血胰岛素水平及HOMA降低；而体重、甘油三酯、总胆固醇在非洛地平组与MS组间无显著差异。与治疗前比较，非洛地平组尾动脉血压、血胰岛素水平及HOMA均降低；而体重、甘油三酯及总胆固醇治疗前后无显著差异。1.4非洛地平对MS大鼠主动脉粘附分子的影响我们应用RT-PCR、免疫组化及Western Blot对非洛地平对粘附分子表达的影响进行了研究。与对照组比较，MS组大鼠主动脉ICAM-I及VCAM-ImRNA及蛋白表达升高（P<O．05--O．001）；与MS组比较，非洛地平治疗组ICAM-I、VCAM-ImRNA及蛋白降低（P<0．001）。1．5非洛地平对大鼠主动脉IRAK-I的影响Western Blot结果显示，与对照组比较，MS组IRAK-1蛋白含量升高；与MS组比较，非洛地平治疗组IRAK-1含量降低，差异有统计学意义（P<0．01）。1．6非洛地平对NF-κB活性的影响以EMSA法检测各组大鼠主动脉NF-κB活性，结果显示与对照组比较，MS组NF-κB活性增强；与MS组相比，非洛地平治疗组NF-κB活性降低。2．西尼地平对高血压患者左室功能的影响2．1临床资料比较40例高血压患者，其中NLVH组25例，LVH组15例。高血压组37例完成实验。三组间年龄、心率比较无显著性差异。与对照组比较，NLVH组及LVH组SBP、DBP、BMI增加。2．2二维、M型超声、脉冲多普勒及TDI指标比较与对照组比较，NLVH组及LVH组E／A、Era／Am降低，IVCT、IVRT及TDI Tei指数增加；与NLVH组比较，LVH组Em降低，TDI Tei指数增加。2．3西尼地平治疗前后各指标比较西尼地平治疗后高血压组E、E／A、Em、Era／Am升高，TDI Tei指数降低。结论1．MS大鼠主动脉炎症反应增强。2．非洛地平通过IRAK-I／NF：kB通路而抑制MS大鼠血管炎症反应3．高血压患者存在左室收缩及舒张功能障碍；4．西尼地平能改善高血压患者左室收缩及舒张功能；5．TDI Tei指数是评价药物对高血压患者左室功能影响的敏感指标。更多还原

【Abstract】 BackgroundThe metabolic syndrome（MS）is a world-wide epidemic disease and consists of the combined presentation of multiple cardiovascular risk factors that include abdominal obesity,glucose intolerance,insulin resistance,hyperinsulinemia,hypertension and dyslipidemia.The overall risk of MS is more than the sum of the risk of its sole components,they maybe reinforced each other.Therefore,it is of great importance to understand the pathogenesis of MS and to detect the patients who are at higher risk of type 2 diabetes and cardiovascular disease.Clinical studies have demonstrated that the prevalence of atherosclerosis is significantly increased in MS patients,and even in young adults MS is also the risk factor for atherosclerosis.These results suggested that vascular structural and functional changes are the basis of cardiovascular disease in patients with MS.But at present,little is know about macro-vascular structural and functional changes in MS.Compared with the controls,patients with MS showed increased serum C-reative protein,interlukin-6,tumor necrosis factor-αand interlukin-18.Animal studies have demonstrated that the mRNA of interlukin-6,monocyte chemoattractant protein-1 was elevated in the kindey of rats with MS.Based on these interesting and significant findings,we can infer that inflammation may play a pivotal role in the development of MS.However,those results can not render us to differentiate whether inflammation is a ’risk marker’ or a ’risk factor’of MS.Interlukin-18（IL-18）is an important inflammatory mediator that regulates immune response and inflammatory reaction.The role of IL-18 in cardiovascular disease is an attracting topic for the researchers.The expression of IL-18 and IL-18 receptor was up-regulated in carotid atherosclerotic plaque in patents with stable and unstable angina pectoris,and the level of IL-18 mRNA was associated with plaque instability.IL-18 enhances atherosclerosis in ApoE deficiency mice,whereas IL-18 knockout prevent the progression of atherosclerosis.Serum IL-18 was elevated in obese subjects,and epidemic study revealed that IL-18 is the independent risk factor for MS.Taken together these results implied that IL-18 play an important role in MS especial in macro-vascular structural and functional alterations.Thus we hypothesized that macro-vascular structural and functional changes, especially enhanced vascular inflammation is the underlying mechanism for cardiovascular complication in MS patients,and IL-18 accelerate the progression of MS and particularly enhance macro-vascular inflammatory reaction.This study aimed to elucidate whether inflammation is a ’risk marker’ or a ’risk factor’ of MS,and to provide evidence for a better understanding of MS.Objective1.To observe whether there are aortic structural abnormalities and vascular inflammation in rat with MS.2.To clarify the influence of IL- 18 on the progression of MS,particularly focused on the effect of IL-18 on vascular inflammation.3.To study the mechanism which underlying the role of IL-18 in vascular inflammatory reaction in MS.Method1.Cloning of rat IL- 18 and constructing of IL- 18 adenovirus vector Based on the rat IL-18 sequence in Genebank,we designed one pair of primers. Using total RNA extracted from rat spleen and reverse transcript polymerase chain reaction,we cloned the CDS sequence of rat IL-18.After the cloned IL-18 was sub-cloned to T vector and sequenced,the Ad-Easy system was used to construct adenovirus containing rat IL-18.293-T cells were infected with the IL-18 plasmid. Recombinant adenovirus from a single plaque was expanded and purified,viral titer was determined by plaque assay.2.Macro-vascular lesions and the role of Interlukin-18 in vascular inflammation Fifty male Wistar rats were randomly divided into control group（n=12）and MS group（n=38）.Control rats were fed with standard chow and tap water,MS rats were fed with standard chow plus high-fructose（10%,w/v）water.After high fructose feeding for 32 weeks,MS rats were further divided into three groups,MS group（n=9）,continuing of high fructose feeding;vehicle group（n=9）,continuing of high fructose feeding plus injection of 1×10¹⁰pfu adenovirus only contain GFP by tail veins;IL-18 vector group （n=13）,continuing of high fructose feeding plus injection of 1×10¹⁰pfu IL-18 adenovirus by tail veins.Rats of control and MS groups were injected with the same volume of PBS by tail veins.After adenovirus transfection for 6 weeks,all the rats were killed and the aortas were harvested and kept at -80℃.The follwing parameters were measured during the study:（1）2 ml blood was drawn from the jugular sinus of all the rats before and after fructose feeding and after transfection with IL-18 adenovirus for 6 weeks,serum was separated and using routine method to measuring lipid,glucose and insulin;（2）1,2,3,4,and 6 weeks after the IL-18 adenovirus transfection,all the rats have their blood drawn from jugular sinus for measuring serum IL-18;（3）body weight and their tail blood pressure measured once per week;（4）before sacrifice,cardiac catheter was performed and SBP,DBP were measured in all the rats.At the end of the experiment,all the animal was sacrificed,the aortas were kept for the following study:（1）pathological study of aorta;（2）verhoeff elastic fibers stain; （3）real-time RT-PCR measurement of IL-18,ICAM-1 and VCAM-1 mRNA;（4） immunohistochemistry of aortic IL-18,ICAM-1,VCAM-1 and macrophages;（5） Western Blot for IL-18,ICAM-1,VCAM-1 and IRAK-1;（6）EMSA for measuring NF-κB acticity.Results1.Cloning of rats IL-18 and constructing IL-18 adenovirusWe have successfully cloned rat IL-18,and its sequence was identical to the rat IL-18 sequence in Genebank.Using Ad-Easy system,we constructed rat IL-18 adenovirus,the vehicle containing only GFP was also constructed.2.Macro-vascular lesions and the role of IL-18 in vascular inflammation in MS2.1 The experimental animalsSeven rats of MS group died during the entire experiment,no rat died in control group.43 rats finished the study,12 rats in control group,9 rats in MS group,9 rats in vehicle group and 13 rats in IL-18 vector group.2.2 Comparison of metabolic indexes between control and MS group after fructose feedingThere is no significant difference in terms of body weight,tail blood pressure, glucose,lipids and insulin before fructose feeding.After feeding with fructose for 32 weeks,body weight,tail blood pressure,triglyceride,insulin and HOMA were significantly increased in MS group than in control group,whereas glucose and total cholesterol showed no difference.This indicated that the rat model of MS was achieved by feed high fructose diet for 32 weeks.2.3 Changes of serum IL-18 after adenoviral transfectionSerum IL-18 was significant increased in MS group before IL-18 adenovirus transfection.After IL-18 adenovirus transfection,serum IL-18 was further increased in IL-18 vector group than in vehicle group at 1 week,the serum concentration of IL-18 reached its summit after 2 weeks transfection,and its level was 4 fold higher than vehicle group（256.53±25.32 vs.60.93±6.57 pg/ml,P＜0.0001）.Serum IL-18 begin decrease at the end of the third week（153.17±29.41 vs.59.67±8.57 pg/ml,P＜0.0001）, and at the end of 4-week,serum level of IL-18 vector group was similar to that of vehicle group（64.40±2.93 vs.56.62±8.46 pg/ml,P=0.070）.2.4 Effect of IL-18 on metabolic parameters in ratsAfter IL-18 transfection for 6 weeks,insulin and HOMA were significantly increased in IL-18 vector group compared to vehicle group（P＜0.001,P＜0.05）;other parameters showed no significant difference.Insulin and HOMA were significantly increased in IL-18 vector group after transfection for 6 weeks compared to the levels of insulin and HOMA before transfection（P＜0.001,P＜0.05）;other parameters showed no significant difference.2.5 Comparison of invasive Blood pressure among four groupsAt the end of the experiment,invasive blood pressure was obtained from all the rats.SBP and DBP were significantly increased in MS group,vehicle group and IL-18 vector group when compared with control rats,but pulse pressure showed no difference among four groups.2.6 Comparison of morphological and ultra-structural index of aortaHE stain demonstrate that the intima of rats in control group,MS group and vehicle group was smooth,the endothelial cells were flat and attached to the internal elastic lamina;the intima of IL-18 vector group was coarse,there are breakages of endothelial cells.Compare to control group,MS rats showed significant increase of MCSA,Mt, WLR（P＜0.05～＜0.001）;LCSA,ECSA,Ld and Vd showed no difference.Compared to vehicle group,Le,Mt,WLR were significantly increased in rats of IL-18 vector group（P＜0.01～＜0.001）.Compared to MS group,Mt,WLR were significantly increased in rats of IL-18 vector group（P＜0.0～0.001）.Compared to controls,MCSA,Le,Mt,WLR were significantly increased in rats of IL-18 vector group（P＜0.05～＜0.001）.2.7 Result of real-time RT-PCRThe levels of IL-18 mRNA were increased in MS group and vehicle group than in controls（1.96±0.16 vs.1.03±0.26;1.87±0.25 vs.1.03±0.26,all P±0.001）;the expression of IL-18 mRNA was significantly increased in IL-18 vector group than in vehicle group（2.59±0.69 vs.1.87±0.25,P＜0.001）.Compared to control group,the levels of ICAM-1 and VCAM-1 mRNA were increased in MS group and vehicle group（P＜0.05～0.001）;the levels of ICAM-1 and VCAM-1 were further increased in IL-18 vector group than in vehicle group（ICAM-1: 2.85±0.89 vs.1.79±0.79,P＜0.01;VCAM-1:4.26±0.68 vs.2.49±0.39,P＜0.001）.2.8 Results of immunohistochemistryThe level of IL-18 protein was lower in control group,and was significantly increased in MS group and vehicle group.Compared to three other groups,IL-18 levels were further increased in IL-18 vector group.IL-18 was abundant in intima and was also presented in medium.The levels of ICAM-1 and VCAM-1 protein were lower in control group,and were significantly increased in MS group and vehicle group.Compared to three other groups, ICAM-1 and VCAM-1 levels were further increased in IL-18 vector group,and ICAM-1 and VCAm-1 were abundant in intima and was also presented in medium.CD68 positive cells were rare in control group（0-1 cell per visual field）;CD68 positive cells were increased in MS group and vehicle group（7.15±1.34 vs.0.59±0.28, P＜0.001;6.71±0.59 vs.0.59±0.28,P＜0.001）.CD68 positive cells were significantly increased in IL-18 vector group than in other groups（11.29±2.38 vs.6.71±0.59, P＜0.001;11.29±2.38 vs.7.15±1.34,P＜0.001;11.29±2.38 vs.0.59±0.28,P＜0.001）.2.9 Results of Western BlotWestern Blot revealed that IRAK-1,ICAM-1 and VCAM-1 were higher in MS group and vehicle group than in control group（P＜0.05～0.001）;IRAK-1,ICAM-1 and VCAM-1 were increased in IL-18 vector group than in other groups（P＜0.01～0.001）.2.10 NF-κB activityEMSA was used to measure NF-κB activity among four groups.NF-κB activity was increased in IL-18 vector group than in other groups,and was increased in MS group and vehicle group than in controls. 2.11 Result of analysis of correlationPerason correlation analysis revealed that ICAM-1 and VCAM-1 were correlated with body weight,tail blood pressure,insulin,HOMA,Mt and WLR.Conclusion1.We have constructed rat IL-18 adenoviral vector successfully,which provide a tool for us to making further study on the role of IL-18 in cardiovascular disease.2.Rats model of MS that mimic human MS can be achieved by feeding Wistar rat high fructose water（10%,v/w）for 32 weeks.3.MS rats showed hypertrophical remodeling of aorta and the vascular inflammation was enhanced in aorta of MS rats.All these abnormalities maybe involved in the high prevalence of cardiovascular complication in MS.4.IL- 18 increase insulin and aggravate insulin resistance in MS rats.5.IL-18 enhanced aortic remodeling and inflammation in MS rats through IRAK- 1/NF-κB dependent pathway. AbstractBackgroundThe prevalence of MS is increased in developed and developing countries as a result of improved living standard. Epidemiologic study found that in Chinese adult, the crude prevalence of MS was 16.5% and the age-standardized prevalence of MS was 10.0% in men and 23.3% in women. Furthermore, the prevalence of the MS was higher in northern than in southern China, and higher in urban than rural residents. MS is a cluster of multiple risk factors in one individual, the major complications of MS is coronary heart disease, diabetes and atherosclerosis. Recent studies indicated that the effect of each component of MS is rather than it sole addition effect, they can enhanced each other. Therefore, further studies are needed to reveal the pathogenisis and the effect of each component of MS in order to prevent and treat patients with MS.The definition of MS changed as our knowledge about MS deepened gradually. Although there is difference in each criterion, they all include obesity, hypertension, dyslipidemia and abnormality in glucose metabolism. The component of MS changed gradually, hypertension is always the major disorder of MS, this is because the prevalence of hypertension is very high in patients with MS. Overweight and obesity are closely related with MS, and is considered as the major risk factor of MS. Because overweight and obesity is correlated with other component of MS, on the other hand, endocrinal disorder in overweight and obesity aggravate MS by different mechanism, especially in central obesity. Obesity is considered to be major component of MS now.Clinical studies have demonstrated that left ventricular dimension, ventricular wall and left ventricular mass increased and ventricular systolic and diastolic function impaired in patients with MS. Left ventricular mass increased and ventricular function impaired in hypertensives with MS. These results suggested that cardiac structural and functional abnormalities is evident in patients with MS, this maybe involved in the cardiovascular complication in those patients. Ventricular function was sustained by myocardial contraction and relaxation and the synchronicity of ventricular segments. Left ventricular systolic and diastolic synchronicity was impaired in hypertensive patients, and ventricular dyssynchrony was also existed in patients with diastolic heart failure. As hypertension and left ventricular hypertrophy are the common causes of diastolic heart failure, it is of great interest to study left ventricular function and ventricular synchronicity in hypertensive patients with overweight or obesity, LVH and ventricular arrhythmias.In summary, as hypertension and obesity are major abnormalities of MS, and also the common reason for cardiac dysfunction. Ventricular synchronicity is important for ventricular function. We hypothesized that left ventricular function and synchronicity are impaired in hypertensive patients with overweight or obesity. In order to test our hypothesis, this study included mild-to-moderate hypertensive patients, and using tissue Doppler imaging （TDI） measured myocardial velocity and synchronicity in different left ventricular segments. To elucidate the influence of obesity, LVH and ventricular arrhythmia on left ventricular function and synchronicity, we divide our patients into different study group acording to different criterion.Objective1. To observe the abnormalities of left ventricular function and synchronicity in hypertensive patients;2. To elucidate the influence of obesity, LVH and ventricular arrhythmias on left ventricular function and synchronicity in hypwertensive patients.MethodsWe selected 125 patients with mild-to-moderate hypertension, 30 patients with hypertension and ventricular arrhythmias and 32 normal subjects for this study. Two dimensional, M mode, pulse Doppler and tissue Doppler imaging echocardiography was performed in all subjects. A 12-segement model was used. Sm, Em and the mean of Sm and Em of six basal segments were measured to reflect left ventricular systolic and diastolic function. Systolic and diastolic asynchrony was determined by measuring time to peak of Sm （Ts） and time to peak of Em （Te）, the maximal differences in Ts （Ts-max） and Te （Te-max） between any two of the left ventricular segments and the standard deviation of Ts （Ts-SD） and Te （Te-SD） of all 12 segments. Results1. Impaired left ventricular function and synchronicity in hypertensive patients with overweight and obesityUsing BMI>24.0 as overweight and >28.0 as obesity diagnostic criteria. Patients whose data are not sufficient and normal subjects with BMI>24.0 were excluded. After matched for age, there are 28 normal subjects and 115 hypertensives were final analyzed, those including 42 patients only with hypertension, 50 patients with hypertension and overweight, 23 patients with hypertension and obesity. All the parameters between patients with overweight and patients with obesity showed no differences except for BMI, we put those 73 patients together and named hypertensive patients with overweight and obesity.1.1 Clinical characteristics of the study populationsSBP, DBP and TG were significantly increased in patients with hypertension and hypertensive patients with overweight and obesity when compared with controls, and HDL-C was decreased in patients groups than in controls. BMI was higher in hypertensive patients with overweight and obesity when compared with hypertensive patients. Other parameters showed no significant difference among three groups.1.2 Echocardiographic parameters among three groupsLVPWd, LVMI, and A wave velocity were significantly increased in patients with hypertension and hypertensive patients with overweight and obesity when compared with controls. E/A was decreased in patients groups than in controls. LVIDd was increased and mean Sm decreased in hypertensive patients with overweight and obesity when compared with controls.1.3 Comparison of left ventricular function among three groupsSm and Em were significantly decreased in hypertensive patients with overweight and obesity when compared with controls （P<0.05-0.01）. Mean Em and Em/Am were significantly decreased in hypertensive patients and hypertensive patients with overweight and obesity when compared with controls （Em: 5.81±1.98 vs. 7.21±1.62 cm/s, P<0.01; 5.19±2.03 vs. 7.21±1.62 cm/s, P<0.001; Em/Am: 1.02±0.45 vs. 1.45±0.67, P<0.01; 0.87±0.46 vs. 1.45±0.67, P<0.001）.Sm, Em, mean Sm and Em/Am were decreased in hypertensive patients with overweight and obesity compared with hypertensive patients （Mean Sm: 5.16±1.07 vs. 5.69±1.24 cm/s, P<0.05; Em/Am: 0.87±0.46 vs. 1.02±0.45, P<0.05）. Ts, Ts-max and Ts-SD were significantly prolonged in hypertensive patients and hypertensive patients with overweight and obesity when compared with controls （P<0.05-0.001）. Ts and Ts-max were significantly increased in hypertensive patients with overweight and obesity compared with hypertensive patients （P<0.05-0.001）.Te-max was significantly prolonged in hypertensive patients and hypertensive patients with overweight and obesity when compared with controls （all P<0.001）. Te-SD was significantly increased in hypertensive patients when compared with controls （44±3 vs. 39±3 ms, P<0.001）. Te-SD was decreased in hypertensive patients with overweight and obesity when compared with hypertensive patients （41±2 vs. 44±3 ms, P<0.01）. There is no significant difference of Te-max among three groups.1.5 Analysis of correlation in hypertensive groupsMean Sm was negatively correlated with BMI, LVMI. Mean Em was positively correlated with E and negatively with BMI and age. Ts-max was positively correlated with BMI and LVMI. Te-max was positively correlated with duration of hypertension and LVMI and negatively correlated with mean Em.2. Impaired left ventricular function and synchronicity in hypertensive patients with ventricular hypertrophyLeft ventricular hypertrophy （LVH） was defined as LVMI>150g/m² for man and >120g/m² for women. Patients whose data are not sufficient were excluded. After matched for age, there are 30 normal subjects and 115 hypertensives were final analyzed, including 84 NLVH patients and 31 LVH patients.2.1 Clinical characteristics of the population studiedThere is no difference in terms of age, sex, heart rate and width of QRS among three groups. SBP, DBP and BMI were significantly increased in NLVH and LVH groups when compared with controls.2.2 Echocardiographic parameters among three groupsLVPWd, FVSd, LVMI, and A wave velocity were significantly increased, and E/A, mean Em and Em/Am were decreased in NLVH and LVH group when compared with controls. LVIDd, LVPWd, IVSd and LVMI were increased in LVH group when compared with NLVH group.2.3 Comparison of left ventricular function among three groupsSm, Em, mean Em and Em/Am were significantly decreased in NLVH group and LVH group when compared with controls （P<0.05-0.001）.Sm, mean Sm, Em and mean Em were significantly decreased in LYH groups when compared with NLVH group （P<0.05-0.001）.2.4 Comparison of left ventricular synchronicity among three groupsTs, Ts-max and Ts-SD were significantly prolonged in NLVH and LVH group when compared with controls （P0.05-0.001）. Ts and Ts-max were significantly increased in LVH group when compared with NLVH group （P<0.05-0.01）.Te-max was significantly prolonged in NLVH and LVH group when compared with controls （all P<0.001）. Te and Te-max were significantly increased in LVH group when compared with NLVH group （P<0.05-0.001）.2.5 Analysis of correlation in hypertensive groupsTs-max was positively correlated with LVMI, and negatively with mean Sm. Te-max was negatively correlated with E, Em and Em/Am.2.6 The prevalence of left ventricular dyssychrony in NLVH and LVH groupUsing a normal cut-off value of more than 84 ms for Tsmax, 71.0% LVH patientsand 37.2% NLVH patients showed prolonged Ts-max （chi-squared 10.45, P=0.001）. Similarly, using a cut-off value of more than 73 ms for Te-max, 29% LVH patients and 10.7% NLVH patients had significantly prolonged Te-max and thus evidence of diastolic asynchrony （chi-squared 5.76, P=0.02）.2.7 The diagnostic value of Ts-max and Te-amxThe ability of Ts-max and Te-max to detect hypertensive patients with LVH was assessed by using ROC curve. The area under the curve of Ts-max was 0.691 [95% confidential interval （CI） 0.582-0.800]. A Ts-max value of more than 88 ms had 68% sensitivity and 71% specificity for detecting hypertensive patients with LVH, but Te-max showed a poor ability to detect LVH patients, and the area under the curve of Te-max was 0.590 （95% CI 0.477-0.704）.3. Impaired left ventricular function and synchronicity in hypertensive patients with ventricular arrhythmiasPatients with family history of cardiac arrhythmias and have arrhythmias during echocardiographic examination were excluded. Patients whose data are not sufficient were also excluded. After matched for age, there are 32 normal subjects and 74 hypertensive patients and 30 hypertensive patients with ventricular arrhythmias were final analyzed.3.1 Clinical characteristics of the study populationsThere is no significant difference in terms of age, sex, heart rate and width of QRS among three groups. SBP, DBP and BMI were significantly increased in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls. Mean duration of arrhythmia was 20±11 monthes. The mean number of ventricular arrhythmias in patients who underwent Holter monitoring was 4,676 beats. 13% patients had taken anti-arrhythmia drugs.3.2 Echocardiographic parameters among three groupsLVPWd and A wave velocity were significantly increased, and E/A was decreased in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls. IVSd was increased in hypertensive patients with ventricular arrhythmias than in controls.3.3 Comparison of left ventricular function among three groupsSm, Em were significantly decreased in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls （P<0.05-0.001）. Mean Em, Em/Am and mean Sm was decreased in hypertensive patients with ventricular arrhythmias when compared with controls.Sm, Em were significantly decreased in hypertensive patients with ventricular arrhythmias when compared with hypertensive patients （P<0.05-0.01）.3.4 Comparison of left ventricular synchronicity among three groupsTs, Ts-max and Ts-SD were significantly prolonged in hypertensive patients and hypertensive patients with ventricular arrhythmias when compared with controls （P<0.05-0.001）. Ts, Ts-max and Ts-SD were significantly increased in hypertensive patients with ventricular arrhythmias when compared with hypertensive patients （P<0.05-0.01）.Te, Te-max and Te-SD showed no differences among three groups.3.5 Analysis of correlation in hypertensive groupsSub-analysis in hypertensive patients with ventricular arrhythmias revealed that Ts-max was positively correlated with the duration of ventricular arrhythmias and LVMI. There were no other significant correlations between parameters of LV systolic synchronicity and age, heart rate, blood pressure, and color Doppler parameters.3.6 The diagnostic value of Ts-max and Te-amxThe ability of Ts-max to detect hypertensive patients with ventricular arrhythmias was assessed by using an ROC curve. The area under the ROC curve was 0.658 （95% confidential interval, 0.543-0.772）. A Ts-max value of 70 ms had 90% sensitivity and 33% specificity for detecting hypertensive patients with ventricular arrhythmia, while Te-max showed a poor ability to detect hypertensive patients with ventricular arrhythmia.Conclusion1. Left ventricular systolic and diastolic function and synchronicity were impaired in hypertensive patients.2. Left ventricular systolic and diastolic function and left ventricular systolic synchronicity were impaired in hypertensive patients with overweight and obesity.3. Compared to hypertensive patients without LVH, left ventricular systolic and diastolic function and synchronicity were further impaired in hypertensive patients with LVH.4. Left ventricular systolic and diastolic function and left ventricular systolic synchronicity were impaired in hypertensive patients with ventricular arrhythmia.5. Ts-max derived from TDI was a useful and sensitive index in evaluating hypertensive patients with other cardiovascular risk factors. BackgroundMS is a cluster of multiple metabolic risk factors in one individual. The component of MS is obesity, especial central obesity, diabetes and glucose intolerance, and dyslipidemia characteristic by hyperglyceridemia and low HDL-C and hypertension. In addition, MS also include tissue insulin resistance, hyperuricemia and micro-proteinuria.Patients with MS are at high risk of coronary heart disease and stroke, and cardiovascular mortality was also markedly increased in those subjects. Cardiovascular disease and all-cause mortality are increased in men with the MS, even in the absence of baseline CVD and diabetes. This means that sub-clinical cardiovascular impairments are the fundamental reasons for higher cardiovascular complications in those patients. Therefore, to finding the drug which reverses or retards cardiovascular impairments in patients with the MS is of great importance.As our knowledge of MS expanded, the role of inflammation in MS and insulin resistance becomes one attracting topic. Many studies have demonstrated that MS is a systematic low inflammation, for the levels of inflammatory mediators increased in MS. Clinical study demonstrated that inflammatory factors positive correlated with CRP, BMI, waist-hip ratio, insulin sensitivity, fasting insulin. Furthermore, the levels of CRP increased as the components of MS increase. These findings indicated that chronic subclinical inflammation is one characteristic of MS. Animal studies revealed that the expressions of interlukin-6, MCP-1 were increased in glomerulus matrix of obesity Zucker rats, and CRP, oxidant stress were significantly increased in rat model of genetic MS. These interesting findings suggest that inflammatory factors such as CRP, IL-6 may participate in the pathogenesis and development of MS.Calcium channel blockers （CCBs） are widely used to treat patients with hypertension and coronary heart disease. Clinical study demonstrated that CCBs decrease cardiovascular events in patients with coronary heart disease and intra-vascular ventricular systolic and diastolic function in hypertensive patients. Further studies revealed that CCBs decrease cardiovascular events is related to its anti-inflammation and anti-oxidant effects.Our study has proved that vascular inflammatory reaction is evident in MS, thus we hypothesized that CCBs inhibit vascular inflammation in MS and improve cardiac function in hypertensive patients.Objective1. To observe the effect of felodipine on vascular inflammation in rat model of MS and to study the possible mechanism of felodipine on vascular inflammation.2. To evaluate effect of cilnidipine on ventricular function in hypertensive patients.Methods1. Felodipine inhibits vascular inflammation in rat model of MSThirty three male Wistar rats were randomly divided into control group （n=12） and MS group （n=21）. Control rats were fed with standard chow and tap water, MS rats were fed with standard chow plus high-fructose （10%, w/v） water. After high fructose feeding for 32 weeks, MS rats were further divided into two groups, MS group （n=9）, continuing of high fructose feeding; felodipine group （n=9）, continuing of high fructose feeding plus treatment with felodipine 5mg/kg.d by gavage. Rats of control and MS groups were given the same volume of saline by gavage. After treated for 6 weeks, all the rats were killed and the aortas were kept at -80℃.The follwing parameters were measured during the study: （1） 2 ml blood was drawn from jugular sinus of all the rats before and after fructose feeding and after treatment with felodipine for 6 weeks, serum was separated and using routine method to measuring lipid, glucose and insulin; （2） all the rats have their body weight and tail blood pressure measured once per week.At the end of the experiment, all the animal was sacrificed, the aortas were kept for the following study: （1） pathological study of aorta; （2） verhoeff elastic fibers stain; （3） real-time RT-PCR measurement of ICAM-1 and VCAM-1 mRNA; （4） immunohistochemistry for aortic ICAM-1, VCAM-1 and macrophages; （5） Western Blot for ICAM-1, VCAM-1 and IRAK-1; （6） EMSA for measuring NF-κB acticity.2. Effect cilnidipine on left ventricular function in hypertensive patientsWe selected 40 patients with mild-to-moderate hypertension and 16 normal subjects for this study. Hypertensive patients were treated with cilnidipine for 8 weeks. Before and after treatment, the participants were examined by two dimensional, M mode, pulse Doppler and tissue Doppler imaging echocardiography. Hypertensives were classified into non-left ventricular hypertrophy （NLVH） group and left ventricular hypertrophy （LVH） group. Sm, Em, Em/Am and TDI Tei index were measured to reflect left ventricular systolic and diastolic function. The control subjects were also examined by echocardiography.Results1. Felodipine inhibits vascular inflammation in rat model of MS1.1 The experimental animalsThree rats of MS group died in the entire experiment, none rat died in control group. A total of 30 rats finished the study, 12 rats in control group, 9 rats in MS group and 9 rats in felodipine group.1.2 Comparison of metabolic indexes between control and MS group after fructose feedingThere is no significant difference in terms of body weight, tail blood pressure, glucose, lipids and insulin before fructose feeding. After feeding with fructose for 32 weeks, body weight, tail blood pressure, triglyceride, insulin and HOMA were significantly increased in MS group than in control group, whereas glucose and total cholesterol showed no difference. This means the rat更多还原