【作者】 宋涛；

【导师】 葛志明；

【作者基本信息】 山东大学 ， 内科学， 2008， 硕士

【摘要】 研究背景原发性高血压病（essential hypertension,EH）是当前最常见的心血管疾病之一。随着患者高血压时间的延长,后负荷持续性增加,收缩末期室壁张力持续性增强,心肌形态学发生改变,出现了心肌重构-左室肥厚（left ventricular hypertrophy,LVH）,因此LVH是高血压的严重并发症之一。左室肥厚不仅是高血压病常见的靶器官损害,也是心力衰竭发展过程中左室重构的标志之一。高血压引起的左室肥厚与心脏舒缩功能的下降、冠脉储量的减少、心律失常的易发及心脏自主神经活性的变化密切相关,已成为许多心血管事件发生的重要预测指标。Frahaming等大型流行病学调查研究显示左室肥厚是影响心血管疾病预后的独立危险因素,高血压患者伴左室肥厚者较不伴左室肥厚者心血管病死率增加8倍。因此,预防和逆转左室肥厚已成为治疗高血压的重要目标之一。同时,长期血压升高可导致外周动脉结构和功能改变,事实上许多高血压患者在未发生明显的左室肥厚之前外周动脉已经发生一系列的变化,主要表现为内皮功能障碍,动脉僵硬度增加以及大中动脉动脉粥样硬化的形成。因此,明确左室肥厚与外周动脉重构两者之间的相互关系,对于防止左室肥厚,改善高血压患者预后是极其重要的。2004年6月国家卫生部批准将血管病变早期检测技术作为十年百项计划向全国推广,应用《血管病变早期检测技术应用指南》中推荐的血管病变早期检测系统来检测反映高血压外周动脉结构和功能改变的多个参数,力求通过多窗口,全方位系统地早期识别外周血管病变的程度。近年来有关高血压患者外周动脉结构和功能改变的研究越来越多,高血压患者出现左室肥厚前后外周动脉究竟如何重构?与左室肥厚相关的影响因素都有哪些?外周动脉重构在左室肥厚的发生发展中起着什么样的作用?以及如何早期识别亚临床血管病变?上述问题构成了本课题的研究目的和设计思路,本课题就以高血压患者外周动脉重构为切入点,探讨外周动脉重构在左室肥厚发生发展中的作用机制。目的（1）探讨原发性高血压左室肥厚患者外周动脉结构和功能的变化,明确外周动脉重构与左室肥厚之间的关系;（2）探讨应用《血管病变早期检测技术应用指南》中推荐的检测系统对全面评价动脉早期结构和功能改变的临床意义,为以后该检测系统及技术的推广提供理论依据。资料与方法1.研究对象及分组选取2006.11～2007.5在山东大学齐鲁医院门诊和查体中心的EH患者100例,男47例,女53例,年龄27～71岁,平均（51.51±9.37）岁。高血压的诊断根据《2005年中国高血压防治指南》的标准,即收缩压（SBP）≥140mm Hg（1m Hg=0.133kPa）和（或）舒张压（DBP）≥90mm Hg或者正在服用降压药者。排除继发性高血压、糖尿病、高血脂、肥厚型心肌病及其心、肝、肾功能不全的患者。依据左室质量指数（LVMI）分成两组,LVH组（LVH）:男性LVMI＞120 g/m²,女性LVMI＞115g/m²,男24例,女26例,年龄27～67岁,平均（50.51±9.42）岁;非LVH组（NLVH）:男性LVMI≤120 g/m²,女性LVMI≤115 g/m²,男23例,女27例,年龄32～71岁,平均（52.51±9.33）岁。对照组选取正常人40例,男20例,女20例,年龄29～73岁,平均（47.88±9.57）岁,经询问病史、体格检查及各项辅助检查均无异常。2.仪器设备应用美国GE公司生产的Vivid7彩色超声诊断仪,探头频率2.5～4.0MHz,高频周围血管超声探头频率5～10MHz,仪器配有二维超声、M型超声、脉冲波多普勒、连续波多普勒和彩色多普勒血流显像等功能,标准Ⅱ导联心电图同步记录。由日本科林公司生产的动脉硬化检查仪（COLIN VP—1000）。3.研究方法3.1超声心动图检查取胸骨旁左室长轴面,测量舒张末期室间隔厚度（IVSTd）、左室后壁厚度（PWTd）、左室内径（LVIDd）。根据Devereux校正公式计算左室质量（LVM）,其公式为:LVM（g）=0.8×1.04[（LVIDd+PWTd+IVSTd）³-（LVIDd）³]+0.6。LVMI（g/m²）=LVM/BSA,BSA=（0.0061×身高+0.0218×体重质量）-0.1529。3.2颈动脉超声检查应用高频周围血管超声探头测量颈总动脉（CCA）、颈总动脉分叉处（BIF）、颈内动脉（ICA）、颈外动脉（ECA）、颈总动脉内径（CCA-D）、内-中膜厚度（IMT）、颈动脉的斑块及斑块指数、动脉顺应性（AC）、弹性系数（Ep）、僵硬系数（β）以及血流动力学参数收缩期峰值血流速度（PSV）、舒张末期血流速度（EDV）、平均速度（MV）、阻力指数（RI）、搏动指数（PI）等参数。3.3肱动脉血管内皮功能参照Celermajer的方法,分别记录静息状态下、反应性充血后肱动脉内径（D₀、D₁）,平均血流速度（V₀、V₁）以及血流量（Q₀、Q₁）。内径变化率（△D%）=（D₁-D₀）/D₀×100%,根据公式计算血流量Q（ml/min）=60·V·π·D²/4,其中D为血管内径,V为平均速度,血流量变化率（△Q%）=（Q₁-Q₀）/Q₀×100%。3.4应用动脉硬化检查测量肱踝脉搏波传导速度（BaPWV）及踝臂指数（ABI）。4.统计学处理采用统计学软件SPSS 11.5进行统计分析,所有计量资料均以（（?）±S）表示,计数资料以例数和百分数描述。三组间计量资料比较用ANOVA检验,组内两两比较用q检验,计数资料的比较采用x²检验。两变量简单相关分析采用Pearson分析,多因素分析采用多元逐步线性回归分析。以P＜0.05作为显著性检验标准。结果1.1一般资料的比较与对照组相比,高血压组除了在血压、BMI和LVMI有显著性差异外（P＜0.01）,各组之间的性别、年龄、体重指数、吸烟史、心率、血脂、血糖均无显著性差异（P＞0.05）,三组之间具有可比性。1.2颈动脉结构及弹性的比较与对照组相比,高血压组在CCA内径、CCA-IMT、斑块检出率均明显升高,并三组间有显著性差异（P＜0.05）;高血压组较对照组Ep、β明显增加,AC明显降低（P＜0.05）,均以LVH组改变最显著。1.3颈动脉血流动力学的比较与对照组相比,高血压组的CCA-PSV、CCA-EDV、ICA-PSV、ICA-EDV、CCA-PI、ICA-PI降低,而CCA-RI、ICA-RI增高,均有显著性差异（P＜0.05）,且CCA-PI、CCA-RI、ICA-PI、ICA-RI在NLVH组和LVH组间有统计学意义（P＜0.05）。1.4各组间内皮功能的比较与对照组相比,在基础状态及反应性充血后高血压组的血管内径及血流量均增加,但无显著性差异（P＞0.05）;反应性充血后LVH组血管内径变化率（△D%）及血流量变化率（△Q%）最低,并且三组之间有显著性差异（P＜0.05）。1.5动脉僵硬度及阻塞程度的比较与对照组相比,BaPWV在LVH组最高,NLVH组次之,均明显高于正常人,三组间均有显著性差异（P＜0.01）;各组之间ABI均在正常范围内,无显著性差异（P＞0.05）。1.6高血压患者LVMI影响因素的相关分析高血压患者LVMI与SBP、DBP、PP、BMI、IMT、RI、baPWV呈正相关（相关系数r值分别为0.517,0.273,0.420,0.386,0.221,0.374,0.575,P＜0.01）,LVMI与AC、EDV、PSV、PI、FMD呈负相关（相关系数r值分别为-0.237,-0.323,-0.257,-0.314,-0.205,P＜0.01）。1.7 LVMI影响因素的多元逐步线性回归分析以LVMI作应变量（Y）,以SBP、DBP、PP、BMI、IMT、AC、EDV、PSV、PI、RI、FMD、baPWVV为自变量,进行多元逐步回归分析,baPWV（X1）、SBP（X2）、PP（X3）和BMI（X4）进入回归方程,Y=5.943+0.545X1+0.457X2+0.372X3+0.321X4。结论1.高血压患者在尚未出现左室肥厚前就发生外周动脉结构和功能的改变,表现为内皮功能损害,动脉顺应性减退、僵硬度增加,颈动脉内-中膜厚度增厚以及粥样硬化斑块形成,同时颈动脉血流动力学参数表现为低流速、高阻力。高血压患者出现左室肥厚后外周动脉结构和功能的损害仍进行性加重,上述指标均以左室肥厚组损害的更显著。2.高血压患者LVMI与SBP、DBP、PP、BMI、IMT、RI、baPWV呈正相关,与AC、EDV、PSV、PI、FMD呈负相关。多元逐步回归分析显示:baPWV、SBP、PP、BMI分别是LVMI的独立危险因素,其中baPWV的作用最为显著。3.高血压患者外周动脉重构早于心肌重构,且外周动脉重构在左室肥厚的发生发展中起着非常重要的作用,其中动脉僵硬度增加是导致左室肥厚的重要原因。4.《血管病变早期检测技术应用指南》中推荐的检测系统能够可靠、全面评价外周动脉早期结构和功能的改变,早期认识和识别亚临床血管病变,对于预防心脑血管事件具有着重要的意义,本课题也为将来该检测系统及技术的推广提供理论依据。更多还原

【Abstract】 Background:Essential hypertension（EH）is one of the most common cardiovascular diseases. With the extension course of hypertension,myocardial morphous develops myocardial remodling such as left ventricular hypertrophy（LVH）in reason of persistent increase of afterload and persistent reinforcement of ventricular tension at diastole,so left ventricular hypertrophy is one of severe complications in hypertensive epatients.Left ventricular hypertrophy is not only the common target organ damage, but also the sign of ventricular remodling in the process of heart failure.Left ventricular hypertrophy which is an important predictor of many cardiovascular envents has close correlation with the degression of heart relaxation and contraction function、the decrease of coronary arterial reserve、the occurrence of arrhythmia and the activity of cardiac autonomic nerve.The large scale epidemiological investi gations such as Frahaming study have manifested that LVH is an independent risk factor of prognosis in cardiovascular diseases.The case fatality rate of hypertensive patients with LVH is eight times than that of hypertensive patients without LVH. Thus,the important therapeutic target of hypertension is the prevention and retro conversion of LVH.Long term arterial hypertension can results in the structural and functional changes of peripheral arteries.In fact,many hypertensive patients have developed a series of changes in peripheral arteries before the appearance of LVH, which manifestes endothelial dysfunction、increase of arterial stiffness and appearance of atheroscleosis in large arteries.Therefore,it is very important to investigate the relationship between arteries remodling and LVH for deferring the development of LVH and improving the hypertensive patients prognosis.In June 2004,the ministry of Public Health has authorized the techniqes for early vascular disease detection and has spreaded it to entire country as one of hundred programs in decade.And the comprehensive appliance of detection techniques in《Chinese Guideline for Early Vascular Disease Detection》can identify vascular disease earlier,defer the development of LVH and prevent acute cadiovascular events.In this study,we detect many parameters reflecting the structural and functional changes in the early vascular disease detection system,and can omnibearingly and systemic identify earlier peripheral vascular disease.In recengt years,the researches based on the structural and functional changes of peripheral arteries in hypertensive patients are more and more.How do peripheral arteries develop some changes before and after the appearance of LVH in hypertensive patients? What are the influential factors of LVH in hypertensive patients? How does peripheral arterial remodling play pole in the in the occurrence and development of LVH? And how to identify subclinical vascular lesion in the early stage? The above problems constitute the objective and contrivable idea of this topic. The cut-in point of this topic bases on arterial remodling in hypertensive patients,and intensively explore the functionary mechanism of peripheral arterial remodling in the occurrence and development of LVH.Objective:（1）To investigate the structural and functional changes of peripheral arteries in hypertensive patients with left ventricular hypertrophy,and indentfy the relationship between peripheral arterial remodling and left ventricular hypertrophy.（2）To apply the detection techniques in《Chinese Guideline for Early Vascular Disease Detection》to overall identify earlier structural and functional changes of peripheral arteries,and provid theoretical evidence for generalization of the detection techniques.Methods:1.Study populationsFrom November 2006 to May 2007,one hundred and forty consecutive subjects in Qilu Hospital of Shandong University were enrolled in this study.They included one hundred hypertensive patients and forty normal subjects.Hypertensive group includes 47 men,53 women,age rang 27～71 years,mean age 51.51±9.37 years. According to《Chinese Guideline for prevention and treatment of hypertension in 2005》,Hypertensive patients were defined as having arterial hypertension if they had blood pressure readings above 140/90 mmHg in the hypertension clinic or in the process of anti-hypertensive therapy.The subjects with medical history of secondary hypertension,hyperlipemia,diabetes,hypertrophic cardiomyopathy and cardiac insufficiency were excluded in this study.LVMI＞120 g/m² in men and＞115 g/m² in women was considered as left ventricular hypertrophy.We divided the hypertensive patients into two groups on the basis of LVMI as follows:①the group of LVH:24 women,26 men,age rang 27～67 years,mean age 50.51±9.42 years;②the group of NLVH:23 women,27 men,age rang 32～71 years,mean age 52.51±9.33 years.The normal subjects included 20 women,20 men,age rang 29～73,mean age 47.88±9.57 years.They had no medical history,normal physical examination and auxiliary examination.2.InstrumentationGE Vivid7 ultrasound machine had a M3S transducer（2.5 to 4.0MHz）and a high resolution linear-array transducer（5 to 10MHz）.The Vivid7 equipped with two-dimen sion echocardiograms,M-mode echocardiograms、pulsed-wave Doppler、continous-wave Doppler and color Doppler flow imaging.An standardⅡlead ECG monitor inte grated with the ultrasound machine was applied.The arteriosclerotic examine device （VP-1000,Colin,Japan）was also applied.3.Examination3.1 Echocardiographic Image AcquisitionIn the parasternal long axis view of left ventricle,two-dimensional guided M-mode echocardiograms measured three cycles of septal（IVSd）and posterior wall thickness（PWTd）as well as left ventricular internal diastolic（LVDd）at the level of chordae tendineae.The following formula was used for the estimation of left ventricularmass: LVM（g）=0.80×[1.04×（IVSd+LVDd+PWTd）³-（LVDd）³]+0.6;LV mass index（g/m²）=LVM/BSA;BSA=（0.0061×height+0.0218×welght）—0.1529.3.2 Carotid ultrasonographyThe carotid artery examination was performed with a high-resolution ultrasound device equipped with a 7.5MHz linear-array transducer.The parameters included ima ges of the common（CCA）,the bifurcation（BIF）,the internal（ICA）and external carotid artery（ECA）,the diameter of common carotid artery（CCA-D）and intima-media thickness （IMT）,the plaques in the both carotid arteries,arterial compliance（AC）,alasticity coefficient（Ep）,stiffness coefficient（β）,peak systolic velocity（PSV）,peak diastolic velocity（EDV）,mean velocity（MV）,resistent index（RI）and pulsatelity index（PI）.3.3 Measurements of FMD in the brachial arteryAccording to Celermajer’s method,we measured the internal dameter（D₀）、mean velocity（V₀）、blood flow volume（Q₀）of brachial artery at rest,and the internal dameter （D₁）、mean velocity（V₁）、blood flow volume（Q₁）of brachial artery after reactive hyperemia.The change rate of the internal dameter（△D%）=（D₁—D₀）/D₀×100%.The brachial blood flow（Q ml/min）=60×V×pD²/4.The change rate of flow volume（△Q%） =[（Q₁—Q₀）]/Q₀×100%.3.4 The measurements of brachial-ankle pulse wave velocity（baPWV）and ankle-brach ial index（ABI）were performed using a arteriosclerotic examine device.4.Statistical analysisAll statistical analysis were performed using SPSS version11.5.The numerical data presented as mean±S.D,and the categorical data were described by example and percentage. Comparisons of among three groups used the ANOVA-test,and comparisons between two groups were performed with the student q-test if necessary.Categorical difference was analyzed by Chi-squared test.Bivariable simple correlationanalysis was performed with Pearson analysis,and multiplicity were used by multiple stepwise regression analysis.All tests were two-sided and a value of P＜0.05 was considered statistically significant.Results1.1 The comparison of common characteristics The common characteristics between the three groups subjects have no statistical significance（P＞0.05）except for blood pressure、BMI and LVMI.So there is comparability among the three groups.1.2 The comparison of carotid arterial structure and elasticityThe internal diameter,IMT and plaques of CCA increased significantly in hyper tensive patients than that of normal subjects（P＜0.05）.Ep andβwere higher in hyper tensive patients than that of the normal subjects,and AC was lower in hypertensive patients（P＜0.05）.All indices were changed most significantly in LVH patients.1.3 The comparison of carotid arterial hemodynamic parametersCompared with the normal subjects,the hemodynamic parameters strikingly decr eased and the resistant parameters significantly increased in hypertensive patients（P＜0.05）.And these parameters such as CCA-PI、CCA-RI、ICA-PI、ICA-RI had statis tical significance between NLVH and LVH groups（P＜0.05）.1.4 The comparison of endothelial functionCompared with the normal subjects,the internal dameter and blood flow volume slightly increased at rest and after reactive hyperemia,but had no statistical significan ce（P＞0.05）.However,the change rate of the internal dameter（△D%）and blood flow volume（△Q%）in brachial artery decreased obviouslly in hypertensive patients（P＜0.05）,especially in LVH patients..1.5 The comparison of arterial stiffness and occlusionBaPWV was highest in LVH subjects,and the second was NLVH patients（P＜0.01）.ABI among the three groups were in the normal range and had no statistical significance（P＞0.05）.1.6 The Pearson analysis of LVMIThe Pearson analysis showed that LVMI was positively correlated with SBP、DBP、PP、BMI、IMT、RI、baPWV（the value of simple correlation coefficient was respectively 0.517,0.273,0.420,0.386,0.221,0.374,0.575,P＜0.01）,and LVMI was negatively correlated with AC、EDV、PSV、PI、FMD in hypertensive patients（the value of simple correlation coefficient was respectively -0.237,-0.323,-0.257,-0.314, -0.205,P＜0.05）. 1.7 Multiple stepwise regression analysis of LVMIMultiple stepwise regression analysis using LVMI（Y）as a dependent variable was conducted to determine the relative contributions made by each variable to the outcome variable.SBP、DBP、PP、BMI、IMT、AC、EDV、PSV、PI、RI、FMD、baPWV were employed as independent variables.The result showed that baPWV（X1）、SBP（X2）、PP（X3）and BMI（X4）were employed into the regression equation,Y=5.943+0.545X1+0.457X2+0.372X3+0.321X4.Conclusions1.Hypertensive patients have developed the structural and functional changes of peripheral arteries before the appearance of LVH.Arterial remodling manifested endothelial dysfunction,impairmen of arterial compliance、increase of IMT and appearance of atheromatous plaques in carotid arteries.Furthermore,hemodynamic parameters of carotid arteries revealed low velocity and high resistence.The structural and functional changes of peripheral arteries aggravated progressively in LVH patients,and all above parameters were changed most significantly in LVH patients.2.The LVMI was positively correlated with SBP、DBP、PP、BMI、IMT、RI、baPWV, and LVMI was negatively correlated with AC、EDV、PSV、PI、FMD in hypertensive patients.Multiple stepwise regression analysis showed that the independent risk factor of LVMI was respectively baPWV、SBP、PP、BMI,especially baPWV.3.Arterial remodling developed before the appearance of LVH,and arterial remodling may paly an important role in the occurrence and development of LVH.The increase of arterial stiffness is an important reason in the occurrence of LVH.4.The detection techniques in《Chinese Guideline for Early Vascular Disease Detecti on》can reliably overall identify earlier structural and functional changes of peripheral arteries.The discrimination of subclinical vascular lesion in the early stage was very important for preventing the future occurrence of acute cardiovascular and cerebral events.Therefore,this study provided theoretical evidence for generalization of the detection techniques.更多还原