【作者】 由倍安；

【导师】 高海青；

【作者基本信息】 山东大学 ， 内科学， 2011， 博士

【摘要】 背景动脉粥样硬化是一种严重威胁人类健康的疾病。过去对动脉粥样硬化的研究大多集中在动脉管腔的狭窄或堵塞,而导致管腔狭窄或堵塞的主要原因是管壁出现了病变。血管壁是心血管多重危险因素作用的靶点,血管壁损害是心血管疾病发生和发展的共同病理基础。面对世界范围内与日俱增的心血管疾病患者,人们已经认识到不应该对血管病变的干预始终仅局限于通过解除管腔的局部机械阻塞而达到治疗目的,早期发现和干预血管病变才是延缓和控制心血管事件的根本措施。研究发现,多种心血管危险因素和氧化应激反应首先影响动脉内皮细胞,内皮损伤可导致动脉弹性下降、僵硬度增加。动脉弹性又称顺应性,是指在一定压力作用下动脉的可扩张性,它取决于动脉腔径的大小和管壁硬度,是反映血管结构和功能的指标。一般而言,内皮功能障碍会导致大动脉首先出现结构性改变,形成时间较长。与大动脉不同,由于一氧化氮对小动脉的舒张和张力起着重要的调控作用,内皮功能障碍在小动脉首先发生功能性改变,以后逐渐发生小动脉的重塑,因此动脉内皮功能障碍的早期表现是小动脉弹性减退。桡动脉舒张期脉搏波形分析是近年开发研究出来的检测动脉弹性功能的方法,它运用改良的Windkessel循环模型原理,分析桡动脉舒张期衰减和振荡波形,得出分别反映大、小动脉弹性功能的参数C1和C2。C1主要反映近段中心大动脉的功能,C2主要反映外周小动脉的功能。多种心血管危险因素,例如增龄、高血压、糖尿病、吸烟等在早期就可检测出C1和(或)C2的下降,冠心病患者的C2也明显低于非冠心病者。但是,有关冠状动脉亚临床病变,即冠状动脉已经发生粥样硬化但是较轻,而尚未达到诊断冠心病标准这样一类患者的动脉弹性的研究尚未见报道。目的本研究拟采用CVProfilor(?)DO-2020型动脉弹性功能测定仪无创测定非老年人群及老年人群中冠状动脉造影正常者、冠状动脉粥样硬化患者和冠心病患者的动脉弹性功能并进行对比分析,然后将无创动脉弹性指标C1、C2与定量冠状动脉造影所得冠状动脉狭窄病变Gensini积分进行相关分析,寻找动脉弹性与冠状动脉病变程度之间的关系,为早期无创诊断冠状动脉粥样硬化提供实验依据。方法(1)首先以年龄为标准将入选者分为老年人群(≥65岁),和非老年人群(<65岁)两个研究群体,然后根据入选和排除标准在每个研究群体中再依据冠状动脉造影的结果分别分成三组入选受试者：冠状动脉造影正常组50例,冠状动脉粥样硬化组55例,冠心病组55例,每组录满为止,共入选320例。(2)所有入选者均进行一般临床资料的登记和测定,包括：性别、年龄、体重指数、心率、血压等,询问记录有无高血压史、糖尿病史、吸烟史以及有无服用阿司匹林、钙离子拮抗剂、血管紧张素转换酶抑制剂或血管紧张素受体拮抗剂、β受体阻滞剂、他汀类调脂药和硝酸酯类药物。(3)清晨抽取空腹静脉血测定血糖、血总胆固醇和甘油三酯。(4)采用CVProfilor(?)DO-2020型动脉弹性功能测定仪无创测定动脉弹性,得出大动脉弹性指数C1和小动脉弹性指数C2。(5)进行冠状动脉造影,在盲法下应用冠脉造影定量分析软件进行冠状动脉狭窄病变Gensini积分的评定。(6)统计学处理：所有资料均应用SPSS11.5统计分析系统进行统计分析。计量资料以均数±标准差(x-±s)表示,多组间均数比较采用单因素方差分析(One-way ANOVA),均数间两两比较采用q检验,分类资料以频数和百分比表示,组间比较采用X2检验。无创动脉弹性指标与冠状动脉狭窄病变程度之间的相关性应用直线相关分析。P<0.05为差异有统计学意义。结果(1)小动脉弹性指数C2在非老年人群各组之间以及老年人群各组之间均有统计学差异,且随着冠状动脉狭窄病变程度的加重而降低。(2)大动脉弹性指数C1在非老年人群各组之间以及老年人群各组之间均无统计学差异。(3)无论在非老年人群还是老年人群,冠状动脉粥样硬化组以及冠心病组的小动脉弹性指数C2均与冠状动脉狭窄病变Gensini积分呈显著负相关,而大动脉弹性指数C1则与冠状动脉狭窄病变Gensini积分无相关关系。结论(1)无论非老年人群还是老年人群,在冠状动脉粥样硬化这一亚临床病变时期小动脉弹性指数C2就已经开始明显下降。而大动脉弹性指数C1则无明显变化。(2)无论在冠状动脉粥样硬化时期还是冠心病时期,小动脉弹性指数C2均随着冠状动脉狭窄病变程度的加重而降低。(3)无论非老年人群还是老年人群,测定小动脉弹性指数C2均有助于冠状动脉粥样硬化的早期发现,且有助于预测冠状动脉的狭窄病变程度。背景近年来,随着对动脉粥样硬化研究的逐步深入,人们逐渐认识到动脉血管病变是各种心血管疾病发生和发展的病理基础,先有血管壁的病变,然后才有血管腔的狭窄以及心血管事件。动脉弹性是动脉血管的一种主要功能,是指在一定压力变化的作用下动脉容积的变化。动脉弹性减退是多种心血管危险因素对血管壁早期损害的综合表现,是早期血管病变的特异性和敏感性标志,也是一种心血管疾病的高危因素,参与了心血管疾病的发生和发展。因此,针对动脉弹性的研究正成为目前的热点。目前用于检测动脉弹性功能的无创方法主要有脉搏波传导速度(pulse wave velocity,PWV)和桡动脉舒张期脉搏波形分析(diastolic pulse contour analysis, DPCA)。临床测定的PWV是某一动脉节段的脉搏波传导速度,即血压波动通过动脉系统内给定两点距离间的传导速度,主要包括颈动脉—股动脉PWV (CFPWV)、肱动脉—踝动脉PWV(BAPWV)和颈动脉—桡动脉PWV (CRPWV),反映的是该动脉节段的动脉缓冲功能。DPCA运用改良的Windkessel模型,分析主动脉压力波形的舒张期部分以分别了解近端大动脉及远端小动脉的顺应性,得出代表大动脉顺应性的C1和代表小动脉顺应性的C2。已有研究发现,PWV、C1、C2可准确地反映动脉弹性的变化,多种心血管危险因素,例如增龄、高血压、糖尿病、吸烟等在疾病早期就可检测出PWV、C1和(或)C2的改变,PWV、C1、C2是心血管事件的独立预测因子,但是,动脉弹性减退的机制尚不完全清楚。一般认为,动脉弹性主要由其管壁内弹性纤维与胶原纤维的含量所决定。除此之外,动脉弹性还受到内皮功能、平滑肌张力以及遗传基因的影响。研究发现,多种心血管危险因素和氧化应激反应首先影响动脉内皮功能,大动脉弹性功能减退通常发生在长期内皮功能障碍引起的粥样斑块形成、胶原纤维增多、弹力纤维断裂等结构性改变之后。由于人体动脉组织来源的稀缺性,有关人动脉弹性功能减退的病理机制方面的研究很少,而有关无创动脉弹性功能与主动脉显微结构成分之间相关性的研究尚未见报道。目的本研究以进行主动脉—冠状动脉旁路移植术的冠心病患者为研究对象,探讨高血压对冠心病患者大动脉弹性、小动脉弹性和升主动脉显微结构成分的影响以及各无创动脉弹性功能指标与升主动脉显微结构成分的相关性,寻找导致这些患者动脉弹性发生变化的组织病理学基础以及能够反映这些病理变化的无创动脉弹性功能指标。方法(1)依据入选和排除标准入选在我院行主动脉—冠状动脉旁路移植术的冠心病患者,根据有无高血压分为两组：非高血压组30例,高血压组30例。每组入选者录满为止,共60例。(2)所有入选者均进行一般临床资料的登记和测定,包括：性别、年龄、体重指数、心率、血压等,询问记录有无高血压史、糖尿病史、吸烟史以及有无服用阿司匹林、钙离子拮抗剂、血管紧张素转换酶抑制剂或血管紧张素受体拮抗剂、β受体阻滞剂、他汀类调脂药和硝酸酯类药物。(3)清晨抽取空腹静脉血测定血糖、血总胆固醇和甘油三酯。(4)采用CVProfilor(?) DO-2020型动脉弹性功能测定仪无创测定动脉弹性,得出大动脉弹性指数C1和小动脉弹性指数C2。(5)应用法国Artech-Medical公司生产的脉搏波速度测定仪测定颈动脉—股动脉PWV。(6)进行冠状动脉造影,在盲法下应用冠脉造影定量分析软件进行冠状动脉狭窄病变Gensini积分的评定。(7)将主动脉—冠状动脉旁路移植术中从升主动脉前壁取下的组织进行病理组织切片,分别用Masson染平滑肌和胶原纤维,Weigert间苯二酚复红法染弹性纤维。光镜下以计算机图像分析系统分别定量测定血管平滑肌、胶原纤维和弹性纤维的相对面积。(8)统计学处理：所有资料均应用SPSS11.5统计分析系统进行统计分析。计量资料以均数±标准差(x-±s)表示,两组间均数比较采用非配对的t检验。分类资料以频数和百分比表示,组间比较采用X2检验。各动脉弹性指标与升主动脉病理结构成分以及冠状动脉病变程度之间的相关性应用直线相关分析。P<0.05为差异有统计学意义。结果(1)无创动脉弹性测定显示,高血压组患者CFPWV明显高于非高血压组患者,高血压组患者大动脉弹性指数C1明显低于非高血压组患者,而两组之间小动脉弹性指数C2则无统计学差异。(2)升主动脉病理可见,高血压组较非高血压组患者升主动脉壁中膜胶原纤维增多,弹性纤维减少,胶原纤维、弹性纤维和平滑肌排列紊乱。光镜下以计算机图像分析系统定量分析显示,高血压组升主动脉壁中膜胶原纤维的相对含量明显高于非高血压组,而弹性纤维的相对含量则明显低于非高血压组。两组间平滑肌的相对含量没有统计学差异。(3)无论非高血压组还是高血压组,CFPWV与升主动脉中膜胶原纤维的相对含量均呈正相关,与弹性纤维的相对含量均呈负相关,而与平滑肌的相对含量无相关关系。(4)无论非高血压组还是高血压组,Cl与升主动脉中膜胶原纤维的相对含量均呈负相关,与弹性纤维的相对含量均呈正相关,而与平滑肌的相对含量无相关关系(5)无论在非高血压组还是高血压组,小动脉弹性指数C2与冠状动脉狭窄病变Gensini积分均呈负相关(P<0.01)。(6)无论在非高血压组还是高血压组,CFPWV与大动脉弹性指数C1均呈负相关。结论(1)高血压可导致冠心病患者大动脉弹性下降,其主要病理基础是胶原纤维增多和弹性纤维减少以及这两种主要成分的排列紊乱。(2)CFPWV和Cl作为大动脉弹性功能的无创性指标能够反映升主动脉中膜胶原纤维和弹性纤维的病理变化。(3)冠心病患者中C1与CFPWV之间均存在显著的负相关,提示CFPWV升高和C1降低在反映大动脉弹性减退方面具有良好的一致性。(4)C2作为反映小动脉弹性功能的无创指标有助于预测冠心病患者冠状动脉的狭窄病变程度。更多还原

【Abstract】 BackgroundCardiovascular disease resulting from arteriosclerosis is a serious worldwide health risk. With the deepening investigation of atherosclerosis, people have realized that functional and structural changes in the artery wall precede and accompany atherosclerosis and its obstructive and thrombotic events. Earlier diagnosis and intervention in vascular disease is important to control the adverse cardiovascular events such as acute myocardial infarction, stroke, and cardiac death.Elasticity is an important characteristic of the arteries and a direct reflection of the condition of these blood vessels, and reduced arterial elasticity is a sensitive marker that indicates damage to the blood vessel wall. It has been reported that capacitive arterial compliance (Cl) and oscillatory arterial compliance (C2) can accurately reflect arterial elasticity. It has also been noted that the compliance of small arteries, defined as the change in volume per unit of pressure (△V/△P) and which reflects the buffering function of the vessel, is lower in postmenopausal women with symptomatic coronary artery disease than in those without coronary artery disease. Small artery compliance also reflects subtle vascular alterations due to aging, hypertension, and type 1 diabetes, and is gender dependent-female subjects have been observed to have lower small artery compliance than male subjects. It has been shown that lower small artery compliance is associated with diffuse-coronary heart disease (CHD). Small artery compliance appears, therefore, to be a useful tool for the clinical screening of individuals of CHD. Few studies, however, have investigated the changes in small artery compliance in people with angiographic coronary atherosclerosis prior to CHD.ObjectivesThis study was designed to investigate whether small artery compliance and large artery compliance were reduced in people with angiographic coronary atherosclerosis before they were diagnosed with CHD, and to search for the relationships between non-invasive arterial elasticity indexes and the Gensini score of coronary artery.Methods(1) Two study populations were observed in this study:elderly subjects(≥65years of age) and non-elderly subjects (<65years of age).Each of the two study populations included 160 consecutive subjects who were divided into three groups according to the results of selective coronary angiography:50 subjects in the normal coronary angiogram group,55 subjects in the coronary atherosclerosis group and 55 subjects in the CHD group.(2) All patients were administered a standardized questionnaire that provided information about their occupation, age, medical history, drug using, and smoking history. Blood pressure and heart rate were measured and body mass index (BMI) was calculated. Levels of total cholesterol (TC), triglyceride (TG) and fasting blood glucose (FBG) were measured from fasting venous blood samples by automatic facilities.(3) The Gensini score of the coronary artery was acquired, and the capacitive arterial compliance (C1) and oscillatory arterial compliance (C2) were measured.(4) One-way ANOVA was used to evaluate the difference of C1 and C2 between the three groups. Bivariate analyses were performed to study the association between the Gensini score and each of C1 and C2.Results(1) One-way ANOVA analysis demonstrated a significant difference in C2 among the three groups:the normal coronary angiogram group, the coronary atherosclerosis group and the CHD group, but there was no significant difference in C1.(2) Bivariate analysis showed a negative correlation between the Gensini score and C2 in the 55 subjects of the coronary atherosclerosis group and in the 55 subjects of the CHD group. There was no significant correlation between Gensini score and C1.Conclusions(1) It can be concluded that C2 decreased in the early stages of the coronary artery atherosclerosis in patients when there were no significant stenoses in the coronary arteries independent of elderly populations or non-elderly populations.(2) Independent of elderly populations or non-elderly populations, C2 was significantly, negatively correlated with Gensine score of the coronary artery.(3) Identification of early coronary atherosclerosis may be aided by the prognostic value of C2. BackgroundWith the deepening investigation of atherosclerosis, people have realized that functional and structural changes in the artery wall precede and accompany atherosclerosis and its obstructive and thrombotic events. It has also been noted that elasticity, defined as the change in volume per unit of pressure(△V/△P), is an important characteristic of the arteries and a direct reflection of the condition of these blood vessels, and that reduced arterial elasticity is a sensitive marker that indicates damage to the blood vessel wall. So the analysis of arterial stiffness and function and of pressure wave reflection has received increasing attention for the past a few decades.A variety of techniques developed in recent years provide quantification of these pathophysiologic changes in the arterial wall. Among the methods to describe arterial stiffness, pulse wave velocity (PWV) and diastolic pulse contour analysis (DPCA) have been the most investigated in a clinical setting. It has been reported that carotid-femoral PWV (CFPWV), capacitive arterial compliance (C1), and oscillatory arterial compliance (C2) can accurately reflect arterial elasticity. Almost all conventional risk factors for atherosclerosis such as hypercholesterolemia, hypertension, diabetes, insulin resistance, smoking, and aging are associated with PWV, C1, or C2.It has been demonstrated that PWV, C1, and C2 are significant predictors of cardiovascular risk in diseased and older healthy populations.The human aorta contains vascular smooth muscle, and is rich in elastin and collagen. A delicate balance of collagen, elastin, and smooth muscle in the aortic wall is clearly essential for a compliant aorta. Thus, we postulate there must be a close relationship between CFPWV, C1, C2 and composition of the human aorta. However, the correlation between arterial elastic indices mentioned above and smooth muscle, elastin, or collagen of the aortic media has not previously been examined in human.ObjectivesThis study was designed first to investigate the influence of hypertension on the arterial elasticity and the histologic structure of the ascending aortic media in patients with coronary heart disease (CHD) undergoing coronary artery bypass graft (CABG) surgery. The second purpose of this study was to examine the relationship between structural changes of the ascending aortic media and the arterial elastic indices such as CFPWV, Cl, and C2.Methods(1) The study population comprised 60 consecutive CHD patients who underwent CABG surgery in Qilu Hospital of Shandong University and were divided into two groups:30 subjects were in the hypertension group and 30 subjects were in the non-hypertension group.(2) All patients were administered a standardized questionnaire that provided information about their occupation, age, medical history, drug using, and smoking history. Blood pressure and heart rate were measured and body mass index (BMI) was calculated. Levels of total cholesterol (TC), triglyceride (TG) and fasting blood glucose (FBG) were measured from fasting venous blood samples by automatic facilities.(3) CFPWV, C1, and C2 were measured in a quiet, temperature controlled room. (4) Selective coronary angiography was performed according to standard clinical practice and quantitative coronary angiographic analyses were performed using the computer-based edge-detection coronary angiography analysis system. Then Gensini score was calculated.(5) The specimens of ascending aorta were stained with Masson and Weigert’s solution separately and examined by light microscopy to measure the percentage of medial surface occupied by smooth muscle, collagen, and elastic fibers by pathologists in a double-blinded manner.(6) All data analyses were performed using the program SPSS11.5 for Windows. Continuous variables were expressed as the means±SD. Categorical data were presented as numbers and percentages. An independent-sample t-test was used to compare continuous data and the X2 test was used to compare categorical variables between the two groups. Bivariate analyses were performed to study the associations between microstructure of the ascending aortic media and each of CFPWV, C1 and C2. A P-value of< 0.05 was considered to be statistically significant.Results(1) There were significant differences between the two groups in CFPWV and C1, but no differences between the two groups in C2.(2) There was a significant decrease in the relative content of elastin and a significant increase in the relative content of collagen in the media of ascending aorta of the hypertension group compared with those of the non-hypertension group. There was no significant difference between the two groups in smooth muscle content of the ascending aorta.(3) CFPWV had positive correlation with the relative contents of collagen and negative correlation with the relative contents of elastin in each of the two groups.(4) C1 had negative correlation with the relative contents of collagen and positive correlation with the relative contents of elastin in each of the two groups. (5) C2 had negative correlation with the Gensini score of the coronary artery in each of the two groups.(6) CFPWV had negative correlation with C1 in each of the two groups.Conclusions(1) It can be concluded that hypertension can cause a decrease in large artery elasticity of CHD patients and that the changes in relative contents of collagen and elastin, as well as alterations in microstructures of the two components in the media of the aortic wall caused by hypertension are responsible for this decrease.(2) The elevated CFPWV and the decreased Cl can reflect the changes in collagen and elastin of the arotic media caused by hypertension.(3) C2 can reflect the severity of coronary artery atherosclerosis in CHD patients.更多还原