【作者】 林乐语；

【导师】 张薇；

【作者基本信息】 山东大学 ， 内科学（专业学位）， 2013， 硕士

【摘要】 研究背景：心房颤动(房颤)是临床上最常见的心律失常之一,血栓栓塞并发症是房颤的最大危害之一。流行病学研究显示,我国住院病人中房颤的脑卒中患病率高达24.8%,远高于无房颤人群,且随年龄有增加的趋势；于此同时,房颤引起的脑卒中往往更严重,其致死率是无房颤患者的2倍；因此,对于房颤患者,对于栓塞危险因素的早期检出和积极预防具有重要的临床意义。以往的研究证明,房颤缺血性卒中的栓子主要来源为左房血栓,而其中90%的左房血栓发生在左心耳；但是,由于非瓣膜性房颤的主要基础病因高血压、糖尿病、冠心病、高龄等同时也是动脉粥样硬化的主要危险因素,非瓣膜性房颤的患者往往也同时存在主动脉和周围动脉粥样硬化性病变。有研究发现,在一般人群中,约有20%-25%的卒中是由动脉粥样硬化斑块引起的,主动脉弓部粥样斑块和颈动脉复合型粥样斑块是缺血性脑卒中的独立危险因素。房颤脑卒中防治的SPAFⅢ(?)勺超声研究也证实,主动脉粥样斑块是房颤患者脑卒中的独立危险因素。但是,对于房颤患者颈动脉粥样硬化与脑卒中发病的关系的研究目前尚未见报道。脑卒中预防是房颤治疗的重要环节,而房颤患者的卒中危险分层有助于临床个体化治疗。目前临床上常用于评估卒中风险的方法主要有2006年美国心脏病学会/美国心脏病协会/欧洲心脏病学会(ACC/AHA/ESC)的房颤指南提出的CHADS2评分系统和2010年ESC房颤治疗指南提出的CHA2DS2-VASc评分系统,国内外已有多项研究证实CHADS2可以有效评估房颤患者卒中风险,提高房颤患者规范化抗凝治疗率。国内外已有研究提示CHADS2评分对房颤患者左心房来源的心血管负性事件有较强的预示作用。但是,对于动脉粥样斑块来源的栓塞,房颤卒中危险分层方式的预测意义尚未明确。动脉粥样硬化被认为是一种全身性血管病变,是由相同的病理过程引起,涉及不同的血.管床。周围动脉粥样硬化与脑学管粥样硬化有着共同的病理基础和危险因素。因此,颈动脉可作为一个间接反映全身动脉粥样硬化病变的程度和范围“窗口”。应用多普勒超声技术检测颈动脉粥样斑块形态、IMT及血流动力学变化,可直观地动态评价颈动脉的结构和功能,从而预测心脑血管事件的发生。速度向量成像(VVI)技术足近年来兴起的用于检测心肌和血管壁运动的新技术,可以用于颈总动脉弹性特点、血管壁弹性及弹性衍生参数,与传统的超声检测指标相结合可以更加全面评价和了解血管壁的弹性状态。研究目的：1、应用多普勒超声技术研究房颤患者颈动脉粥样硬化病变特征;2、应用速度向量成像(WI)技术研究房颤患者颈总动脉长轴管壁的力学特征;3、探讨房颤患者颈动脉粥样斑块形成是否是其患缺血性脑卒中的独立危险因素；4、探讨CHADS2评分、CHA2DS2-VASc评分与房颤患者颈动脉粥样硬化疾病、颈动脉粥样斑块形成的关系及其意义。材料与方法：1、选择受试者159例,分为以下三组：(1)对照组：均为在三东大学齐鲁医院就诊的健康查体者和健康志愿者,经详细询问病史、体格检查、12导联常规心电图检查、常规超声心动图检查、血液生化检查、血脂检查、肝肾功能检查等均无异常发现,排除高血压、糖尿病、肾病、心律失常、心力衰竭及器质性心脏病。共50例,其中男性22例,女性28例,年龄38-76岁,平均55.98+7.19岁。(2)阵发性房颤组：通过详细询问病史、体格检查、常规超超声心动图检查,排除器质性心脏病,经12导联常规心电图或(和)24h动态心电图检查证实为阵发性心房颤动者纳入本组。共59例,其中男性22例,女性37例,年龄30～75岁,平均58.32±10.18岁。(3)持续性房颤组：通过洋细询问病史、体格检查、常规超声心动图检查,排除器质一性心脏病,经12导联常规心电图或(和)24h动态心电图检查证实为持续性心房颤动者纳入本组。共50例,其中男性18例,女性32例,年龄25-78岁,平均59.30±8.94岁。2、仪器设备：采用Siemens Sequoia512彩色多普勒超声诊断仪,15L8高频探头(频率8.0～14.0MHz),WI脱机分析软件(syngo US workplace)由Siemens公司提供。3、研究方法：对所有参与者进行体格检查,测量身高、体重、腰围、臀围、血压和心率等,并询问既往史、家族史和用药史。所有参与者均经隔夜禁食12-14小时,次日清晨抽取空腹肘静脉血,测定空腹血糖(FBG)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-c)、高密度脂蛋白胆固醇(HDL-c);参与者取平卧位,应用颈动脉超声测量颈动脉粥样斑块、颈动脉内-中膜厚度、颈动脉内径、颈动脉血流速度。开启WI检查预设值采集储存颈总动脉长轴二维实时灰阶动态图像供脱机分析。4、统计学分析：所有计量资料均以χ±SD表示,计数资料和非等级参数资料的比较采用χ2检验,两组间参数比较采用两组独立样本资料的t检验,多组间参数比较采用ANOVA,组间两两比较采用LSD-t检验,变量间做Pearson直线相关分析及多因素线性逐步回归分析,应用非条件Logistic回归模型筛选危险因素,计算OR值和95%置信区间。所有数据分析都采用统计学软件包SPSS18.0进行,当P<0.05时具有统计学意义。结果：1、与正常对照组相比,间歇性房颤组临床资料中收缩压、脉压、腰臀比、饮酒史、高血压病、糖尿病、冠状动脉粥样硬化性心脏病、高血脂症均显著增加；颈动脉超声指标中斑块指数、平均IMT、Ds、Dd、AC明显升高,同时,Vs、Vd明显减低；WI指标中,反映颈动脉长轴纵向运动的指标(包括PvS、PvD、PsS、 PsD、PsrS、PsrD、PdS、PdD和tLoD)均明显降低,同时反映颈动脉长轴径向运动的指标中PvD亦明显降低。2、与正常对照组相比,持续性房颤组收缩压、脉压、心率、腰臀比、吸烟史、饮酒史、冠状动脉粥样硬化性心脏病、卒中史均显著增加,斑块指数、平均IMT、最大IMT、Ds、Dd、β、AC、Ep、Ep*明显升高,同时,Vs、Vd明显减低；与间歇性房颤组相比,持续性房颤组心率和卒中史显著增高,斑块指数明显升高,RI明显减低。3、与对照组相比,间歇性房颤组；与对照组相比,持续性房颤组反映颈动脉长轴纵向运动的指标(包括PvS、PvD、PsS、PsD、PsrS、PsrD、PdS、PdD和tLoD)均明显降低,同时同时反映颈动脉长轴径向运动的指标中PvS、PdS和PdD亦明显降低：间歇性房颤组与续性房颤组之间各指标的差异均未达到统计学意义。4、与对照组相比,间歇性房颤组舒张早期位移达峰时间明显增加;其余同步性各指标各组间差异未达到统计学意义。5、缺血性脑卒中事件：109例房颤忠者中，16例经颅脑CT或MRI证实为缺血性脑卒中患者,占全部房颤患者的14.5%。与颈预动脉无斑块组比较,颈动脉斑块组缺血性脑卒中发病率明显升高。6、与对照组相比,间歇性房颤组和持续性房颤组CHADS2评分和CHA2DS2-VASc评分均明显升高；间歇性房颤组与持续性房颤组CHADS2评分和CHA2DS2-VASc评分的差异术达到统计学差异。7、CHADS2评分与斑块指数、平均IMT、最大IMT、Ds、Dd、Vs、Vd、β、 DC、AC、Ep、Ep*等反映颈动脉结构和功能的指标均相关，与PvS、PsD、PsrS、 PdD、tLoD等反映颈动脉长轴运动弹性和TPvS、TPsrS等反映颈动脉长轴运动同步性的指标亦相关。8、CHA2DS2-VASc评分与斑块指数、平均IMT、最大IMT、Ds、Dd、Vs、Vd、 p、AC、Ep、E p*等反映颈动脉结构和功能的指标均相关,与PvS、PsrS等反映颈动脉长轴运动弹性和TPvS、TPsS、TPsD、TPsrS、TPsrD、TPdS等反映颈动脉长轴运动同步性的指标亦相关。9、使用LogistiC回归筛选斑块指数增大的危险因素,CHADS2评分、性别和心率进入回归方程，表明CHADS2评分高,男性和心率快者是颈动脉斑块指数增大的易感者。10、使用Logistic回归筛选IMT增厚的危险因素,CHADS2评分、总胆固醇和LDL-C进入回归方程，表明CHADS2评分高,总胆固醇升高和LDL-C升高者是IMT增厚的易感者。11、多元线性回归结果如下：平均IMT=年龄×0.004+腰臀比×0.358+CHADS2评分×0.022;最大IMT=年龄×0.005+CHADS2评分x0.040+腰臀比×0.438：DC=CHADS2评分×0.022-收缩压×0.002+舒张压×0.002；AC=收缩压×0.096-舒张压×0.102+CHADS2评分×0.383；表示以上变量与CHADS2评分存在线性依存关系。结论：1、房颤患者的颈动脉结构和功能发生了显著的改变,主要表现为斑块指数增大、内膜增厚、管径扩大、弹性减低、僵硬度增大和血流速度减低；2、在房颤患者中,颈动脉内膜增厚是缺血性脑卒中发病的危险因素,提示房颤并发的动脉粥样硬化对缺血性脑卒中的发生有重要影响,对临床上房颤的抗凝治疗有一定提示意义；12、CHADS2评分和CHA2DS2-VASc评分与颈动脉超声指标存在相关关系,说明房颤卒中风险分层可以反映颈动脉结构和功能受损的程度；3、速度向量成像技术可以用于评价房颤患者颈总动脉长轴管壁力学特征的受损情况,其临床意义值得深入研究。更多还原

【Abstract】 BackgroundAtrial fibrillation (AF) is one of the most common cardiac arrhythmia, of which the biggest hazard is its thromboembolic complication. According to epidemiological studies, the prevalence rate of stroke in hospitalized patients of AF in our nation is up to24.8%, which is far above that in population without AF. What is more, stroke caused by AF are much pernicious and its lethality is two times higher than stroke caused by reasons other than AF. Therefore, it is of great importance to find methods that can early detect and prevent the risk factors of thromboembolism in patients with AF. Previous studies have proved that the main source of embolus of ischemic stroke in AF is left atrial thrombus, and90%of which rest in the left atrial appendage. At the same time, as the major fundamental causes of non-valvular atrial fibrillation (NVAF) are also the major risk factors of atherosclerosis, such as hypertension, diabetes, coronary heart disease and advanced age, patients with NVAF may suffer from aortic and peripheral atherosclerosis simultaneously as well. In the general population, aortic and carotid atherosclerotic plaques, as source of20%～25%of cerebral emboli, were documented to be strong and independent risk factors for ischemic stroke. Furthermore, the ultrasonic study of SPAFIII has indicated that aortic atherosclerotic plaque was an independent risk factor for ischemic stroke in patients with AF. Nevertheless, the contributions of carotid plaque to ischemic stroke in patients with AF are not quite clear.Prevention of stroke is an important part of atrial fibrillation treatment and stroke risk stratification in patients with atrial fibrillation would greatly help the clinical individualized treatment. Methods currently used in clinical practice to evaluate the risk of stroke are the CHADS2score system put forward by the2006AF guidelines of ACC/AHA/ESC and the CHA2DS2-VASc scoring system proposed by ESC in2010AF guidelines. There have been several studies both in our nation and abroad that have confirmed that CHADS2scoring system can effectively assess the risk of stroke in patients with atrial fibrillation, as well as improve the standardization of anticoagulant therapy in patients with AF. Existing research in our nation and abroad also have proved that CHADS2score has a strong signal effect for left atrial origined cardiovascular events in patients with atrial fibrillation. But for atherosclerosis plaque source embolism, the forecast effect of stroke risk stratification is not clear.Atherosclerosis is considered to be a systemic vascular lesion, which is caused by the same pathologic process involving in different vascular beds. Peripheral artery atherosclerosis and cerebral atherosclerosis enjoy the same pathologic basis and risk factors. Subsequently, carotid artery can be used as an indirect reflection of the extent of systemic atherosclerosis. Using doppler ultrasound detection of carotid artery atherosclerosis plaque morphology, IMT and hemodynamic changes, one can visually and dynamically evaluate the structure and function of carotid artery, and predict future cardiovascular events. Velocity vector imaging (VVI) technology is a new risen technology in recent years for determination of myocardial and vascular wall motion, which can be used in detecting the elasticity characteristics, vessel wall elasticity and elastic-derived parameters of common carotid. By combining VVI with the traditional ultrasonic testing indicators, one can more comprehensively evaluate and understand the elasticity and mechanism factors of arteries.Objectives1. Investigate the characteristics of atherosclerotic lesions in patients with AF using the technology of Doppler Ultrasound;2. Investigate the mechanic characteristics and movement synchronization characteristics of the long axis of the common carotid artery in patients with AF using velocity vector imaging(VVI);3. Explore whether carotid atherosclerosis in patient of AF is an independent risk factor of ischemic stroke; 4. Explore the relationships between CHADS2score, CHA2DS2-VASc score and carotid atherosclerosis and its significance.Subjects and methods1. A total of159subjects were enrolled, divided into the following three groups:(1) The control group consists50subjects(22males and28females, aged38-76,55.98±7.19in average), all of whom are health examinees and health volunteers in Qilu Hospital of Shandong university. There is no abnormality found during detailed history collection, physical examination, routine12lead ECG examination, routine echocardiography examination, blood biochemical examination, hypertension, diabetes, kidney disease, arrhythmia, heart failure, and organic heart disease excluded.(2)The paroxysmal atrial fibrillation group consists59subjects(22males and37females, aged30-75,58.32±10.18in average). Cases that can exclude organic heart disease by detailed history collection, physical examination, conventional echocardiography and have the routine12lead electrocardiogram (ECG) or (and)24h dynamic electrocardiogram examination confirmed for paroxysmal atrial fibrillation were included in this group.(3) The persistent atrial fibrillation group consists50subjects(18males and32females, aged25-78,59.30±8.94in average), Cases that can exclude organic heart disease by detailed history collection, physical examination, conventional echocardiography and have the routine12lead electrocardiogram (ECG) or (and)24h dynamic electrocardiogram examination confirmed for persistent atrial fibrillation were included in this group.2. Instruments and equipments:Adopting the Siemens Sequoia512color Doppler ultrasonic diagnostic apparatus,15L8high frequency transducers (8.0～14.0MHz frequency). VVI offline analysis software (syngo US workplace) is provided by Siemens Company.3. Research methods:All participants have take full physical examinations; including height, weight, waist circumference, hip circumference, blood pressure and heart rate, etc. Full medical history, family history and medication history is documented. After overnight fasting12to14hours, extract fasting venous blood the next morning to determinate fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and high density lipoprotein cholesterol (HDL). Participants lie down for application of carotid artery ultrasound measurement of carotid artery athermanous plaque and carotid artery IMT, carotid artery diameter and carotid artery blood flow velocity.Turn on VVI mode to storage two-dimensional dynamic real-time gray-scale images of long axis common carotid artery for future offline analysis.4. Statistical analysis:Statistical analysis was performed by SPSS18.0software package, whereas P<0.05reveals statistically significant. Continuous data are given as X±SD, comparison of which was performed by independent-sample t-test. Discrete variables were expressed as absolute frequencies and percentages when appropriate and analyzed by chi-square test. Binary logistic regression analysis was performed to screen possible independent risk factors for carotid atherosclerotic plaque. Parameter comparison between groups using one-way ANOVA, and comparing two groups using LSD-t test, Pearson variables linear correlation analysis and multiple factor linear stepwise regression analysis is preformed, and screening of risk factors using the unconditional Logistic regression model, calculate the OR values and95%confidence interval.Result1. Compared with control group, the paroxysmal atrial fibrillation group’s clinical data (including systolic blood pressure, pulse pressure, waist-to-hip ratio, history of drinking, hypertension, diabetes, coronary atherosclerosis heart disease, hyperlipidemia) were significantly increased (P<0.05-0.001); Carotid ultrasound indexes of plaque index, average IMT, Ds, Dd, AC are also increased significantly, while at the same time Vs, Vd reduced significantly; For indexes of VVI, those reflecting the long axis longitudinal motion index of the carotid artery (including PvS, PvD, PsS, PsD, PsrS, PsrD, PdS, PdD and tLoD) were significantly lower, and at the same time indicator of PvD (reflect the carotid long axial radial movement) is also significantly lower.2. Compared with normal control group, the persistent atrial fibrillation group’s clinical data (including systolic blood pressure, pulse pressure, heart rate, waist-to-hip ratio, smoking history, drinking history, history of coronary atherosclerotic heart disease, stroke) were significantly increased, and average IMT, maximum IMT, plaque index, Ds, Dd, AC, Ep and Ep*increased significantly, while at the same time Vs, Vd reduced significantly; Compared with the paroxysmal atrial fibrillation group, persistent AF group’s heart rate and stroke history were significantly higher, plaque index significantly increased, and RI significantly reduced.3. Compared with control group, the paroxysmal atrial fibrillation group; Compared with control group, the persistent AF group’s indexes reflect the carotid long axis longitudinal motion (including PvS, PvD, PsS, PsD, PsrS, PsrD, PdS, PdD and tLoD) were significantly lower, while at the same time reflect the carotid long axial radial movement indicators PvS, PdS and PdD also significantly lower; paroxysmal and persistent AF group did not show any statistical differences between each index.4. Compared with the control group, the diastolic peak displacement of paroxysmal atrial fibrillation group was obviously increased; The rest of the synchronicity index did not show any statistical differences between groups.5. Ischemic cerebral stroke events:Between the109cases of atrial fibrillation in patients,15cases were confirmed by craniocerebral CT or magnetic resonance imaging (MRI) for ischemic stroke patients accounted for14%of all patients with atrial fibrillation. Compared with carotid artery without plaque group, ischemic stroke incidence of carotid artery plaque group was obviously increased.6. Compared with control group, the paroxysmal AF and persistent AF groups’ CHADS2score and CHA2DS2-VASc scores were significantly higher; CHADS2score and CHA2DS2-VASc score between paroxysmal AF and persistent AF group did not reach statistical difference.7. CHADS2score is related to average IMT, maximum IMT, plaque index, Ds, Dd, Vs, Vd, DC, AC, Ep and Ep*, which reflect carotid artery structure and function. PvS, PsD, PsrS, PdD, tLoD, which reflect the carotid elasticity of long axis movement and TPvS, TPsrS, which reflect the carotid artery long axis movement synchronization indexes are also related to it. 8. CHA2DS2-VASc score is related to average IMT, maximum IMT, plaque index, Ds, Dd, Vs, Vd, DC, AC, Ep and Ep*, the indexes related to carotid artery structure and function, including PvS, PsD, PsrS, PdD, tLoD, which reflect the carotid elasticity of long axis movement and TPvS, TPsrS, which reflect the carotid artery long axis movement synchronization index are also related to it.9. When using Logistic regression to screen risk factors for plaque index increase, CHADS2score, sex, and heart rate went into the regression equation, indicate that when CHADS2score is high, male with the rapid heart rate is susceptible to carotid artery plaque index increase.10. When using Logistic regression to screen risk factors of IMT thickening, CHADS2score, total cholesterol and LDL-C into the regression equation, indicate that when CHADS2score is high, ones with higher total cholesterol and LDL-C is susceptible to IMT thickening increase.11. Multiple linear regression results are as follows: Mean IMT=Age×.004+WHR×0.358+CHADS2score×0.022; Max IMT=Age×0.005+CHADS2score×0.040+WHR×0.438; DC=CHADS2scpre×0.022-SBP×0.002+DBP×0.002; AC=SBP×0.096-DBP×0.102+CHADS2score×0.383.Shown the above variables have linear dependence relationships with CHADS2score.Conclusion1. The structure and function of carotid artery in patients with atrial fibrillation have changed significantly, which mainly presents as increased plaque index, reduced IMT, artery diameter expansion, increased flexibility and stiffness and decreased blood flow velocity;2. In patients with atrial fibrillation, thickening of carotid artery intimae is a risk factor for ischemic stroke onset, which reveals that atherosclerosis complicated by atrial fibrillation may have important effects on the happening of ischemic stroke, which could be a guidance for clinical anticoagulant therapy of atrial fibrillation;3. The CHADS2score and CHA2DS2-VASc score was correlated with parameters of carotid ultrasound, shows that atrial fibrillation stroke risk stratification can reflect the degree of carotid artery structure and function damaging;4. Velocity vector imaging can be used in assessment of mechanism characteristics of carotid artery wall in patients with atrial fibrillation; its clinical significance is worth future research.更多还原