【摘要】：背景:高血壓病是一種由多種基因突變和環(huán)境因素互相作用為結果,以動脈血壓持續(xù)增高為特點的慢性心血管疾病。高血壓病的持續(xù)進展加速靶器官損害,從而導致心腦腎器官的衰竭。根據(jù)2010年中國高血壓防治指南,高血壓引起的無癥狀靶器官損害定義為:左心室肥厚,超聲心動圖左室質量指數(shù)(LVMI):男≥125g/m2,女≥120g/m2;頸動脈內膜中層厚度(IMT)≥0.09mm或動脈粥樣斑塊;頸-股動脈脈搏波速度≥12m/s或肱踝脈搏波傳導速度(BaPWV)≥14m/s;踝/臂血壓指數(shù)0.9等。近年來高血壓合并靶器官損害的發(fā)生率日趨增高,左心室肥厚的高血壓患者易發(fā)生心臟缺血,心律失�；蜮�。有研究表明,勁動脈內膜中層厚度增厚和斑塊形成與高血壓等危險因素密切相關。高血壓合并靶器官損害顯著增加患者的死亡風險和經(jīng)濟負擔,降低患者的生活質量。頸動脈超聲可作為"窺視"全身動脈粥樣硬化進展的一個窗口。經(jīng)胸超聲心動圖、頸動脈超聲及脈搏波速度是目前篩查高血壓合并靶器官損害較常用的方法。SIRT3(Sirtuins3),一類依賴NAD+輔酶的去乙酰化酶家族成員之一,近年來備受關注。研究發(fā)現(xiàn)SIRT3參與了多種細胞進程,包括細胞增殖、細胞自噬、細胞代謝、壽命基因的調控以及抑制腫瘤。最新發(fā)現(xiàn)小鼠SIRT3通過改善脂質代謝紊亂從而抑制心肌肥厚。然而,高血壓合并靶器官損害患者中SIRT3的表達情況是否異常未有報道。Endocan(ESM-1),由血管內皮細胞分泌的特異性糖蛋白,是參與維持內皮功能穩(wěn)態(tài)的重要因子之一。近年研究發(fā)現(xiàn)endocan與炎癥、血管重構、凝血機制、腫瘤侵入有關。也有學者報道其與心血管疾病的關系,升高的血清endocan水平可能是動脈硬化發(fā)展的跡象之一。目前SIRT3與endocan在原發(fā)性高血壓疾病中的研究極少,而高血壓合并$靶器官損害患者中SIRT3與endocan的表達水平未曾有報道。本研究通過ELISA技術檢測高血壓患者血清中SIRT3和endocan水平,結合經(jīng)胸超聲心動圖、頸動脈超聲和PWV檢查,綜合評估血清SIRT3與endocan在原發(fā)性高血壓患者的變化,并探討其與高血壓合并靶器官損害的相關性。研究目的:1.研究血清SIRT3、endocan與原發(fā)性高血壓病的相關性。2.探討血清SIRT3、endocan與高血壓合并靶器官損害的相關性。3.評估血清SIRT3、endocan在原發(fā)性高血壓的發(fā)生和進展中是否具有預測作用。研究方法:連續(xù)收集2015年10月至2016年11月就診于我院心內科門診的高血壓患者85例作為病例組。經(jīng)胸超聲心動圖和頸動脈彩超將病例組分為高血壓合并靶器官損害組(target-organ damage,TOD)和高血壓無靶器官損害組(non-target-organ damage,NTOD)。收集同期門診健康者47例作為正常對照組(control)。本研究已通過醫(yī)院倫理委員會,病例組及對照組均簽署知情同意書。完成病史采集及一般情況測量,包括血壓、身高、體重。并抽取空腹靜脈血4ml(EDTA抗凝),應用ELISA方法測定血清SIRT3和endocan水平。三組進行彩超及PWV檢查,測量頸總動脈收縮期內徑及舒張期內徑,頸動脈內膜中層厚度,評估斑塊及斑塊積分,測量各個心腔結構的大小,著重記錄左室內徑,左室后壁厚度,舒張末期室間隔厚度等;使用VP1000測量脈搏波傳導速度及踝臂指數(shù)等。應用SPSS20軟件包進行統(tǒng)計學處理,正態(tài)分布計量資料皆以均數(shù)±標準誤(mean±SEM)表示,多組間比較采用單因素方差分析,有差異之后的兩兩比較采用最小顯著性差異法(LSD),排除影響因素比較使用協(xié)方差分析,主效應對比采用最小顯著性差異法。相關性分析采用偏相關分析,回歸分析采用多元線性回歸分析。指標均以P0.05為具有統(tǒng)計學差異。研究結果:1.一般資料顯示,TOD組、NTOD組與control組在年齡(Age)、性別(Sex)、體重指數(shù)(BMI)、血糖、肌酐、尿素氮(BUN)、甘油三酯(TG)等危險因素無顯著性差異(P0.05)。而在收縮壓(SBP)、舒張壓(DBP)、高密度脂蛋白(HDLC)、低密度脂蛋白(LDLC)、尿酸(UA)等均有明顯差異(P0.05)。2.頸動脈超聲和BaPWV結果顯示:TOD組的頸動脈內膜中層厚度(IMT)、頸動脈舒張期內徑(Dd)、頸動脈收縮期內徑(Ds)、頸動脈僵硬度(SC)、肱踝脈搏波速度(BaPWV)明顯高于NTOD組與control組,而頸動脈緊張度(Strain)和頸動脈擴張性系數(shù)(DC)明顯低于后兩組(P0.05)。3.超聲心動圖結果顯示:TOD組的室間舒張末期室間隔厚(IVSTd)、舒張末期左室內徑(LVIDd)、左室后壁舒張期厚度(LVPWTd)和左室質量指數(shù)(LVMI)均大于 NTOD 和 control 組(P0.05)。4.TOD組血清SIRT3水平遠低于NTOD組和control組(P0.05)。TOD組血清endocan水平遠高于NTOD組和control組(P0.05)。5.所有患者中,血清SIRT3水平與左室質量指數(shù)、頸動脈內膜中層厚度、肱踝脈搏波速度顯著負相關(r=-0.331,P0.001;r=-0.314,P0.001;r=-0.473,P0.001)。血清endocan水平與左室質量指數(shù)、頸動脈內膜中層厚度、肱踝脈搏波速度顯著正相關(r=0.233,P0.01;r=0.219,P0.05;r=0.188,P0.05)。結論:1.高血壓合并靶器官損害組血清SIRT3水平低于高血壓無靶器官損害組及對照組,提示SIRT3可能在高血壓及靶器官損害的發(fā)生發(fā)展中起保護作用。2.高血壓合并靶器官損害組血清endocan水平高于高血壓無靶器官損害組及對照組,提示endocan促進高血壓及靶器官損害的發(fā)展,可以為臨床治療提供新的治療靶點。3.血清SIRT3、endocan水平在高血壓及靶器官損害的發(fā)展中呈負相關,其因果關系有待進一步研究。
[Abstract]:Background: Hypertension is a chronic cardiovascular disease characterized by a variety of genetic mutations and environmental factors interacting with each other as a result. The sustained progression of hypertension accelerates the target organ damage, leading to failure of the renal organ of the liver. According to the guidelines for prevention and cure of hypertension in China in 2010, asymptomatic target organ damage caused by hypertension was defined as left ventricular hypertrophy, echocardiographic left ventricular mass index (LVMI): male tongue 125g/ m2, female gametocyte 120g/ m2, intima-media thickness (IMT) of carotid artery 0.09mm or atherosclerosis plaque; The pulse wave velocity of the neck-femoral artery was 12m/ s or the brachial ankle pulse wave conduction velocity (BaPWV) was 14m/ s; the ankle/ arm blood pressure index was 0. 9 and so on. In recent years, the incidence of hypertension combined with target organ damage is increasing, and hypertension patients with left ventricular hypertrophy are prone to cardiac ischemia, arrhythmia or sudden death. It has been shown that the thickening of middle layer thickness and plaque formation are closely related to the risk factors such as hypertension. High blood pressure combined with target organ damage significantly increases the risk of death and economic burden of patients, and decreases the quality of life of patients. Carotid ultrasound can be used as peephole A window of progression of systemic atherosclerosis. Transthoracic echocardiography, carotid ultrasound and pulse wave velocity are commonly used methods for screening high blood pressure combined target organ damage. SIRT3 (Sirtuins3), one of the members dependent on NAD + coenzyme, has attracted much attention in recent years. The study found that SIRT3 was involved in various cell processes, including cell proliferation, cell autophagy, cell metabolism, longevity gene regulation and tumor suppression. Recently, SIRT3 has been found to inhibit myocardial hypertrophy by improving lipid metabolism disorder. However, the abnormal expression of SIRT3 in patients with hypertension and target organ damage was not reported. Endoderm (OPG-1), a specific glycoprotein secreted by vascular endothelial cells, is one of the important factors involved in maintaining the homeostasis of endothelial function. Recent studies have found endocan associated with inflammation, vascular remodeling, coagulation mechanisms, and tumor invasion. Some scholars also reported that their relationship with cardiovascular disease, elevated serum endosan levels, could be one of the signs of atherosclerosis. At present, the study of SIRT3 and endocan in essential hypertension is very rare, while the expression level of SIRT3 and endocan in patients with hypertension complicated with $target organ damage has not been reported. In this study, the levels of SIRT3 and endosan in serum of patients with hypertension were detected by ELISA. Combined with transthoracic echocardiography, carotid ultrasound and PWV, the changes of serum SIRT3 and endocan in patients with essential hypertension were assessed. Purpose of Study: 1. To study the correlation of serum SIRT3, endocan and essential hypertension. To explore the correlation of serum SIRT3, endocan and hypertension combined with target organ damage. To assess whether serum SIRT3, endocan has a predictive role in the occurrence and progression of essential hypertension. Methods: 85 patients with hypertension from October 2015 to November 2016 were collected as case group. The cases of hypertension were combined with target organ damage group (TOD) and non-target organ damage group (NTOD) by transthoracic echocardiography and carotid ultrasound. Forty-seven out-of-patient health patients were collected as control. Informed consent was signed by the hospital ethics committee, case group and control group. Complete medical history collection and general measurement, including blood pressure, height, body weight. The serum SIRT3 and endosan levels were determined by ELISA. Three groups of color Doppler and PWV examination were performed to measure the systolic and diastolic diameter, carotid intima-media thickness of carotid artery, evaluate plaque and plaque scores, measure the size of each cardiac cavity structure, and focus on recording the left ventricular diameter, the posterior wall thickness of the left chamber, the end diastolic ventricular septal thickness, and so on. Pulse wave conduction velocity and ankle brachial index were measured using VP1000. The SPSS20 software package was used for statistical processing, and the normal distribution measurement data were expressed by means of single-factor analysis of variance (MEAN _ SEM). A single factor analysis of variance was used to compare the differences between the two groups, and the difference was used to compare the two groups with the least significant difference method (LSD). Covariance analysis was used to exclude the influence factors, and the least significant difference method was used for the main effect comparison. Multivariate linear regression analysis was used to analyze the correlation between correlation analysis and regression analysis. All the indexes were statistically different with P0.05. Results of the study: 1. In general, there was no significant difference in the risk factors such as age (Age), sex (Sex), body mass index (BMI), blood glucose (BMI), glucose (BMI), triglyceride (TG), etc. (P0.05). The systolic blood pressure (SBP), diastolic blood pressure (DBP), high density lipoprotein (HDLC), low density lipoprotein (LDLC) and uric acid (UA) were significantly different (P0.05). Carotid ultrasound and BaPWV showed that carotid intima-media thickness (IMT), carotid artery diastolic diameter (Dd), carotid systolic internal diameter (Ds), carotid stiffness (SC), brachial ankle pulse wave velocity (BPWV) were significantly higher than those in control group. Carotid artery tension and carotid expansion coefficient (DC) were significantly lower than that in the latter two groups (P0.05). The results of echocardiography showed that the interventricular septum thickness (IVSTd) and the end-diastolic left ventricular diameter (LVIDD) in the TOD group. The left ventricular diastolic thickness (LVPWTd) and the left ventricular mass index (LVMI) were all greater than those of NTOD and control group (P0.05). In all patients, the serum SIRT3 level was negatively correlated with the left ventricular mass index, carotid intima-media thickness and brachial ankle pulse wave velocity (r =-0.331, P0.001; r =-0.314, P0.001; r =-0.473, P0.001). The level of serum endocan was positively correlated with left ventricular mass index, carotid intima-media thickness and brachial ankle pulse wave velocity (r = 0.233, P0.01; r = 0.0219, P0.05; r = 0.188, P0.05). Conclusion: 1. The serum SIRT3 level of patients with hypertension complicated with target organ damage was lower than that of non-target organ damage group and control group of hypertension, suggesting that SIRT3 could play a protective role in the development of hypertension and target organ damage. The level of serum endocan in hypertensive patients with target organ damage group is higher than that of non-target organ damage group and control group of hypertension. It is suggested that endocan can promote the development of hypertension and target organ damage, and can provide new therapeutic target for clinical treatment. There was a negative correlation between the serum SIRT3 and endocan levels in the development of hypertension and target organ damage.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R544.11

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