本文選題：同型半胱氨酸 + 腦卒中　； 參考：《鄭州大學(xué)》2014年博士論文

【摘要】：背景：同型半胱氨酸(homocysteine,Hcy)被認(rèn)為一種潛在的心腦血管疾病危險(xiǎn)因素,通過多種途徑促進(jìn)機(jī)體血栓前和動(dòng)脈粥樣硬化前狀態(tài)形成。研究發(fā)現(xiàn)補(bǔ)充B族維生素可以降低血中Hcy水平,但這一措施減少心腦血管疾病風(fēng)險(xiǎn)的肯定結(jié)果并未獲得。而Hcy對心腦血管疾病預(yù)后復(fù)發(fā)的影響也備受關(guān)注,升高的Hcy水平和冠心病人群的復(fù)發(fā)死亡事件正相關(guān),但Hcy在缺血性卒中預(yù)后發(fā)展中的影響尚不明確。近來,一些試驗(yàn)后再分析報(bào)道了B族維生素干預(yù)在某些人群中的獲益,動(dòng)物實(shí)驗(yàn)也觀察到了Hcy抑制劑所帶來的腦梗死灶體積縮小的病理變化,為更深入的研究奠定了基礎(chǔ)。目的：本研究旨在通過前瞻性登記研究和Meta分析相結(jié)合的方法,分析Hcy對缺血性卒中預(yù)后的影響和預(yù)測作用,降Hcy治療對腦血管疾病風(fēng)險(xiǎn)的影響,為腦血管疾病的防治措施提供科學(xué)證據(jù)。方法：本研究分為兩個(gè)部分。第一部分基于河南省腦卒中登記研究數(shù)據(jù)庫進(jìn)行,采用前瞻性觀察性隊(duì)列研究的方法,以數(shù)據(jù)庫中連續(xù)性納入的、符合研究標(biāo)準(zhǔn)的急性缺血性腦卒中患者為研究人群,收集人口社會(huì)學(xué)特征、危險(xiǎn)因素、臨床特征及神經(jīng)功能評(píng)分、實(shí)驗(yàn)室指標(biāo),并對腦卒中患者結(jié)局進(jìn)行前瞻性隨訪,結(jié)局包括全因死亡、神經(jīng)功能預(yù)后和腦卒中復(fù)發(fā)。運(yùn)用多因素logistic回歸分別分析Hcy與急性期神經(jīng)功能缺損、功能預(yù)后、卒中復(fù)發(fā)和全因死亡的關(guān)系。以受試者工作特性(ROC)曲線分析Hcy預(yù)測嚴(yán)重神經(jīng)功能缺損和不良預(yù)后的最佳切入點(diǎn)。第二部分采用Meta分析的研究方法,通過檢索PubMed數(shù)據(jù)庫,Embase數(shù)據(jù)庫,Cochrane協(xié)作網(wǎng)圖書館、中國生物醫(yī)學(xué)數(shù)據(jù)庫(CBM)、相關(guān)期刊論文(CNKI)、中文科技期刊數(shù)據(jù)庫(VIP)、萬方數(shù)據(jù)庫,收集相關(guān)文獻(xiàn)并進(jìn)行篩選,由兩名研究員獨(dú)立重復(fù)進(jìn)行數(shù)據(jù)的提取并運(yùn)用Revman52軟件進(jìn)行分析,采用卡方檢驗(yàn)(χ2 test, Chi square test)進(jìn)行各試驗(yàn)間的異質(zhì)性檢驗(yàn),據(jù)此選擇固定效應(yīng)或隨機(jī)效應(yīng)的統(tǒng)計(jì)學(xué)處理模型合并分析數(shù)據(jù),計(jì)算RR值(risk ratio)以及95%可信區(qū)間(confidence interval,CI),觀察試驗(yàn)組人群和對照組人群終點(diǎn)事件的差別。引入基于人群基線特點(diǎn)和試驗(yàn)干預(yù)特點(diǎn)的分層分析,分別對不同亞組的納入試驗(yàn)進(jìn)行數(shù)據(jù)合并分析,觀察試驗(yàn)組人群和對照組人群終點(diǎn)事件的差別。試驗(yàn)結(jié)果均進(jìn)行敏感性分析和發(fā)表性偏倚評(píng)定。結(jié)果：第一部分本部分研究共納入1460例急性缺血性腦卒中患者,男性991例(67.9%),女性469例(32.1%),人群年齡61(51-69)歲。按Hcy四分位值將研究人群分組,觀察到隨Hcy水平升高,年齡(P=0.022)、男性(P=0.000)、合并高血脂(P=0.000)、吸煙(P=0.001)、飲酒(P=0.016)比例明顯升高,合并糖尿病(P=0.014)比例降低。以美國國立衛(wèi)生院卒中量表評(píng)分(NIHSS)進(jìn)行急性期神經(jīng)功能缺損評(píng)定。設(shè)NIHSS≥16分為嚴(yán)重神經(jīng)功能缺損,觀察到嚴(yán)重神經(jīng)功能缺損組人群年齡(P=0.020)、Hcy (P=0.009)、合并糖尿病(P=0.017)、房顫(P=0.000)比例明顯升高,吸煙(P=0.007)比例下降,將單因素分析中P0.1的變量作為自變量引二項(xiàng)多因素Logistic回歸分析,觀察到Hcy ( OR1.02;95%CI1.01-1.04)、合并糖尿病(OR 1.75；95%CI 1.14-2.69)、房顫(OR 5.30；95%CI2.68-10.50)是急性期嚴(yán)重神經(jīng)功能缺損的獨(dú)立危險(xiǎn)因素；而吸煙(OR0.55；95%CI0.34-0.87)減少急性期嚴(yán)重神經(jīng)功能缺損的風(fēng)險(xiǎn)。1342例納入對象(91.9%)完成12月隨訪,以改良的Rankin評(píng)分(mRS)為標(biāo)準(zhǔn)進(jìn)行人群3月、6月、12月神經(jīng)功能預(yù)后評(píng)定,設(shè)mRS≥3分為預(yù)后不良,觀察到預(yù)后不良組人群年齡、Hcy、合并糖尿病、房顫、腦卒中史比例明顯升高,男性、吸煙人群比例下降,將單因素分析中P0.1的變量作為自變量引二項(xiàng)多因素Logistic回歸分析,觀察到預(yù)后不良的獨(dú)立危險(xiǎn)因素為年齡、Hcy、合并糖尿病、腦卒中史,男性則減少其風(fēng)險(xiǎn)。按終點(diǎn)事件分組,觀察到卒中復(fù)發(fā)組人群年齡(P=0.042)、既往腦卒中史(P=0.000)、飲酒史(P=0.001)比例明顯升高,死亡組人群年齡(P=0.000)、合并糖尿病(P=0.024)、冠心病(P=0.001)、既往腦卒中史(P=0.005)比例明顯升高,男性(P=0.041)比例下降。將單因素分析中P0.1的變量作為自變量引入,分別進(jìn)行二項(xiàng)Logistic回歸分析,觀察到飲酒(OR2.02；95%CI 1.31-3.12)、既往腦卒中史(OR2.14；95%CI 1.47-3.25)是卒中復(fù)發(fā)的危險(xiǎn)因素,年齡(OR1.05;95%CI 1.03-1.07)、冠心病(OR 1.98；95%CI 1.08-3.64)是全因死亡的正相關(guān)危險(xiǎn)因素。運(yùn)用受試者工作特征曲線(Receiver Operating Characteristic, ROC)曲線分析Hcy預(yù)測急性期嚴(yán)重神經(jīng)功能缺損最佳切入點(diǎn)為17.64umol/L,3月預(yù)后不良為17.28umol/L,6月預(yù)后不良為17.28umol/L,12月預(yù)后不良為14.78umol/L。第二部分本部分研究共納入20個(gè)隨機(jī)對照試驗(yàn)和2個(gè)亞試驗(yàn),包含52494名研究對象,觀察到補(bǔ)充B族維生素人群同型半胱氨酸水平的下降(1.3-10.4μmol/L),補(bǔ)充B族維生素組腦卒中事件下降(RR 0.92,95%CI,0.85-1.00；P=0.04),而心肌梗死(RRl.00,95%CI0.94-1.06)、短暫性腦缺血發(fā)作(RR 0.94,95%CI 0.72-1.22)、全因死亡(RR 1.01,95%CI0.97-1.05)和血管源性死亡(RR 1.02,95%CI0.94-1.10)事件無明顯改變。亞組分析顯示,試驗(yàn)組缺血性或出血性腦卒中事件無明顯改變(RR 0.98,95%CI 0.90-1.06；RR 0.76,95%CI0.56-1.03)；在腦卒中一級(jí)預(yù)防(RR 0.84,95%CI0.72-0.97),血同型半胱氨酸水平下降達(dá)3umol/L以上(RR 0.92,95%CI0.84-1.01),隨訪期限3年以上(RR 0.91,95%CI0.84-0.99),無谷物葉酸強(qiáng)化背景(RR 0.91,95%CI0.83-1.00)或慢性腎病(RR 0.93,95%CI0.85-1.00)等亞組中觀察到腦卒中事件的明確下降或下降趨勢。在收縮壓超過130m Hg(RR 0.86,95%CI 0.76-0.97)和低血小板使用率(RR 0.84,95%CI0.70-1.00)的亞組中也觀察到了B族維生素補(bǔ)充后人群腦卒中事件有意義的減少。亞組分析還顯示接受聯(lián)合補(bǔ)充B族維生素和中等基線血B12水平的人群腦卒中風(fēng)險(xiǎn)存在下降趨勢(RR 0.93,95%CI0.86-1.01；RR 0.90,95%CI0.80-1.01),而接受單獨(dú)葉酸補(bǔ)充(RR 0.57,95%CI0.28-1.14)和低或過高基線血B12水平的人群未顯示腦卒中事件的下降,不同的維生素B12干預(yù)劑量也未帶來人群腦卒中事件的差別。結(jié)論：1.河南省缺血性腦卒中人群中,同型半胱氨酸水平在高齡、男性、吸煙、飲酒人群中明顯升高。2.血同型半胱氨酸水平升高是缺血性卒中急性期神經(jīng)功能嚴(yán)重缺損、預(yù)后不良的獨(dú)立危險(xiǎn)因素。推測同型半胱氨酸通過其炎性作用機(jī)制影響缺血性卒中的神經(jīng)功能缺損和預(yù)后。由于卒中發(fā)病機(jī)制的多樣化,關(guān)于同型半胱氨酸對卒中復(fù)發(fā)、死亡事件的影響尚需進(jìn)一步探討。3.補(bǔ)充B族維生素降血同型半胱氨酸水平可以獲得人群腦卒中風(fēng)險(xiǎn)的下降。4.補(bǔ)充B族維生素在無葉酸強(qiáng)化背景、代謝性B族維生素缺乏、基礎(chǔ)腎病,合并高血壓和低抗血小藥物使用率,隨訪周期長、接受聯(lián)合B族維生素干預(yù)、同型半胱氨酸水平下降幅度大的人群中獲益明顯,腦卒中風(fēng)險(xiǎn)下降突出。
[Abstract]:Background: homocysteine (Hcy) is considered to be a potential risk factor for cardiovascular and cerebrovascular disease, promoting the formation of prethrombotic and pre atherosclerotic states in a variety of ways. The study found that supplementation of B vitamins can reduce the level of Hcy in blood, but this measure reduces the positive results of the risk of cardiovascular and cerebrovascular diseases, The effect of Hcy on the recurrence of cardiovascular and cerebrovascular diseases is also concerned. The elevated Hcy level is positively related to the recurrent death events in the coronary heart disease population, but the effect of Hcy on the prognosis of ischemic stroke is not clear. The pathological changes in the volume reduction of cerebral infarction caused by Hcy inhibitors have also been observed. Objective: the purpose of this study was to analyze the effect and pretest of Hcy on the prognosis of ischemic stroke by combining prospective registration and Meta analysis, and reduce the risk of Hcy for cerebrovascular disease. This study provides scientific evidence for the prevention and treatment of cerebrovascular diseases. Methods: This study is divided into two parts. The first part is based on the database of stroke registration in Henan province. The method of prospective observational cohort study is based on the continuity of the database and the research standards of acute ischemic stroke patients. We collected demographic characteristics, risk factors, clinical features, neurological function scores, laboratory indicators, and prospectively followed up the outcome of stroke patients, including all causes of death, neurological prognosis and stroke recurrence. Multiple factor Logistic regression was used to analyze Hcy and acute neurological deficits and functional prognosis, respectively. The relationship between stroke recurrence and total cause of death. The best entry point for predicting severe neurological deficit and poor prognosis by Hcy is analyzed with the subjects' ROC curve. The second part adopts the method of Meta analysis, through the retrieval of the PubMed database, the Embase database, the Cochrane collaboration network library, and the Chinese biomedical database (CBM). The national journal full text database (CNKI), the Chinese sci-tech journal database (VIP), the Wanfang database, collected the related literature and screened. The data were extracted by two researchers independently and analyzed by Revman52 software. The chi square test (chi 2 test, Chi square test) was used to test the heterogeneity of each test. The statistical processing model of fixed effect or random effect combined with analysis data, calculated RR value (risk ratio) and 95% confidence interval (confidence interval, CI), observed the difference between the end events of the experimental group and the control group. The results were both sensitivity analysis and publication bias assessment. Results: the first part of the study included 1460 cases of acute ischemic stroke, 991 males (67.9%), 469 females (32.1%) and 61 (51-69) years old. According to the Hcy four division value, the study group was grouped and observed with the increase of Hcy level, age (P=0.022), male (P=0.000), hyperlipidemia (P=0.000), smoking (P=0.001), drinking (P=0.016), and diabetes (P=0.014) in the proportion of diabetes (P=0.014). The assessment of acute nerve function defect was evaluated by the National Health Institute Stroke Scale score (NIHSS). Set NIHSS > 16 as serious nerve function defect, and observed the age (P=0.020) of severe nerve function defect group (P=0.020), Hcy (P=0.009), diabetes (P=0.017), atrial fibrillation (P=0.000), the proportion of smoking (P=0.007) decreased, and the variable of P0.1 in the single factor analysis was used as the independent variable to analyze the multiple regression analysis of multiple factors. Hcy (OR1.02; 95%CI1.01-1.04), combined diabetes (OR 1.75; 95%CI 1.14-2.69), atrial fibrillation (OR 5.30; 95%CI2.68-10.50) were independent risk factors for severe neurological deficits, and smoking (OR0.55; 95%CI0.34-0.87) reduced the risk of severe neurological deficits in the acute phase (91.9%) followed up in December. A modified Rankin score (mRS) was used to evaluate the prognosis of the population in March, June, and December. The prognosis of the prognosis was mRS > 3. The age of the group with poor prognosis, Hcy, diabetes, atrial fibrillation, stroke history were significantly increased, and the proportion of men, smoking group decreased, and the variable of P0.1 in the single factor analysis was cited as the independent variable. Two multiple factor Logistic regression analysis showed that the independent risk factors for poor prognosis were age, Hcy, diabetes, stroke history, and men's risk. The age of stroke recurrence group (P=0.042), previous stroke history (P= 0), drinking history (P=0.001) increased significantly, and the death group year was in the year of death. Age (P=0.000), diabetes (P=0.024), coronary heart disease (P=0.001), previous stroke history (P=0.005) ratio was significantly increased, the proportion of male (P=0.041) decreased. The variables of P0.1 in single factor analysis were introduced as independent variables, and two Logistic regression analysis were carried out to observe alcohol (OR2.02; 95%CI 1.31-3.12), previous stroke history (OR2.14; 95%). CI 1.47-3.25) is a risk factor for stroke recurrence, age (OR1.05; 95%CI 1.03-1.07), coronary heart disease (OR 1.98; 95%CI 1.08-3.64) is a positive correlation risk factor for all causes of death. The best breakthrough point for predicting severe neurological impairment in acute stage is 17. by using the subject working characteristic curve (Receiver Operating Characteristic, ROC) curve. 64umol/L, the poor prognosis was 17.28umol/L in March, poor prognosis in June was 17.28umol/L, and the poor prognosis in December was 14.78umol/L. second part of this part of the study, which included 20 randomized controlled trials and 2 subtrials, including 52494 subjects, and observed the decrease of homocysteine levels in the B vitamin population (1.3-10.4 mu mol/L), supplemented with B Cerebral apoplexy of vitamin group decreased (RR 0.92,95%CI, 0.85-1.00; P=0.04), myocardial infarction (RRl.00,95%CI0.94-1.06), transient ischemic attack (RR 0.94,95%CI 0.72-1.22), all causes of death (RR 1.01,95%CI0.97-1.05) and vascular death (RR 1.02,95%) events did not change significantly. Subgroup analysis showed that the experimental group was ischemic. There was no significant change in the event of sexual or hemorrhagic stroke (RR 0.98,95%CI 0.90-1.06; RR 0.76,95%CI0.56-1.03); the level of blood homocysteine decreased more than 3umol/L (RR 0.92,95%CI0.84-1.01) in the first-order prevention of stroke (RR 0.84,95%CI0.72-0.97), and the duration of follow-up was more than 3 years (RR 0.91,95%CI0.84-0.99). 0.91,95%CI0.83-1.00) or chronic renal disease (RR 0.93,95%CI0.85-1.00) and other subgroups observed a clear decline or decline in stroke events. In subgroups of systolic pressure exceeding 130m Hg (RR 0.86,95%CI 0.76-0.97) and low platelet use rate (RR 0.84,95%CI0.70-1.00), B vitamin supplementation was also observed in a group of stroke events. Subgroup analysis also showed a decline in stroke risk in people receiving combined supplemental B vitamins and moderate baseline blood B12 levels (RR 0.93,95%CI0.86-1.01; RR 0.90,95%CI0.80-1.01), while individuals receiving individual folic acid supplementation (RR 0.57,95%CI0.28-1.14) and low or high baseline blood B12 levels did not show stroke. The decrease of events and different doses of vitamin B12 intervention did not bring difference in stroke events in the crowd. Conclusion: 1. of the ischemic stroke population in Henan Province, homocysteine levels are at the age of age, male, smoking, and drinking people obviously increase the level of.2. blood homocysteine, which is a severe neurological deficit in the acute stage of ischemic stroke. The effect of homocysteine on the neural function defect and prognosis of ischemic stroke is affected by the mechanism of homocysteine. The effect of homocysteine on stroke recurrence and death is still necessary to explore the.3. supplementation of B vitamins in the same type. Cystine levels can lead to a decrease in the risk of stroke in the population.4. supplemented by B vitamins in the absence of folate enhanced background, metabolic B vitamin deficiency, basic kidney disease, hypertension and low anti blood drug use, long follow-up period, combined with B vitamin intervention, and the benefit of a large decrease in homocysteine levels Obviously, the risk of stroke is down.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R743
，

本文編號(hào)：1922876