同型半胱氨酸对脑血管病预后及发生风险的影响

发布时间：2018-05-22 16:52

  本文选题：同型半胱氨酸 + 脑卒中　； 参考：《郑州大学》2014年博士论文

【摘要】：背景：同型半胱氨酸(homocysteine,Hcy)被认为一种潜在的心脑血管疾病危险因素,通过多种途径促进机体血栓前和动脉粥样硬化前状态形成。研究发现补充B族维生素可以降低血中Hcy水平,但这一措施减少心脑血管疾病风险的肯定结果并未获得。而Hcy对心脑血管疾病预后复发的影响也备受关注,升高的Hcy水平和冠心病人群的复发死亡事件正相关,但Hcy在缺血性卒中预后发展中的影响尚不明确。近来,一些试验后再分析报道了B族维生素干预在某些人群中的获益,动物实验也观察到了Hcy抑制剂所带来的脑梗死灶体积缩小的病理变化,为更深入的研究奠定了基础。目的：本研究旨在通过前瞻性登记研究和Meta分析相结合的方法,分析Hcy对缺血性卒中预后的影响和预测作用,降Hcy治疗对脑血管疾病风险的影响,为脑血管疾病的防治措施提供科学证据。方法：本研究分为两个部分。第一部分基于河南省脑卒中登记研究数据库进行,采用前瞻性观察性队列研究的方法,以数据库中连续性纳入的、符合研究标准的急性缺血性脑卒中患者为研究人群,收集人口社会学特征、危险因素、临床特征及神经功能评分、实验室指标,并对脑卒中患者结局进行前瞻性随访,结局包括全因死亡、神经功能预后和脑卒中复发。运用多因素logistic回归分别分析Hcy与急性期神经功能缺损、功能预后、卒中复发和全因死亡的关系。以受试者工作特性(ROC)曲线分析Hcy预测严重神经功能缺损和不良预后的最佳切入点。第二部分采用Meta分析的研究方法,通过检索PubMed数据库,Embase数据库,Cochrane协作网图书馆、中国生物医学数据库(CBM)、相关期刊论文(CNKI)、中文科技期刊数据库(VIP)、万方数据库,收集相关文献并进行筛选,由两名研究员独立重复进行数据的提取并运用Revman52软件进行分析,采用卡方检验(χ2 test, Chi square test)进行各试验间的异质性检验,据此选择固定效应或随机效应的统计学处理模型合并分析数据,计算RR值(risk ratio)以及95%可信区间(confidence interval,CI),观察试验组人群和对照组人群终点事件的差别。引入基于人群基线特点和试验干预特点的分层分析,分别对不同亚组的纳入试验进行数据合并分析,观察试验组人群和对照组人群终点事件的差别。试验结果均进行敏感性分析和发表性偏倚评定。结果：第一部分本部分研究共纳入1460例急性缺血性脑卒中患者,男性991例(67.9%),女性469例(32.1%),人群年龄61(51-69)岁。按Hcy四分位值将研究人群分组,观察到随Hcy水平升高,年龄(P=0.022)、男性(P=0.000)、合并高血脂(P=0.000)、吸烟(P=0.001)、饮酒(P=0.016)比例明显升高,合并糖尿病(P=0.014)比例降低。以美国国立卫生院卒中量表评分(NIHSS)进行急性期神经功能缺损评定。设NIHSS≥16分为严重神经功能缺损,观察到严重神经功能缺损组人群年龄(P=0.020)、Hcy (P=0.009)、合并糖尿病(P=0.017)、房颤(P=0.000)比例明显升高,吸烟(P=0.007)比例下降,将单因素分析中P0.1的变量作为自变量引二项多因素Logistic回归分析,观察到Hcy ( OR1.02;95%CI1.01-1.04)、合并糖尿病(OR 1.75；95%CI 1.14-2.69)、房颤(OR 5.30；95%CI2.68-10.50)是急性期严重神经功能缺损的独立危险因素；而吸烟(OR0.55；95%CI0.34-0.87)减少急性期严重神经功能缺损的风险。1342例纳入对象(91.9%)完成12月随访,以改良的Rankin评分(mRS)为标准进行人群3月、6月、12月神经功能预后评定,设mRS≥3分为预后不良,观察到预后不良组人群年龄、Hcy、合并糖尿病、房颤、脑卒中史比例明显升高,男性、吸烟人群比例下降,将单因素分析中P0.1的变量作为自变量引二项多因素Logistic回归分析,观察到预后不良的独立危险因素为年龄、Hcy、合并糖尿病、脑卒中史,男性则减少其风险。按终点事件分组,观察到卒中复发组人群年龄(P=0.042)、既往脑卒中史(P=0.000)、饮酒史(P=0.001)比例明显升高,死亡组人群年龄(P=0.000)、合并糖尿病(P=0.024)、冠心病(P=0.001)、既往脑卒中史(P=0.005)比例明显升高,男性(P=0.041)比例下降。将单因素分析中P0.1的变量作为自变量引入,分别进行二项Logistic回归分析,观察到饮酒(OR2.02；95%CI 1.31-3.12)、既往脑卒中史(OR2.14；95%CI 1.47-3.25)是卒中复发的危险因素,年龄(OR1.05;95%CI 1.03-1.07)、冠心病(OR 1.98；95%CI 1.08-3.64)是全因死亡的正相关危险因素。运用受试者工作特征曲线(Receiver Operating Characteristic, ROC)曲线分析Hcy预测急性期严重神经功能缺损最佳切入点为17.64umol/L,3月预后不良为17.28umol/L,6月预后不良为17.28umol/L,12月预后不良为14.78umol/L。第二部分本部分研究共纳入20个随机对照试验和2个亚试验,包含52494名研究对象,观察到补充B族维生素人群同型半胱氨酸水平的下降(1.3-10.4μmol/L),补充B族维生素组脑卒中事件下降(RR 0.92,95%CI,0.85-1.00；P=0.04),而心肌梗死(RRl.00,95%CI0.94-1.06)、短暂性脑缺血发作(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)事件无明显改变。亚组分析显示,试验组缺血性或出血性脑卒中事件无明显改变(RR 0.98,95%CI 0.90-1.06；RR 0.76,95%CI0.56-1.03)；在脑卒中一级预防(RR 0.84,95%CI0.72-0.97),血同型半胱氨酸水平下降达3umol/L以上(RR 0.92,95%CI0.84-1.01),随访期限3年以上(RR 0.91,95%CI0.84-0.99),无谷物叶酸强化背景(RR 0.91,95%CI0.83-1.00)或慢性肾病(RR 0.93,95%CI0.85-1.00)等亚组中观察到脑卒中事件的明确下降或下降趋势。在收缩压超过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)的亚组中也观察到了B族维生素补充后人群脑卒中事件有意义的减少。亚组分析还显示接受联合补充B族维生素和中等基线血B12水平的人群脑卒中风险存在下降趋势(RR 0.93,95%CI0.86-1.01；RR 0.90,95%CI0.80-1.01),而接受单独叶酸补充(RR 0.57,95%CI0.28-1.14)和低或过高基线血B12水平的人群未显示脑卒中事件的下降,不同的维生素B12干预剂量也未带来人群脑卒中事件的差别。结论：1.河南省缺血性脑卒中人群中,同型半胱氨酸水平在高龄、男性、吸烟、饮酒人群中明显升高。2.血同型半胱氨酸水平升高是缺血性卒中急性期神经功能严重缺损、预后不良的独立危险因素。推测同型半胱氨酸通过其炎性作用机制影响缺血性卒中的神经功能缺损和预后。由于卒中发病机制的多样化,关于同型半胱氨酸对卒中复发、死亡事件的影响尚需进一步探讨。3.补充B族维生素降血同型半胱氨酸水平可以获得人群脑卒中风险的下降。4.补充B族维生素在无叶酸强化背景、代谢性B族维生素缺乏、基础肾病,合并高血压和低抗血小药物使用率,随访周期长、接受联合B族维生素干预、同型半胱氨酸水平下降幅度大的人群中获益明显,脑卒中风险下降突出。
[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.
【学位授予单位】：郑州大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R743
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