冠心病发病机制的代谢组学初步探索及优化冠心病介入治疗的临床研究
发布时间：2018-08-28 12:30
【摘要】：基于UHPLC-QTOF/MS的冠心病非靶向代谢组学分析及代谢标志物的探索目的:不同人群受到不同遗传因素和环境危险因素相互作用后将最终影响共同的生物代谢过程,因此通过代谢组学手段从小分子代谢物水平的变化研究冠心病动脉粥样硬化的病理形成机制已成为新的研究方向。本研究旨在通过非靶向代谢组学方法探索中国冠心病患者群体的血浆小分子代谢特点及其与疾病发生发展的关系。方法:经过严格的冠脉造影资料审查,从中国医学科学院国家心血管病中心阜外心血管病医院的795位通过筛选的患者中抽取300位患者建立了一个独立的代谢组学研究队列:150人严重冠脉狭窄的冠心病患者组(severe coronary heart disease,sCHD)和年龄与性别1:1匹配的150人冠脉造影正常对照组(angiographically normal controls,ANC)。我们将冠状动脉造影显示至少一支主支冠状动脉管腔直径缩窄≥80%定义为sCHD组,将经冠脉造影确认冠状动脉管腔直径缩窄≤ 20%定义为ANC组。抽取患者的静脉血分离血浆,运用超高效液相色谱-飞行时间质谱联用(UHPLC-QTOF/MS)的代谢组学检测方法,从阳离子相和阴离子相两种电离模式进行了血浆代谢组学分析。将筛选出的具有明确二级质谱定性信息的小分子代谢物分别加入多元线性回归模型(P0.05),分析校正传统冠心病危险因素(年龄、性别、体重指数、糖尿病、高血压、高脂血症、冠心病家族史、吸烟史)和检测批次等因素。为了防止n次检验可能带来的Ⅰ类错误,又进行了 Bonferroni correction校正(P8.2×10-5(0.05/611)),并使用logistic回归模型分析了这些小分子代谢物与冠心病患病风险关联的方向和程度。结果:除年龄和性别进行了匹配,冠心病传统危险因素在严重冠脉狭窄的冠心病患者组皆显著高于冠脉造影正常对照组。300个血浆样本上机检测后我们一共获得611个(466个阳离子模式、145个阴离子模式)具有明确定性半定量信息的有效峰,多元线性回归分析(P0.05)校正传统冠心病危险因素和检测批次后我们一共筛选出105个差异代谢物(其中21个实为未知代谢物)在两组间血浆水平具有显著性差异:主要包含51种磷脂、10种肉毒碱、8种游离脂肪酸类、5种胆汁酸代谢中间产物、3种氨基酸和7种未统一分类代谢物(吲哚、己酮酸、4-吡哆酸、水杨尿酸、咖啡因、睾酮、对甲氧基苯乙酸)。经 Bonferroni correction 校正(P8.2×10-5(0.05/611))从 105种差异代谢物中筛选出了 6种组间差异最为显著的血浆代谢物(吡哆酸、棕榈酸、亚油酸、脂酰肉毒碱(14:1)、石胆酸、磷脂酰甘油(20:3/2:0)),且这些代谢物皆表现出与冠心病患病风险显著的正相关(oddsratio,OR值范围2.79-7.24)。结论:本研究借助非靶向代谢组学方法获得了中国冠心病患者群体的代谢指纹图谱,并首次报道了吡哆酸、石胆酸和磷脂酰甘油(20:3/2:0)这三种与冠心病病理生理过程有强关联的潜在生物标志物,为从整体水平探索冠心病动脉粥样硬化发病机制及寻求新的治疗途径提供了依据。吡哆酸对血管内皮细胞增殖及单核巨噬细胞炎症反应的影响目的:我们前期的研究通过血浆代谢组学检测发掘了一种在严重冠脉狭窄的冠心病患者组和冠脉造影正常对照组之间存在显著性差异的小分子代谢物吡哆酸，并且发现血浆吡哆酸每增加1%冠心病患病风险就增加4.879倍。为了进一步探讨吡哆酸在动脉粥样硬化形成进展过程中的作用，我们在细胞水平初步探索了吡哆酸可能对两种冠状动脉粥样硬化病理形成紧密相关的细胞(人脐静脉内皮细胞(HUVEC)，人单核细胞系(THP-1))产生的影响。方法:我们先后使用不同刺激浓度(20 nmol/L、50 nmol/L、100 nmol/L、200 nmol/L、500 nmol/L、1000 nmol/L、2000 nmol/L)的吡哆酸溶液刺激体外培养的人脐静脉内皮细胞(HUVEC)、人单核细胞系(THP-1)，于不同刺激时点(12h24h48h和72h)通过细胞活力检测分析吡哆酸对人脐静脉内皮细胞产生的增殖影响，于吡哆酸刺激 48h 时通过实时荧光定量 PCR(Real-time quantitative Polymerase Chain ReactionqRT-PCR)的方法检测白介素1β(IL-1β)、肿瘤坏死因子(TNF-α)和细胞粘附因子(ICAM)的表达变化以评估炎症反应变化。结果:研究发现给予吡哆酸刺激48小时，人脐静脉内皮细胞增殖活力开始发生了显著下降且随着吡哆酸浓度增加而逐渐降低2000nmol/L浓度刺激时最低可下降10.7%。给予吡哆酸刺激72小时，人脐静脉内皮细胞增殖活力从刺激浓度20nmol/L起即表现出增殖活力显著下降，随着吡哆酸浓度增加而逐渐降低，1000nmol/L浓度刺激时最低可下降10.56%。低浓度的吡哆酸刺激没有诱发单核细胞的炎症反应，而当吡哆酸浓度为1000nmol/L和2000nmol/L时，THP-1细胞IL-1β、TNF-α和ICAM表达显著高于空白对照组细胞，，IL-1β表达量最高升高到1.22倍、TNF-α的表达量最高升高到1.4倍、ICAM的表达量最高升高到1.74倍。结论:吡哆酸能够诱导人脐静脉内皮细胞出现增殖抑制、人单核细胞系炎症因子(IL-1β、TNF-α、ICAM)表达上调，因此推测血浆吡哆酸水平升高与动脉粥样硬化的形成、发展相关。混合置入药物洗脱支架和金属裸支架治疗多处病变冠心病患者的远期疗效和安全性评价目的:药物洗脱支架(DES)有效降低了金属支架置入后的再狭窄发生率及靶血管或靶病变的血运重建率,但其涂层药物能够导致靶血管内皮修复延迟以及致死性支架内血栓形成风险升高,引起了学界对DES使用安全性的关注与探讨。因此针对冠状动脉多处病变患者,术者们开始尝试药物洗脱支架和金属裸支架混合置入(Hybrid支架)的介入治疗策略,以期通过适度减少药物支架置入数量来提高PCI治疗安全性并获得最佳的临床效果。本研究旨在评估混合置入药物洗脱支架(Hybrid支架)和金属裸支架治疗多处病变冠心病患者的远期疗效和安全性。方法:本研究入选了 2004年4月至2006年10月期间,在我院行择期经皮冠状动脉介入治疗(PCI)的冠状动脉多处病变患者共计6495例,并根据支架置入种类分为药物洗脱支架和金属裸支架混合置入组(Hybrid组,848例)和单纯药物洗脱支架置入组(5647例)。按1:1的比例进行倾向性评分匹配后,共823对患者最终纳入研究。临床随访资料包括术后30天、1年和2年的死亡、心肌梗死、靶病变血运重建、靶血管血运重建、主要心脏不良事件和支架内血栓形成。研究对比分析了两组术后2年内的各种临床事件的累积发生率差异,并通过Cox比例风险模型对临床事件风险进行了评估。结果:经过倾向性评分匹配后COX比例风险模型分析显示术后2年Hybrid支架治疗组靶病变血运重建(风险比2.38,95%可信区间1.50-3.70)、靶血管血运重建(风险比1.61,95%可信区间1.15-2.27)以及主要心脏不良事件(风险比1.37,95%可信区间1.02-1.85)的风险显著高于单纯DES支架治疗组,两组间全因死亡、心肌梗死和全因死亡/心肌梗死差异无统计学意义。术后2年Hybrid支架治疗组累积晚期血栓发生率显著低于单纯DES支架治疗组(P=0.0112),而2年累积支架内其他血栓形成事件:肯定的血栓、肯定+可能血栓、早期血栓及极晚期血栓发生率无明显差异。结论:对于冠状动脉多处病变需置入多支架的患者而言,单纯药物洗脱支架置入的远期有效性明显优于混合置入药物洗脱支架和金属裸支架,两种支架置入策略安全性相当。冠状动脉介入治疗后围术期心肌梗死风险模型及评分系统研究目的:既往国内外关于经皮冠状动脉介入治疗(PCI)后围术期心肌梗死的发生风险并无系统、全面的研究,本研究旨在针对美国心血管介入学会(SCAI)制定的PMI定义,系统的筛选出围术期心肌梗死的独立危险因素,并建立PMI风险模型及评分系统,用于全面评估多个危险因素共同作用下围术期心肌梗死的风险。方法:本研究入选了 2013年1月至2013月12月间在中国医学科学院阜外医院成功行择期PCI治疗并具备围术期心脏损伤标志物监测资料的患者共3371例(3516次PCI治疗)。根据患者术后是否发生SCAI所定义的围术期心肌梗死(PMI),分为围术期心肌梗死组和无围术期心肌梗死组。筛选可能影响围术期心肌梗死的危险因素:患者临床基线资料、心肌损伤标志物等生化指标、冠状动脉造影特点、介入操作特点等,纳入Logistic多元回归分析识别出围术期心肌梗死的独立危险因子并建立围术期心肌梗死风险模型。根据各个危险因素对围术期心肌梗死的危险度分配相应的分数,形成PMI风险评分系统。通过Bootstrap方法从入选患者中内部验证评分系统(样本量n=3516,再抽样次数B=1000),进一步验证风险模型和评分系统的预测能力和有效性。结果:在所有成功实施经皮冠状动脉介入治疗的3371例患者患者中,有107例患者(3.1%)对应108次PCI治疗发生了围术期心肌梗死。通过多因素Logistic回归分析发现,影响围术期心肌梗死的独立危险因素有:年龄(比值比(OR)为1.037,95%置信区间(CI):1.016-1.058;P0.01)、多支血管治疗(OR 为 1.697,95%CI:1.095-2.629;P=0.02)、至少一处分叉病变治疗(OR 为 1.869,95%CI:1.213-2.878;P0.01)、靶病变总长度(OR为1.016,95%CI:1.009-1.024;P0.01)。由此建立的PMI评分系统 ROC 曲线下面积为 0.71(95%CI:0.66-0.76),H-L p=0.5;经 Bootstrap 方法内部验证得到PMI风险评分系统平均ROC曲线下面积为0.707,中位ROC曲线下面积为0.708;根据PMI评分的四分位数,将前三个四分位Q1-Q3合并定义为非PMI高危组(对应风险评分10分)而第四四分位Q4定义为为PMI高危组(对应风险评分≥10分),围术期心肌梗死风险在PMI高危组显著高于非PMI高危组(P0.01)。结论:本研究全面系统的筛选出了影响围术期心肌梗死的独立危险因素:年龄、靶病变总长度、多支血管治疗、至少一处分叉病变治疗,并建立了简便易用的PCI后围术期心肌梗死风险评分,准确划分出围术期心肌梗死的高风险患者,为临床决策提供客观依据。
[Abstract]:Untargeted metabolomic analysis and exploration of metabolic markers for coronary heart disease based on UHPLC-QTOF/MS Objective: Different populations will eventually affect the common metabolic processes after interaction between different genetic and environmental risk factors, so the changes of small molecular metabolites in coronary heart disease atherosclerosis will be studied by metabonomics. The aim of this study was to explore the characteristics of plasma small molecule metabolism and its relationship with the occurrence and development of coronary heart disease in Chinese population by non-targeted metabonomics. An independent metabonomic cohort of 795 selected patients from the Cardiovascular Hospital outside Heart Fuwai was established: 150 patients with severe coronary heart disease (sCHD) and 150 age-and sex-matched normal coronary angiographic con. Trols, ANC. We defined coronary artery angiography showing at least one main coronary artery lumen narrowing (> 80%) as the sCHD group and coronary artery lumen narrowing (< 20%) as the ANC group. METABOLOGICAL DETECTION METABOLOGICAL METABOLISM METABOLOGICAL ANALYSIS OF PLASMA FROM IONIZATION MODELS OF CATIONIC AND ANIONIC PHASES. The selected small molecular metabolites with definite qualitative information of secondary mass spectrometry were added to the multiple linear regression model (P 0.05) to analyze and correct the traditional risk factors of coronary heart disease (age, sex, body mass index, diabetes mellitus). Bonferroni correction (P8.2 x 10-5 (0.05/611)) was used to prevent class I errors caused by n tests, and logistic regression model was used to analyze the direction and course of the association between these small molecular metabolites and coronary heart disease risk. Results: Except for age and sex matching, the traditional risk factors of coronary heart disease in patients with severe coronary stenosis were significantly higher than those in the normal control group. A total of 105 metabolites (21 of which were unknown metabolites) were screened out after adjusting for the risk factors and batches of traditional coronary heart disease (P 0.05). There were significant differences in plasma levels between the two groups: 51 phospholipids, 10 carnitines, 8 free fatty acids, and 5 bile acid metabolites. Products, 3 amino acids and 7 undifferentiated metabolites (indole, pentoxylic acid, 4-pyridoxic acid, salicyluric acid, caffeine, testosterone, p-methoxyphenylacetic acid). The plasma metabolites (pyridoxic acid, palmitic acid, subunit) with the most significant difference were screened from 105 different metabolites by Bonferroni correction. Oleic acid, lipoacyl carnitine (14:1), cholic acid, phosphatidylglycerol (20:3/2:0), and these metabolites all showed significant positive correlation with the risk of coronary heart disease (odds ratio, OR value range 2.79-7.24). Conclusion: The metabolic fingerprints of CHD patients in China were obtained by non-targeted metabonomics method, and piperidine was reported for the first time. These three potential biomarkers, namely, oxalic acid, cholic acid and phosphatidylglycerol (20:3/2:0), are strongly associated with the pathophysiological process of coronary heart disease. These biomarkers provide a basis for exploring the pathogenesis of coronary atherosclerosis at the overall level and for seeking new therapeutic approaches. Pyridoxic acid has effects on vascular endothelial cell proliferation and inflammation of mononuclear macrophages. Impact Objectives: Our previous study identified a small molecule metabolite pyridoxine with significant differences between patients with severe coronary artery stenosis and normal controls on coronary angiography, and found that the risk of coronary heart disease increased by 4.879 times for each 1% increase in plasma pyridoxine. To investigate the role of pyridoxine in the development of atherosclerosis, we initially explored the effect of pyridoxine on two types of cells (human umbilical vein endothelial cells (HUVEC) and human monocyte line (THP-1) closely related to the pathological formation of coronary atherosclerosis at the cellular level. Human umbilical vein endothelial cells (HUVEC) and human monocyte lines (THP-1) were stimulated by pyridoxic acid at concentrations (20 nmol/L, 50 nmol/L, 100 nmol/L, 200 nmol/L, 500 nmol/L, 1000 nmol/L, 2000 nmol/L) in vitro. The proliferation of human umbilical vein endothelial cells (HUVEC) and human monocyte lines (THP-1) at different stimulation points (12 h, 24 h, 48 h and 72 h) was analyzed by cell viability assay. Reproductive effects were assessed by real-time quantitative polymerase chain reaction (Real-time quantitative polymerase Chain ReactionqRT-PCR) with the expression of interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and cell adhesion factor (ICAM) at 48 h after pyridoxine stimulation. The proliferative activity of human umbilical vein endothelial cells (HUVECs) began to decrease markedly and decreased by 10.7% when the concentration of pyridoxine increased, and decreased by 2 000 nmol/L. After 72 hours of stimulation with pyridoxine, the proliferative activity of HUVECs decreased markedly from 20 nmol/L to 20 nmol/L, and with pyridoxine, the proliferative activity of HUVECs decreased significantly. The expression of IL-1beta, TNF-alpha and ICAM in THP-1 cells was significantly higher than that in blank control cells, and the expression of IL-1beta and ICAM in THP-1 cells was up to 1.5% when the concentration of pyridoxine was 1000 nmol/L and 2000 nmol/L. Conclusion: Pyridoxic acid can induce the proliferation inhibition of human umbilical vein endothelial cells, and the expression of human monocyte inflammatory factors (IL-1 beta, TNF-a, ICAM) is up-regulated. Therefore, it is speculated that the increase of plasma pyridoxic acid level and the formation and development of atherosclerosis. Long-term efficacy and safety of drug-eluting stents and bare metal stents in the treatment of multiple coronary artery disease Objective: Drug-eluting stents (DES) can effectively reduce the incidence of restenosis after metal stent implantation and the revascularization rate of target vessel or target lesion, but their coated drugs can lead to target vessel endothelial repair. Delayed and increased risk of fatal stent thrombosis has attracted attention and discussion in academia on the safety of DES use. Therefore, for patients with multiple coronary artery lesions, surgeons have begun to try the intervention strategy of drug-eluting stent and metal bare stent implantation (Hybrid stent), with a view to reducing drug-eluting stent implantation appropriately. The aim of this study was to evaluate the long-term efficacy and safety of a combination of drug-eluting stents (Hybrid stents) and bare metal stents in the treatment of multiple lesions of coronary artery disease. A total of 6495 patients with multiple coronary artery lesions underwent coronary interventional therapy (PCI) were divided into drug-eluting stent and bare metal stent implantation groups (Hybrid group, 848 cases) and drug-eluting stent implantation group (5647 cases). Clinical follow-up data included 30-day, 1-year and 2-year mortality, myocardial infarction, revascularization of target lesions, revascularization of target vessels, major adverse cardiac events and stent thrombosis. The cumulative incidence of various clinical events during the 2-year follow-up period was compared between the two groups, and the clinical events were analyzed by Cox proportional hazard model. Results: The COX proportional hazard model after propensity score matching showed target revascularization (risk ratio 2.38,95% CI 1.50-3.70), target revascularization (risk ratio 1.61,95% CI 1.15-2.27) and major adverse cardiac events (risk ratio 1.37,95% Cocoa) in the Hybrid stent group 2 years after surgery. The risk of all-cause mortality, myocardial infarction, and all-cause mortality / myocardial infarction was not significantly different between the two groups. The cumulative incidence of late thrombosis in the Hybrid stent group was significantly lower than that in the DES stent group at 2 years after surgery (P = 0.0112), while other stent thrombosis was cumulative in 2 years. Events: There was no significant difference in the incidence of positive thrombosis, positive + possible thrombosis, early thrombosis and very late thrombosis. Conclusion: For patients with multiple coronary lesions requiring multi-stent implantation, the long-term efficacy of drug-eluting stent implantation alone was significantly better than that of drug-eluting stent and bare metal stent implantation. The risk model and scoring system for perioperative myocardial infarction after percutaneous coronary intervention (PCI) Objective: There was no systematic and comprehensive study on the risk of perioperative myocardial infarction after PCI at home and abroad. This study was aimed at PMI formulated by American Society of Cardiovascular Intervention (SCAI). Definition, systematic screening of independent risk factors for perioperative myocardial infarction, and establishment of a PMI risk model and scoring system for a comprehensive assessment of the risk of perioperative myocardial infarction under the combined effects of multiple risk factors. A total of 3 371 patients (3 516 PCIs) were treated and monitored for perioperative cardiac injury markers. The patients were divided into perioperative myocardial infarction group and non-perioperative myocardial infarction group according to the occurrence of perioperative myocardial infarction (PMI) defined by SCAI. The independent risk factors of perioperative myocardial infarction were identified by logistic multivariate regression analysis and the perioperative myocardial infarction risk model was established. The predictive power and effectiveness of the risk model and scoring system were further validated by the Bootstrap method (sample size n = 3516, sample number B = 1000). Results: Of the 3 371 patients who had successfully undergone percutaneous coronary intervention, 107 were enrolled. Perioperative myocardial infarction occurred in 108 PCI patients (3.1%). The independent risk factors for perioperative myocardial infarction were age (OR) 1.037,95% confidence interval (CI): 1.016-1.058; P 0.01), multi-vessel therapy (OR: 1.697,95% CI: 1.095-2.629; P = 0.02). Treatment of fork lesions (OR 1.869, 95% CI: 1.213-2.878; P 0.01), total length of target lesions (OR 1.016, 95% CI: 1.009-1.024; P 0.01). The area under the ROC curve of the PMI scoring system was 0.71 (95% CI: 0.66-0.76) and H-L P = 0.5. The average area under the ROC curve of the PMI risk scoring system was 0.707 and the median ROC curve was obtained by internal verification of Bootstrap method. According to the quartile of PMI score, the first three quartile Q1-Q3 was defined as non-PMI high-risk group (corresponding risk score 10 points), while the fourth quartile Q4 was defined as PMI high-risk group (corresponding risk score < 10 points), and the perioperative risk of myocardial infarction was significantly higher in PMI high-risk group than in non-PMI high-risk group (P 0.01). Independent risk factors affecting perioperative myocardial infarction were systematically screened: age, total length of target lesion, multi-vessel therapy, to
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R541.4
本文编号：2209406
[Abstract]:Untargeted metabolomic analysis and exploration of metabolic markers for coronary heart disease based on UHPLC-QTOF/MS Objective: Different populations will eventually affect the common metabolic processes after interaction between different genetic and environmental risk factors, so the changes of small molecular metabolites in coronary heart disease atherosclerosis will be studied by metabonomics. The aim of this study was to explore the characteristics of plasma small molecule metabolism and its relationship with the occurrence and development of coronary heart disease in Chinese population by non-targeted metabonomics. An independent metabonomic cohort of 795 selected patients from the Cardiovascular Hospital outside Heart Fuwai was established: 150 patients with severe coronary heart disease (sCHD) and 150 age-and sex-matched normal coronary angiographic con. Trols, ANC. We defined coronary artery angiography showing at least one main coronary artery lumen narrowing (> 80%) as the sCHD group and coronary artery lumen narrowing (< 20%) as the ANC group. METABOLOGICAL DETECTION METABOLOGICAL METABOLISM METABOLOGICAL ANALYSIS OF PLASMA FROM IONIZATION MODELS OF CATIONIC AND ANIONIC PHASES. The selected small molecular metabolites with definite qualitative information of secondary mass spectrometry were added to the multiple linear regression model (P 0.05) to analyze and correct the traditional risk factors of coronary heart disease (age, sex, body mass index, diabetes mellitus). Bonferroni correction (P8.2 x 10-5 (0.05/611)) was used to prevent class I errors caused by n tests, and logistic regression model was used to analyze the direction and course of the association between these small molecular metabolites and coronary heart disease risk. Results: Except for age and sex matching, the traditional risk factors of coronary heart disease in patients with severe coronary stenosis were significantly higher than those in the normal control group. A total of 105 metabolites (21 of which were unknown metabolites) were screened out after adjusting for the risk factors and batches of traditional coronary heart disease (P 0.05). There were significant differences in plasma levels between the two groups: 51 phospholipids, 10 carnitines, 8 free fatty acids, and 5 bile acid metabolites. Products, 3 amino acids and 7 undifferentiated metabolites (indole, pentoxylic acid, 4-pyridoxic acid, salicyluric acid, caffeine, testosterone, p-methoxyphenylacetic acid). The plasma metabolites (pyridoxic acid, palmitic acid, subunit) with the most significant difference were screened from 105 different metabolites by Bonferroni correction. Oleic acid, lipoacyl carnitine (14:1), cholic acid, phosphatidylglycerol (20:3/2:0), and these metabolites all showed significant positive correlation with the risk of coronary heart disease (odds ratio, OR value range 2.79-7.24). Conclusion: The metabolic fingerprints of CHD patients in China were obtained by non-targeted metabonomics method, and piperidine was reported for the first time. These three potential biomarkers, namely, oxalic acid, cholic acid and phosphatidylglycerol (20:3/2:0), are strongly associated with the pathophysiological process of coronary heart disease. These biomarkers provide a basis for exploring the pathogenesis of coronary atherosclerosis at the overall level and for seeking new therapeutic approaches. Pyridoxic acid has effects on vascular endothelial cell proliferation and inflammation of mononuclear macrophages. Impact Objectives: Our previous study identified a small molecule metabolite pyridoxine with significant differences between patients with severe coronary artery stenosis and normal controls on coronary angiography, and found that the risk of coronary heart disease increased by 4.879 times for each 1% increase in plasma pyridoxine. To investigate the role of pyridoxine in the development of atherosclerosis, we initially explored the effect of pyridoxine on two types of cells (human umbilical vein endothelial cells (HUVEC) and human monocyte line (THP-1) closely related to the pathological formation of coronary atherosclerosis at the cellular level. Human umbilical vein endothelial cells (HUVEC) and human monocyte lines (THP-1) were stimulated by pyridoxic acid at concentrations (20 nmol/L, 50 nmol/L, 100 nmol/L, 200 nmol/L, 500 nmol/L, 1000 nmol/L, 2000 nmol/L) in vitro. The proliferation of human umbilical vein endothelial cells (HUVEC) and human monocyte lines (THP-1) at different stimulation points (12 h, 24 h, 48 h and 72 h) was analyzed by cell viability assay. Reproductive effects were assessed by real-time quantitative polymerase chain reaction (Real-time quantitative polymerase Chain ReactionqRT-PCR) with the expression of interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and cell adhesion factor (ICAM) at 48 h after pyridoxine stimulation. The proliferative activity of human umbilical vein endothelial cells (HUVECs) began to decrease markedly and decreased by 10.7% when the concentration of pyridoxine increased, and decreased by 2 000 nmol/L. After 72 hours of stimulation with pyridoxine, the proliferative activity of HUVECs decreased markedly from 20 nmol/L to 20 nmol/L, and with pyridoxine, the proliferative activity of HUVECs decreased significantly. The expression of IL-1beta, TNF-alpha and ICAM in THP-1 cells was significantly higher than that in blank control cells, and the expression of IL-1beta and ICAM in THP-1 cells was up to 1.5% when the concentration of pyridoxine was 1000 nmol/L and 2000 nmol/L. Conclusion: Pyridoxic acid can induce the proliferation inhibition of human umbilical vein endothelial cells, and the expression of human monocyte inflammatory factors (IL-1 beta, TNF-a, ICAM) is up-regulated. Therefore, it is speculated that the increase of plasma pyridoxic acid level and the formation and development of atherosclerosis. Long-term efficacy and safety of drug-eluting stents and bare metal stents in the treatment of multiple coronary artery disease Objective: Drug-eluting stents (DES) can effectively reduce the incidence of restenosis after metal stent implantation and the revascularization rate of target vessel or target lesion, but their coated drugs can lead to target vessel endothelial repair. Delayed and increased risk of fatal stent thrombosis has attracted attention and discussion in academia on the safety of DES use. Therefore, for patients with multiple coronary artery lesions, surgeons have begun to try the intervention strategy of drug-eluting stent and metal bare stent implantation (Hybrid stent), with a view to reducing drug-eluting stent implantation appropriately. The aim of this study was to evaluate the long-term efficacy and safety of a combination of drug-eluting stents (Hybrid stents) and bare metal stents in the treatment of multiple lesions of coronary artery disease. A total of 6495 patients with multiple coronary artery lesions underwent coronary interventional therapy (PCI) were divided into drug-eluting stent and bare metal stent implantation groups (Hybrid group, 848 cases) and drug-eluting stent implantation group (5647 cases). Clinical follow-up data included 30-day, 1-year and 2-year mortality, myocardial infarction, revascularization of target lesions, revascularization of target vessels, major adverse cardiac events and stent thrombosis. The cumulative incidence of various clinical events during the 2-year follow-up period was compared between the two groups, and the clinical events were analyzed by Cox proportional hazard model. Results: The COX proportional hazard model after propensity score matching showed target revascularization (risk ratio 2.38,95% CI 1.50-3.70), target revascularization (risk ratio 1.61,95% CI 1.15-2.27) and major adverse cardiac events (risk ratio 1.37,95% Cocoa) in the Hybrid stent group 2 years after surgery. The risk of all-cause mortality, myocardial infarction, and all-cause mortality / myocardial infarction was not significantly different between the two groups. The cumulative incidence of late thrombosis in the Hybrid stent group was significantly lower than that in the DES stent group at 2 years after surgery (P = 0.0112), while other stent thrombosis was cumulative in 2 years. Events: There was no significant difference in the incidence of positive thrombosis, positive + possible thrombosis, early thrombosis and very late thrombosis. Conclusion: For patients with multiple coronary lesions requiring multi-stent implantation, the long-term efficacy of drug-eluting stent implantation alone was significantly better than that of drug-eluting stent and bare metal stent implantation. The risk model and scoring system for perioperative myocardial infarction after percutaneous coronary intervention (PCI) Objective: There was no systematic and comprehensive study on the risk of perioperative myocardial infarction after PCI at home and abroad. This study was aimed at PMI formulated by American Society of Cardiovascular Intervention (SCAI). Definition, systematic screening of independent risk factors for perioperative myocardial infarction, and establishment of a PMI risk model and scoring system for a comprehensive assessment of the risk of perioperative myocardial infarction under the combined effects of multiple risk factors. A total of 3 371 patients (3 516 PCIs) were treated and monitored for perioperative cardiac injury markers. The patients were divided into perioperative myocardial infarction group and non-perioperative myocardial infarction group according to the occurrence of perioperative myocardial infarction (PMI) defined by SCAI. The independent risk factors of perioperative myocardial infarction were identified by logistic multivariate regression analysis and the perioperative myocardial infarction risk model was established. The predictive power and effectiveness of the risk model and scoring system were further validated by the Bootstrap method (sample size n = 3516, sample number B = 1000). Results: Of the 3 371 patients who had successfully undergone percutaneous coronary intervention, 107 were enrolled. Perioperative myocardial infarction occurred in 108 PCI patients (3.1%). The independent risk factors for perioperative myocardial infarction were age (OR) 1.037,95% confidence interval (CI): 1.016-1.058; P 0.01), multi-vessel therapy (OR: 1.697,95% CI: 1.095-2.629; P = 0.02). Treatment of fork lesions (OR 1.869, 95% CI: 1.213-2.878; P 0.01), total length of target lesions (OR 1.016, 95% CI: 1.009-1.024; P 0.01). The area under the ROC curve of the PMI scoring system was 0.71 (95% CI: 0.66-0.76) and H-L P = 0.5. The average area under the ROC curve of the PMI risk scoring system was 0.707 and the median ROC curve was obtained by internal verification of Bootstrap method. According to the quartile of PMI score, the first three quartile Q1-Q3 was defined as non-PMI high-risk group (corresponding risk score 10 points), while the fourth quartile Q4 was defined as PMI high-risk group (corresponding risk score < 10 points), and the perioperative risk of myocardial infarction was significantly higher in PMI high-risk group than in non-PMI high-risk group (P 0.01). Independent risk factors affecting perioperative myocardial infarction were systematically screened: age, total length of target lesion, multi-vessel therapy, to
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R541.4
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本文编号：2209406
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