【作者】 刘瑜；

【导师】 董波；

【作者基本信息】 山东大学 ， 内科学（心血管）（专业学位）， 2023， 硕士

【摘要】 背景:冠心病是一种常见的心血管疾病,其发病率和死亡率在全球范围内居高不下。长期以来,人们普遍认为冠心病是由于动脉粥样硬化导致的血管狭窄和阻塞引起的,因此治疗重点一直放在了血管重建和血栓溶解上。然而,近年来越来越多的研究表明,慢性炎症在冠心病的发生和发展中也起着重要的作用。在冠心病中,慢性炎症主要表现为动脉粥样硬化斑块中的炎症细胞浸润、炎性因子的释放以及内皮细胞的损伤等。这些炎症反应导致了斑块的稳定性降低,易于破裂形成血栓,从而引起急性冠脉综合征等严重并发症。随着分子生物学和免疫学等领域的不断发展。研究人员发现,许多炎症介质如C-反应蛋白(CRP)、白细胞计数以及炎性因子等,与冠心病的发生和病情严重程度密切相关。总之,慢性炎症在冠心病中的研究进展逐渐引起了广泛的关注,对于深入了解冠心病的发病机制以及开发新的预防和治疗策略具有重要的意义。目的:慢性炎症在冠心病和糖尿病的发病机制中起关键作用。本研究主要探讨炎性相关指标中性粒细胞/淋巴细胞比值(Neutrophil-lymphocyte ratio,NLR)、中性粒细胞明胶酶相关脂质运载蛋白(Neutrophil gelatinase associated lipocalin,NGAL)与冠心病合并糖尿病疾病的关系,并更深一步探讨其与病情严重程度之间的关系,以及服用钠-葡萄糖连接转运体2抑制剂(Sodium dependent glucose transporters 2 inhibitors,SGLT2-i)和胰高血糖素样肽-1 激动剂(glucagon-like peptide-1 receptor agonist,GLP-1 Ra)药物对这两项指标的影响。方法:研究对象为2021年8月至2022年8月就诊于山东省立医院心血管内科、内分泌科及健康体检者。健康体检者作为对照组70例,诊断2型糖尿病而无冠心病者作为糖尿病组69例,诊断冠心病而无糖尿病者作为冠心病组136例,诊断冠心病合并糖尿病组281例,共556例。后将冠心病合并糖尿病组根据冠心病诊断、糖化血红蛋白四分位数及观察治疗期间有无应用SGLT2-i及GLP-1Ra药物治疗进行分组讨论,根据纳入及排除标准收集患者临床及实验室相关资料。应用SPSS 26.0对所收集资料进行统计分析,连续变量采用T检验、单因素方差分析和秩和检验,分类变量采用卡方检验。单因素及多因素分析采用Logistic回归,并绘制ROC曲线评估NGAL、NLR对冠心病合并糖尿病疾病的预测价值。均以P<0.05为差异具有统计学意义。结果:1.四组之间任意两组NLR水平差异比较均有明显差异(P<0.05),对照组水平较低,其次为糖尿病组、冠心病组,糖尿病合并冠心病组水平最高。对照组与糖尿病组NGAL水平无明显差异(P=0.37),但显著低于冠心病组与冠心病合并糖尿病组(P<0.05),且冠心病合并糖尿病组NGAL水平明显高于冠心病组(P<0.05)。2.将冠心病合并糖尿病组根据其冠脉造影评估记录与临床冠心病诊断分组中,三组之间任意两组NLR值比较均有统计学意义(P<0.01),稳定性心绞痛组水平较低,其次为不稳定性心绞痛组,心肌梗死组水平最高。不稳定性心绞痛组与心肌梗死组NGAL L比较时无明显差异(P=0.465),但两组NGAL水平均显著高于稳定性心绞痛组(P<0.01)。3.将NLR、NGAL作为冠心病合并2型糖尿病的预测指标分析,NLR、NGAL及其联合预测概率曲线作为诊断的ROC曲线下面积分别为0.820、0.797、0.891(P<0.01)。当NLR、NGAL及联合预测概率曲线最佳临界值分别取2.792、52.95、0.742 时,诊断敏感度、特异度分别为 0.491、0.698、0.822 和 0.986、0.771、0.8。4.将冠心病合并糖尿病组患者根据患者临床资料分为应用SGLT2-i组、GLP-1Ra组与基础治疗组,基础治疗组为平时应用胰岛素控制血糖者。观察期间SGLT2-i、GLP-1Ra组与基础治疗组NLR水平均显著降低(P<0.05),而SGLT2-i组、GLP-1Ra组降低水平更明显。基础治疗组NGAL水平变化不大,SGLT2-i组、GLP-1Ra组NGAL水平治疗前后差异具有统计学意义(P<0.05),但SGLT2-i组降低水平更显著。5.将冠心病合并糖尿病组根据HbA1c四分位数水平分为四组比较,结果显示NLR、NGAL在各组间比较均无明显差异(P>0.05)。6.多因素 Logistic 回归分析结果示,NGAL、NLR、HbA1c、NT-ProBNP 是冠心病合并2型糖尿病的重要危险因素。结论:NLR、NGAL作为炎症生物标志物可有效反映冠心病合并2型糖尿病患者冠心病严重程度,但并不能有效反映患者血糖控制水平。两项指标在单独或联合预测冠心病合并2型糖尿病方面均具有一定价值。NGAL、NLR、HbA1c、NT-ProBNP是疾病的重要危险因素。应用SGLT2-i及GLP-1Ra药物治疗能有效降低循环NLR、NGAL水平延缓疾病进展。更多还原

【Abstract】 Background:Coronary heart disease(CHD)is a common cardiovascular disease with a high morbidity and mortality rate worldwide.It has long been widely accepted that coronary heart disease is caused by the narrowing and blockage of blood vessels due to atherosclerosis,and therefore the focus of treatment has been on revascularisation and thrombolysis.However,in recent years,a growing number of studies have shown that chronic inflammation also plays an important role in the development and progression of coronary heart disease.In coronary artery disease,chronic inflammation is mainly manifested by inflammatory cell infiltration in the atherosclerotic plaque,release of inflammatory factors and damage to the endothelium.These inflammatory responses lead to reduced plaque stability and ease of rupture to form thrombi,leading to serious complications such as acute coronary syndromes.As the fields of molecular biology and immunology continue to develop.Researchers have found that many inflammatory mediators such as C-reactive protein(CRP),white blood cell counts,and inflammatory factors are strongly associated with the development and severity of coronary heart disease.In conclusion,advances in the study of chronic inflammation in coronary heart disease are gradually attracting widespread attention and are important for gaining insight into the pathogenesis of coronary heart disease as well as for developing new preventive and therapeutic strategies.Objective:Chronic inflammation plays a key role in the pathogenesis of coronary heart disease and diabetes mellitus.This study focuses on the relationship among neutrophil-lymphocyte ratio(NLR),neutrophil gelatinase-associated lipocalin(NGAL)and coronary heart disease combined with diabetes mellitus.In addition,the relationship between the use of sodium dependent glucose transporters 2 inhibitors(SGLT2-i)and glucagon-like peptide-1 agonists(GLP-1Ra)on these two indicators.Methods:The subjects were those who attended the Department of Cardiovascular Medicine、Endocrinology and health check-ups at Shandong Provincial Hospital from August 2021 to August 2022.The healthy check-up patients were used as the control group of 70 cases,those diagnosed with type 2 diabetes without coronary heart disease as the diabetic group of 69 cases,those diagnosed with coronary heart disease without diabetes as the coronary heart disease group of 136 cases,and those diagnosed with coronary heart disease combined with diabetes as the group of 281 cases,a total of 556 cases.The coronary heart disease combined with diabetes group was later divided into groups according to the diagnosis of coronary heart disease,glycated haemoglobin quartiles and the presence or absence of SGLT2-i and GLP-1Ra medication during the observation and treatment period,and clinical and laboratory related data were collected according to the inclusion and exclusion criteria.SPSS 26.0 was applied for statistical analysis of the collected data.T-test,one-way ANOVA and rank sum test were used for continuous variables,and chi-square test was used for categorical variables.Logistic regression was used for univariate and multifactorial analyses,and ROC curves were plotted to assess the predictive value of NGAL and NLR for coronary artery disease combined with diabetic disease.All differences were considered statistically significant at P<0.05.Results:1.There was a significant difference(P<0.05)in the difference in NLR levels between any two of the four groups,with lower levels in the control group,followed by the diabetic group,the coronary heart disease group and the highest levels in the diabetic combined with coronary heart disease group.There was no significant difference in NGAL levels between the control group and the diabetic group(P=0.37),but they were significantly lower than those in the coronary artery disease group and the coronary artery disease combined with diabetes group(P<0.05),and the NGAL levels in the coronary artery disease combined with diabetes group were significantly higher than those in the coronary artery disease group(P<0.05).2.In grouping the coronary artery disease combined with diabetes group according to their coronary angiographic assessment records with clinical coronary diagnosis,there was a statistically significant(P<0.01)comparison of NLR values between any two of the three groups,with lower levels in the stable angina group,followed by the unstable angina group,and the highest levels in the myocardial infarction group.There was no significant difference in NGAL when comparing the unstable angina group with the myocardial infarction group(P=0.465),but both groups had significantly higher levels of NGAL than the stable angina group(P<0.01).3.When NLR and NGAL are analysed as predictors of coronary artery disease combined with type 2 diabetes,the area under the ROC curve for NLR,NGAL and their combined predictive probability curve as a diagnosis is 0.820,0.797 and 0.891 respectively(P<0.01).The sensitivity and specificity of the diagnosis are 0.491,0.698,0.822 and 0.986,0.771,0.8 when the optimal critical values of NLR,NGAL and combined predictive probability curves are 2.792,52.95 and 0.742,respectively.4.Patients with coronary heart disease and diabetes are divided into SGLT2-i group,GLP-1Ra group and basal treatment group according to their clinical data.During the observation period,NLR levels in the SGLT2-i,GLP-1Ra and basal treatment groups are significantly reduced(p<0.05),while the reduction in the SGLT2i and GLP-1Ra groups is more significant.There is no significant change in NGAL levels in the basic treatment group,but the difference between NGAL levels in the SGLT2-i and GLP-1Ra groups before and after treatment is statistically significant(P<0.05),the reduction level in the SGLT2-i group is more significant.5.The coronary heart disease combined with diabetes group is divided into four groups according to HbAlc quartile levels for comparison,and the results show that there is no significant difference in NLR and NGAL between the groups for comparison(P>0.05).6.Multi-factor logistic regression analysis showed that NGAL,NLR,HbA1c and NT-ProBNP were significant risk factors for coronary artery disease combined with type 2 diabetes.Conclusion:NLR and NGAL as inflammatory biomarkers can effectively reflect the severity of coronary artery disease in patients with coronary artery disease combined with type 2 diabetes,but not the level of glycemic control in patients.NGAL,NLR,HbA1c and NT-ProBNP are important risk factors for the disease.The use of SGLT2-i and GLP-1Ra drug therapy can effectively reduce circulating levels of NLR and NGAL and delay disease progression.更多还原