基于血液代谢组学分析缺血性心脏病患者疾病进程的代谢紊乱特征

Blood Metabolomics Reveals the Metabolic Disorder in Disease Progression for Patients with Ischemic Heart Disease

本研究以47例心绞痛患者、51例心肌梗死患者和80例心力衰竭患者的血浆作为样本,结合超高效液相色谱-高分辨质谱(UPLC-HRMS)技术和化学计量学方法,分析缺血性心脏病患者疾病进程的代谢紊乱特征。实验共定性、定量鉴定97种内源性代谢物,基于t检验、主成分分析、偏最小二乘-判别分析、变量重要性投影等方法,分别筛选出28种和32种可区分心绞痛与心肌梗死患者,心肌梗死与心力衰竭患者的差异性特征代谢物。代谢通路分析结果表明,从心绞痛到心肌梗死,以及从心肌梗死到心力衰竭的疾病进程中,氨基酸代谢和三羧酸循环等能量代谢均发生了紊乱;从心肌梗死到心力衰竭的疾病进程中,以甘油磷脂代谢和脂肪酸生物合成为代表的脂质代谢显著紊乱;通过分析受试者工作曲线(ROC),糖胆酸、富马酸、棕榈酸、肌钙蛋白、高密度脂蛋白、谷丙转氨酶和谷草转氨酶等联合指标可提高心肌梗死诊断精度,ROC曲线下面积(AUC)值达到1.0000;瓜氨酸、柠檬酸、硬脂酸、甘油磷酸胆碱和NT-proBNP联合指标可提高心力衰竭诊断精度,AUC值达到0.9570。本研究可为缺血性心脏病患者的精准诊断和疾病发展过程中的药物、营养干预提供重要的代谢靶标。

Ischemic heart disease is one of the main causes of death worldwide.In this study,the plasma samples of 47 patients with angina,51 patients with myocardial infarction,and 80 patients with heart failure were collected.Ultra-performance liquid chromatography-high resolution mass spectrometry(UPLC-HRMS)and chemometrics were used to analyze the plasma metabolic disorder in disease progression for patients with ischemic heart disease.Chromatographic separation was performed on an ACE3 C18 column(150 mm×3.0 mm×3μm),and MS analysis was carried out by electrospray ionization(ESI)source at positive and negative modes combined with full scanning.In total,97 endogenous metabolites were identified and quantitative analyzed.Principal component analysis and partial least square-discriminant analysis were applied in combination with variable importance projection(VIP)and t-test to screen differentially characteristic metabolites.Metabolite concentration was analyzed using SPSS and the metabolites with significant differences(P<0.05)were found between different processes of diseases.Discriminant analysis using partial least squares-discriminant analysis(PLS-DA)was conducted on various disease processes.Classification models were established for angina,myocardial infarction,and heart failure patients.The variables with VIP>1 were selected using Variable Importance in Projection screening.Finally,disease-specific metabolites were identified using VIP>1 and t-test P<0.05.Accordingly,28 and 32 characteristic metabolites were selected to distinguish between patients with angina and myocardial infarction,and with myocardial infarction and heart failure,respectively.The metabolic pathway analysis revealed disorders in both amino acid metabolism and the tricarboxylic acid cycle during the progression from angina to myocardial infarction,and from myocardial infarction to heart failure.In the progression from myocardial infarction to heart failure,there is a significant disturbance in lipid metabolism,including glycerophospholipid metabolism and fatty acid biosynthesis.Based on the results of 1 receiver operating character(ROC)analysis,several indicators including glycocholic acid,fumaric acid,palmitic acid,troponin,high-density lipoprotein,alanine aminotransferase,and aspartate aminotransferase,were found to have diagnostic significance for distinguishing between angina and myocardial infarction,with respective area under curve(AUC)values of 0.7376,0.8319,0.8277,0.9387,0.6460,0.7045 and 0.7589.When these indicators were combined,the AUC was increased to 1.0000.Similarly,citrulline,citric acid,stearic acid,glycerophospholine,and NT-proBNP were found to have diagnostic significance for distinguishing between myocardial infarction and heart failure,with respective AUC values of 0.6194,0.7487,0.8784,0.6360 and 0.8121.When these indicators were combined,the AUC was increased to 0.9570.At present,there have been some advances in understanding the metabolic characteristics of patients with angina or heart failure based on metabolomics,but there is limited research on the metabolic characteristics of patients with ischemic heart disease.The findings of this study can provide important metabolic targets for precise diagnosis of ischemic heart disease and drug and nutritional interventions during disease development.