Screening And Clinical Application Of Serum Biomarkers In AS And ACS

Background and Objective:Atherosclerosis （AS） is the primary cause of cardiovascular disease. The rupture of atherosclerotic unstable plaque may lead to acute coronary syndrome （ACS）, which is the global leading cause of human death. Using serum biomarkers could aid in risk prediction and early diagnosis of AS and ACS, thus effectively reduce the morbidity and mortality. This study aimed to screen effective serum markers for AS and ACS.Methods:（1） Multi-parameter analysis were performed to compare conventional serum biochemical indexes in 110 early AS patients and 292 healthy controls as well as 221 ACS patients and 38 SAP patients. Independent risk factors were identified and combined diagnostic models for early AS and ACS subclasses were built. （2） A total of 116 ACS patients,67 AS patients and 129 healthy controls were recruited in this study. Serum HDL subfractions, including HDL2 and HDL3 were detected by automatic biochemical analyzer. Serum HDL2b were determined by microfluidic chip. The association between HDL subfractions and mean HDL particle size with lipids, cardiac biomarkers, carotid IMT and severity of coronary artery stenosis were analyzed. （3） A optimized qRT-PCR method was adopted to validate the new predicted miRNAs, which were predicted by Solexa sequencing in previous study, in 65 AS patients and 154 ACS patients. The relationship of the new predicted miRNAs to lipids, cardiac biomarkers and severity of coronary artery stenosis were analyzed. The functions of key miRNA were also predicted by using bioinformatics technologies.Results:（1） LDL-C/HDL-C ratio （β=0.132, P<0.001） is independent variable that interacted on carotid IMT. LDL-C （OR; 1.325,95%CI; 1.046-1.821, p=0.033） and HDL-C levels （OR; 0.093,95%CI; 0.038-0.227, P<0.001） were significantly associated with the presence of carotid plaque. Furthermore, LDL-C combined with HDL-C levels showed the highest diagnostic value of carotid plaque （AUC =0.788,95%CI; 0.740-0.837, P<0.001）. TnT exhibited excellent differential diagnostic value for AMI and UAP （AUC=0.988,95%CI; 0.973-1.000, P<0.001）. Multi-parameter model including CK, P and GSP showed the highest differential diagnostic value for STEMI and NSTEMI （AUC=0.900,95%CI; 0.839-0.961, P <0.001）. AST showed the highest differential diagnostic value for UAP and SAP （AUC=0.756,95%CI; 0.635-0.876, P=0.002）. （2） Mean HDL particle size was found to correlate inversely with BMI （r=-0.331, P<0.001） and GLU （r=-0.185, P=0.002）, as well as TG （r=-0.779, P<0.001） and apoB （r=-0.254, P<0.001）. Serum HDL2b concentrations correlated inversely with carotid IMT in AS patients （r=-0.205, P=0.005）. In ACS patients, serum HDL2b concentrations were significantly lower compared with healthy controls, and inversely correlated with TnT （r=-0.500, P<0.001）, Mb （r=-0.282, P=0.037）, CK-MB （r=-0.269, P=0.038）, LDH （r=-0.247, P=0.025） and severity of coronary artery stenosis （P=0.034）. （3） Serum novel mir₇5 and novel_mir₃44 levels were higher in UAP patients than healthy controls, and serum novel_mir₃44 levels were also higher in UAP patients compared with SAP patients, whereas serum novel_mir₇4 and novel_mir₃44 levels were higher in AMI patients than healthy controls. Novel_mir₇4 showed negetive correlation with cardiac biomarkers and severity of coronary artery stenosis, but positive correlation with HDL2b concentrations. Novel_mir₇4 was predicted to mainly regulate cAMP, PI3K-Akt, Ras, mTOR, p53 and FoxO signaling pathway by targeting FOXO1, GPX8 PTEN, TRAPPC6B, TWF1, FAM108B1, CCDC85C, PLAGL2, EPB41L1 and COL6A6 genes.Conclusion:（1） Multi-parameter diagnositc model could take full advantage of conventional serum biochemical indexes and improve their diagnostic value of AS and ACS. （2） HDL2b was the key protective factor for AS and ACS. （3） Novel_mir₇4 may play important roles in DNA transcription, heart development, projection neuronal development, B cell activation and angiogenesis.