Relationship Between The Plaque Instability And The Levels Of Intraplaque Specialized Pro-resolving Mediators In The Patients With Carotid Atherosclerosis

Background:The process of atherosclerosis（AS）plaque formation and progression is closely related to the persistence of inflammatory responses.In early AS plaque formation,damaged vascular endothelial cells release monocyte chemoattractant protein（MCP）-1,intercellular cell adhesion molecule（ICAM）-1,vascular cell adhesion molecule（VCAM）-1,and chemokines.They attract monocytes,lymphocytes,and neutrophils to infiltrate the subintima.In advanced AS plaques,many macrophages secrete inflammatory cytokines,such as interleukin（IL）-1,IL-6,and tumor necrosis factor（TNF）-αto trigger a persistent inflammatory response that accelerates the formation of vulnerable plaques.However,although treatment that suppresses the inflammatory response within the plaque reduces the occurrence of clinical events,it also has adverse consequences for the organism due to immunosuppression,such as an increased rate of pneumonia infection.Recent studies have shown that the inflammatory response within plaques does not simply disappear passively.Instead,it is an actively terminating process controlled by specialized pro-resolving lipid mediators（SPMs）.This raised our concern about whether intraplaque SPMs could contribute to plaque stabilization.Objective:Exploring the relationship between human cervical AS plaque stability and intraplaque SPMsMethods:（1）From October 2021 to September 2022 at the First Hospital of Jilin University,we obtained data on 47 patients with severe stenosis of combined carotid AS plaques confirmed by carotid ultrasound,head and neck CTA,or DSA.These patients also met the indications for endarterectomy and were willing to undergo surgical treatment.（2）Histological observation（HE staining）was performed on all postoperatively obtained plaque specimens.The main criteria for vulnerable plaques were:（i）Thin cap with a large lipid core,（ii）active inflammation,（iii）endothelial denudation with superficial platelet aggregation,（iv）fissured plaque,and（v）stenosis>90%.The secondary criteria were:（i）superficial calcified nodule,（ii）glistening yellow,（iii）Intraplaque hemorrhage,（iv）endothelial dysfunction,and（v）outward（positive）remodelling.One of the primary criteria or two or more of the secondary criteria can be identified as vulnerable plaques^[5].（3）Enzyme linked immunosorbent assay（ELISA）was performed to detect the levels of RVD1,LTB₄,Ma R1,and Anx A1 in plaque tissue homogenates.（4）To record general clinical data such as patient’s age,gender,with or without symptoms,history of hypertension,history of diabetes,history of cerebral infarction,history of heart disease,history of smoking,history of alcohol consumption,low-density lipoprotein cholesterol（LDL-C）,high-density lipoprotein cholesterol（HDL-C）,triglycerides（TG）,cholesterol（CHOL）,homocysteine（HCY）,ultrasensitive C-reactive protein（hs-CRP）,fasting blood glucose（FBG）,2-hour postprandial glucose,glycosylated hemoglobin（Hb A1c）and uric acid（UA）.（5）SPSS 25.0 software and Graph Pad Prism 8.0 software were used to analyze the data and produce graphs.Results:（1）Compared to the stable plaque group,RVD1/LTB₄ values,as well as Anx A1 in plaque tissue homogenates,were significantly lower in patients in the vulnerable plaque group,with statistically significant differences（P<0.05）,while the differences in RVD1,LTB₄,and Ma R1 in plaque tissue homogenates between the two groups were not statistically significant（P>0.05）.（2）The stable plaque group was set as a positive judgment event and the unstable plaque group as a negative event.The area under the ROC curve for RVD1/LTB₄ value was 0.688,P value=0.032,and its Cut-off value was 0.153pg/ml,with a sensitivity of 79.3%and specificity of 61.1%;the area under the ROC curve for Anx A1 was 0.712,P value=0.022,and its Cut-off value was4070.238 pg/ml.The sensitivity was 95.5%and the specificity was 44.4%.（3）We analyzed the correlations between RVD1,LTB₄,RVD1/LTB₄ values,Ma R1 and Anx A1 in plaque tissue homogenates and patients’general clinical data,such as age,LDL-C,HDL-C,TG,CHOL,HCY,hs-CRP,FBG,2-hour postprandial glucose,Hb A1c and UA.The correlations of RVD1/LTB₄ values and Ma R1 in plaque tissue homogenates were found to be positively correlated with age（r=0.323,P=0.027;r=0.302,P=0.039）and not with other indicators;Anx A1 was positively correlated with FBG,2-hour postprandial glucose,and Hb A1c（r=0.415,P<0.05;r=0.495,P<0.05;r=0.345,P<0.05）,which did not correlate with other indicators;RVD1 and LTB₄ did not correlate with any of the above indicators.Conclusions:（1）Elevated intraplaque RVD1/LTB₄ ratio and elevated Anx A1 may be protective factors for cervical AS plaque stability.（2）Abnormal blood glucose may affect the intraplaque Anx A1 content change.