Study On The Predictive Value Of GDF15 Combined With Bleeding Score For Post-PCI Bleeding And The Exploration Of The Pathogenesis Of GDF15 Affecting CAD

Objective: Coronary artery disease(CAD)is a common cardiovascular disease and one of the leading causes of disability and death,and effective prevention and treatment can substantially improve the prognosis of CAD patients.Percutaneous coronary intervention(PCI)and dual antiplatelet therapy are currently the main clinical treatments for CAD,but their postoperative antithrombotic treatment has a certain risk of bleeding,resulting in poor patient prognosis.Therefore,this study aims to explore the prognostic value of GDF15 on bleeding events by measuring the serum GDF15 level of patients,based on the important issue of bleeding after PCI,starting from the newly discovered serum marker GDF15 associated with bleeding,and combining with the existing bleeding risk score.We also explored the mechanism of the effect of GDF15 on CAD by bioinformatics method,and searched for ways to treat CAD with GDF15 as a breakthrough.Methods: Two hundred and twenty-eight consecutive patients with CAD who underwent PCI and received dual antiplatelet therapy(DAPT)were enrolled in Fu Wai Yunnan Cardiovascular Hospital.Bleeding events,as defined by the Bleeding Academic Research Council(BARC),occurred within six months after PCI was recorded,including 2 cases of loss to follow-up and 1 case of non-bleeding death,with a valid count of 225 points.The patients were divided into the bleeding group according to the bloody events that occurred in the follow-up(n=31)and the non-bleeding group(n=194)to clarify the relationship between GDF15 levels and bleeding events,and to calculate the HAS-BLED and CRUSADE bleeding scores of enrolled patients,to analyze the prediction of GDF15 combined with HAS-BLED and CRUSADE bleeding scores,and the combined application of HAS-BLED and CRUSADE bleeding scores on bleeding events value,to assess the role of GDF15 on the predictive value of bleeding scores.CAD-related datasets were downloaded from the GEO dataset,then standardized,and the results were analyzed for differential expression.Meanwhile,the Spearman algorithm was used to calculate the GDF15-related genes and obtain the common genes.In addition,single gene GSEA was performed for GDF15.Finally,enrichment analysis of common genes was performed using a meta-scape database.Results:1.The differences in GDF15,HAS-BLED and CRUSADE bleeding scores were statistically significant in both groups(P < 0.05).2.logistic regression analysis showed that the GDF15(OR=13.408,95% CI:3.130-57.442,P=0.000),HAS-BLED score(OR=2.394,95% CI: 1.313-4.364,P=0.004)and CRUSADE score(OR= 1.065,95% CI: 1.010-1.123,P=0.019),the results of regression analysis were associated with bleeding events.3.ROC curve analysis showed that the area under the GDF15 curve AUC=0.720,95% CI(0.623-0.817),the area under the HAS-BLED bleeding score ROC curve analysis AUC=0.730,95% CI(0.635-0.825),and the area under the CRUSADE bleeding score ROC curve analysis AUC= 0.689,95% CI(0.598-0.781).4.GDF15 combined with HAS-BLED bleeding score predicted the area under the ROC curve for bleeding events AUC= 0.794,95% CI(0.711-0.876).GDF15 combined with CRUSADE bleeding score predicted the area under the ROC curve for bleeding events AUC= 0.788,95% CI(0.711-0.865).HAS-BLED and CRUSADE bleeding score predicted the area under the ROC curve for bleeding events AUC=0.733,95% CI(0.635-0.831).5.There were 1407 GDF15-related genes,897 differentially expressed genes for coronary artery disease,and 75 genes common to both.6.Single gene GSEA analysis resulted in enrichment analysis to olfactory conduction,neuroactive ligand receptor interactions,pyrimidine metabolism and other related pathways.There are also biological pathways such as heme metabolism,epithelial mesenchymal transition,delayed estrogen response,and myogenesis,protein secretion,oxidative phosphorylation,interferon gamma response,TNF-α signaling via NF-KB,MTORC1 signaling,and G2M checkpoint.7.Common gene enrichment analysis resulted in KEGG enrichment analysis involving Th17 differentiation,choline metabolism in cancer,purine metabolism,and apoptosis.results of GO analysis: enrichment for positive regulation of protein modification by protein splicing or removal,positive regulation of cell-matrix adhesion,regulation of microtubule polymerization,response to inorganic substances The results of GO analysis enriched the biological processes of purine-containing compounds catabolism,cellular components such as calcium channel complexes,leading edge membranes,encapsulated vesicle membranes and centrosomes,molecular functions such as protein structural domain specific binding,kinase activity,kinase binding,and decapping enzyme activity.Coronary heart disease-related datasets were downloaded from the GEO dataset and then normalized.Then differential expression analysis was performed.GDF15-related genes were also calculated using the spearman algorithm to obtain the common genes of both.Then single gene GSEA was performed for GDF15.finally,enrichment analysis of common genes was performed using meta scape database.Conclusion:1.GDF15,HAS-BLED and CRUSADE bleeding scores all predict the risk of bleeding after PCI;2.the predictive value of the HAS-BLED bleeding score for the risk of bleeding fter PCI was higher than that of the GDF15 and CRUSADE bleeding scores;3.The combined GDF15 bleeding score is superior to the combined application of existing bleeding scores.The combined GDF15 bleeding score will improve the predictive accuracy of bleeding after PCI and help accurately identify people at high risk of bleeding.4.Based on bioinformatics analysis,GDF15 may mediate the development of CAD by affecting IFN-γ response,TNF-α via NF-KB signaling pathway,and oxidative phosphorylation response;common genes may act on GDF15 and CAD through Th17 cell differentiation,apoptosis pathway.