| Coronary artery disease(CAD)is currently one of the leading causes of death worldwide.Despite the remarkable amelioration of pharmaceutical and operative treatments,the clinical prognosis of patients with CAD is still poor,accurately estimating and managing the prognostic risk of CAD remains a challenge for current healthcare systems.Furthermore,pathological left ventricular remodeling characterized by left ventricular dysfunction(LVD)often occurs in the progression of CAD and seriously affect the survival and prognosis of patients with CAD.Dyslipidemia is significantly related to the risk of death,major adverse cardiovascular events(MACE)and left ventricular remodeling.However,it is insufficient to reflect the abundance and specificity of altered lipid metabolism associated with clinical outcomes and left ventricular remodeling due to the complexity and mixed nature of traditional plasma lipids.Therefore,this study aims to assess the effect of the lipid species measured by widely targeted lipidomic profiling on clinical endpoints and left ventricular remodeling and identify the disordered lipid metabolic pathways related to it,develop the prognostic models of clinical outcomes and LVD in the Chinese single-center follow-up cohort with CAD.Next,the genome-wide association study(GWAS)was used to identify the single nucleotide polymorphism(SNP)loci which hava on effect on the plasma level of lipid species associated with death and LVD.Finally,the above results will be furtherly verified in an independent multi-center follow-up cohort.The main results are as follows:(1)Firstly,the study aimed to assess the effect of plasma lipid species measured by widely targeted lipidomic profiling on the risk of clinical endpoints,and the independent lipid species of death and MACE were used to develop related prognostic models in the internal training cohort composed of 1011 single-center patients with CAD.The results showed that ten(Cer(d18: 1/20: 1),Cer(d18: 1/24: 1),PE(30: 2),PE(32: 0),PE(32: 2),LPC(18: 2/0: 0),LPE(0: 0/24: 6),PC(16: 1/22: 2),PC(O-36: 4)and PC(O-38: 2))and two(Cer(d18: 1/20: 1)and LPC(20: 0/0: 0))independent predictive biomarkers of death and MACE were identified,respectively.Furtherly,the predictive performance of the model for death based on the 10 independent lipid metabolites and 2 traditional risk factors(age and AST)was significantly higher than the predictive model comtaining traditional risk factors only(area under the curve [AUC] 83.65% vs.76.56%),while the performance of the model for MACE combined two independent lipid metabolites with 6 traditional risk factors were slightly improved compared with the traditional model(AUC: 60.73% vs 60.70%).Next,the newly developed predictive model were successfully applied to differentiate multicenter 558 CAD patients with high,medium,and low death or MACE risks(P <0.05).Finally,we also discovered and verified that the number of double bonds of phosphatidylcholine(PC)and the number of carbon atoms of phosphatidylethanolamine(PE)were inversely related to the risk of death in patients with CAD.(2)The effect of the the level of plasma lipid metabolites detected by widely targeted lipidomic profiling on left ventricular ejection fraction(LVEF),left ventricular end systolic diameter(LVESD),left ventricular end diastolic diameter(LVEDD)and left ventricular dysfunction(LVD)were evaluated and the related disordered lipid metabolic pathways were identified in the discovery cohort containing 800 single-center patients with CAD.Subsequently,the risk predictive model for LVD based on the identified independent biomarkers was established.These results were furtherly confirmed in the validation cohort composed of 464 multicenter patients with CAD.Firstly,we discovered and verified that 7 lipid species(Cer P(d18: 1/18: 1),PC(18: 1/18: 1),PC(14: 0/22: 6),PC(16: 0/22: 6),PC(18: 0/22: 6),PC(18: 2/22: 6)and PC(20: 1/20: 5))were significantly associated with LVEF,4 lipid species(PC(14: 0/22: 6),PC(16: 1/22: 6),PC(18: 2/22: 6)and TG(16: 1/16: 1 / 22: 5))were significantly correlated with LVESD,and 2 lipid species(PC(14: 0/22: 6)and PC(18: 2/22: 6))were significantly correlated with LVD.Secondly,the disordered pathway of glycerophospholipid metabolism,linoleic acid metabolism,and α-linolenic acid metabolism were venrified that associated with higher risk of left ventricular remodeling.Finally,the predictive model of LVD based on traditional risk factors and three lipid metabolites(PE(34: 1),Hex Cer(d18: 1/18: 1)and TG(14: 0/18: 0/18: 4))showed improvement prognostic performance compared with the model composed of traditional risk factors only(AUC: 75.2% vs 72.3%).(3)The SNP mutations which have an effect on the plasma level of lipid species that related to death and LVD were discovered and verified by GWAS in the discovery cohort composed of 953 single-center patients with CAD and validation cohort composed of 524 multicenter patients with CAD,respectively.Finally,the effect of these confirmed independent SNP mutations on the risk of death were investigated.The results showed that rs174601,rs174602 and rs2524299 located on the FADS2 gene,rs198476 and rs2071213 located on the MYRF gene,and rs9735635 located on the DAGLA gene were discovered and verified that significantly correlated with the plasma concentration of LPC(20:4/0:0)(P <1.7E-07),and rs174570 located on the FADS2 gene was significantly correlated with plasma concentration of LPE(0:0/18:2)(P <1.7E-07).Finally,Cox regression analysis indicated that the 7 independent SNP mutations did not directly affect the risk of death in patients with CAD(P> 0.05).In conclusion,we discovered and verified specific biomarkers for the risk of death and left ventricular remodeling for CAD,and the predictive model for death and LVD combined independent lipid species with traditional risk factors showed improvement performance compared with the model composed of traditional risk factors only.These findings have a significant improvement effect on the assessment and management of the risk of death and left ventricular remodeling for CAD.The SNPs located in FADS2,MYRF and DAGLA gene could significantly affect the plasma concentrations of LPC(20:4/0:0)and LPE(0:0/18:2),which clarified the relationship between SNP mutations and dyslipidemia in patients with CAD from genetic perspective. |
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