| Coronary artery disease（CAD）has become one of the most important risk factors of death,which threatens the human society.CAD could lead to left ventricular remodeling,which accelerates the disease progression and will ultimately affect the clinical outcomes.The development of CAD is a kind of complex process involving the changes in a series of metabolites,thus a single metabolic marker cannot specifically and effectively predict the risks of clinical event.At present,a general metabolomic study to evaluate the predictive value of plasma metabolites on the clinical outcomes in patients with CAD is still lacking.Therefore,this study aims to access the effects and predictive value of the metabolites profile on the clinical outcomes and left ventricular remodeling through a widely targeted metabolomic study in a Chinese follow-up cohort with CAD,to determine key metabolic pathways and validate the effects of the key metabolites in an independent follow-up cohort,furtherly,using genomic analysis to reveal the ADME genetic variants that affect the metabolite level of tryptophan metabolic pathway in two follow-up cohorts with CAD.The main content of this thesis includes the following four parts:Firstly,the effects and predictive value of metabolite level measured by widely targeted metabolomics on death and major adverse cardiovascular events（MACE）were investigated in a follow-up cohort with 1040 CAD patients.The result showed that the biomarkers trimethylamine increased the death risk,and elevatedβ-pseudouridine and L-kynurenine and reduced triiodothyronine（T3）independently increased mortality risk.Further,the predictive value of the model for death risk constructed by multivariable analysis,was significantly higher than the TMAO plus traditional risk factors（AUC of 86.3%vs.74.8%）.Moreover,high L-kynurenine and 5-methyluridine and low LysoPC 20:2 and L-tryptophan levels were independent predictors of MACE risk,and the predictive value of the model for MACE risk was also higher than that of TMAO plus traditional risk factors（AUC of 67.4%vs.61.7%）.Tryptophan metabolic pathway was the key disturbed metabolic pathway associated with the clinical outcomes.Secondly,the effects and predictive value of metabolites measured by widely targeted metabolomics on left ventricular remodeling were investigated in 842 CAD patients.The results showed that 2-（dimethylamino）guanosine significantly promoted left ventricular remodeling,the synthesis and degradation pathway of ketone bodies was key metabolic pathway that associated with left ventricular dysfunction（LVD）and the accumulation of 3-hydroxybutyrate was positively correlated with LVD.Furthermore,2-（dimethylamino）guanosine,hexanoylglycine,3-methylhistidine,L-cystine,phenyllactate and dodecanedioic acid were independent risk factors for LVD,and a predictive model for LVD constructed by multivariable analysis was with AUC of 79.4%.2-（dimethylamino）guanosine,phenyllactate,dulcitol,kynurenine,kynurenine and L-cystine not only promoted LVD but also increased the risk of the clinical outcomes.Thirdly,the effects of the key metabolites of tryptophan metabolic pathway on the clinical outcomes and left ventricular remodeling were validated in an independent cohort with 524 CAD patients.The results indicated that low tryptophan and high kynurenine level in the plasma of CAD patients could predict the increased risk of death and LVD,which are consisted with the results of the first and the second chapter.Finally,genomic analysis focused on 295 key ADME genes was performed in the follow-up cohort of CAD patients,to elucidate the effects of the SNPs affecting tryptophan and its metabolites.In the genomic analysis of 1028 patients at the discovery stage,a total of 10,9,12 and 7 SNPs related to kynurenine,kynurenine acid,tryptophan and indolepopionic acid were screened respectively,and we validated that SLC7A5（rs8051149 and rs11865049）were significantly associated with kynurenine levels,CHST11 rs79373731 was associated with indolepopionic acid level in an independent cohort with 375 CAD patients.In conclusion,this study has innovatively found specific biomarkers for the risks of death and MACE as well as left ventricular remodeling,which improved the predictive efficacy for the clinical outcomes of CAD patients,and pointed out and validated that dysregulation of tryptophan metabolic pathway is a key metabolic pathway underlying the risk of death and LVD in patients with CAD.Genomic analysis found that SLC7A5 polymorphism significantly affect kynurenine level.Concentration of metabolites in tryptophan metabolic pathway can be used as important reference index of early warning for the clinical prognosis of CAD. |
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