Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease

Abstract

Background Coronary artery disease (CAD) is a metabolically perturbed pathological condition. However, the knowledge of metabolic signatures on outcomes of CAD and their potential causal effects and impacts on left ventricular remodeling remains limited. We aim to assess the contribution of plasma metabolites to the risk of death and major adverse cardiovascular events (MACE) as well as left ventricular remodeling. Results In a prospective study with 1606 Chinese patients with CAD, we have identified and validated several independent metabolic signatures through widely-targeted metabolomics. The predictive model respectively integrating four metabolic signatures (dulcitol, β-pseudouridine, 3,3ʹ,5-Triiodo-l-thyronine, and kynurenine) for death (AUC of 83.7% vs. 76.6%, positive IDI of 0.096) and metabolic signatures (kynurenine, lysoPC 20:2, 5-methyluridine, and l-tryptophan) for MACE (AUC of 67.4% vs. 59.8%, IDI of 0.068) yielded better predictive value than trimethylamine N-oxide plus clinical model, which were successfully applied to predict patients with high risks of death (P = 0.0014) and MACE (P = 0.0008) in the multicenter validation cohort. Mendelian randomisation analysis showed that 11 genetically inferred metabolic signatures were significantly associated with risks of death or MACE, such as 4-acetamidobutyric acid, phenylacetyl-l-glutamine, tryptophan metabolites (kynurenine, kynurenic acid), and modified nucleosides (β-pseudouridine, 2-(dimethylamino) guanosine). Mediation analyses show that the association of these metabolites with the outcomes could be partly explained by their roles in promoting left ventricular dysfunction. Conclusions This study provided new insights into the relationship between plasma metabolites and clinical outcomes and its intermediate pathological process left ventricular dysfunction in CAD. The predictive model integrating metabolites can help to improve the risk stratification for death and MACE in CAD. The metabolic signatures appear to increase death or MACE risks partly by promoting adverse left ventricular dysfunction, supporting potential therapeutic targets of CAD for further investigation. Graphical Abstract

RETRACTED: Phenylacetyl glutamine (PAGln) enhances cardiomyocyte death after myocardial infarction through β1 adrenergic receptor

“…15 A followup study found that PAGln was significantly associated with risk death or major adverse cardiovascular events as well as left ventricular remodeling. 16 And using untargeted and targeted metabolomic approaches, Yu et al revealed an elevated plasma PAGln levels in ischemic stroke (IS) patients, compared with healthy controls, which is independently associated with IS and the risk of unfavorable shortterm outcomes. 17 Furthermore, the increased PAGln was indicated to be associated with atrial fibrillation (AF) and facilitate AF pathogenesis by inducing oxidative stress and apoptosis in atrial myocytes.…”

“…Subsequently, they demonstrated that PAGln could foster platelet responsiveness and thrombosis potential via adrenergic receptors (ARs) 15 . A follow‐up study found that PAGln was significantly associated with risk death or major adverse cardiovascular events as well as left ventricular remodeling 16 . And using untargeted and targeted metabolomic approaches, Yu et al revealed an elevated plasma PAGln levels in ischemic stroke (IS) patients, compared with healthy controls, which is independently associated with IS and the risk of unfavorable short‐term outcomes 17 .…”

Blood immune inflammatory indicators predict prognosis in patients with coronary artery disease

“…A two‐stage least squares (2SLS) regression method calculated in R (version 4.2.2) was used in this MR analysis process. The detailed analysis steps have been described previously [16]. The outcome was regressed over the predicted values of exposure using linear regression to calculate estimates and SE for LVEF and BNP; a p ‐value <0.05 was used to define causality.…”

Correction: Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease

“…In this article [ 1 ], during proof correction process, the correction in Figure 4c was incorrectly updated. The correct version of Figure 4c should have appeared as shown in this correction.…”