TCA Cycle Metabolites Associated with Adverse Outcomes After Acute Coronary Syndrome: Mediating Effect of Renal Function

Aims: To examine relationships of tricarboxylic acid (TCA) cycle metabolites with risk of cardiovascular events and mortality after acute coronary syndrome (ACS), and evaluate the mediating role of renal function in these associations.

Methods: This is a prospective study performed among 309 ACS patients who were followed for a mean of 6.7 years. During this period 131 patients developed major adverse cardiovascular events (MACE), defined as the composite of myocardial infarction, hospitalization for heart failure, and all-cause mortality, and 90 deaths were recorded. Plasma concentrations of citrate, aconitate, isocitrate, succinate, malate, fumarate, α-ketoglutarate and d/l-2-hydroxyglutarate were quantified using LC-tandem MS. Multivariable Cox regression models were used to estimate hazard ratios, and a counterfactual-based mediation analysis was performed to test the mediating role of estimated glomerular filtration rate (eGFR).

Results: After adjustment for traditional cardiovascular risk factors and medications, positive associations were found between isocitrate and MACE (HR per 1 SD, 1.25; 95% CI: 1.03, 1.50), and between aconitate, isocitrate, d/l-2-hydroxyglutarate and all-cause mortality (HR per 1 SD, 1.41; 95% CI: 1.07, 1.84; 1.58; 95% CI: 1.23, 2.02; 1.38; 95% CI: 1.14, 1.68). However, these associations were no longer significant after additional adjustment for eGFR. Mediation analyses demonstrated that eGFR is a strong mediator of these associations.

Conclusion: These findings underscore the importance of TCA metabolites and renal function as conjunctive targets in the prevention of ACS complications.