Abstract
BACKGROUND: Disrupted tricarboxylic acid (TCA) cycle metabolism drives ischemic mitochondrial stress in the pathophysiology of acute myocardial infarction (AMI), yet its clinical prognostic utility remains poorly defined. This study aimed to (1) develop a novel metabolic index quantifying TCA cycle disturbance; (2) evaluate its prognostic value for adverse outcomes in patients with AMI; and (3) assess its incremental predictive value beyond established risk factors. METHODS: We analyzed 4071 AMI patients from a hospital-based prospective cohort enrolled between February 2017 and June 2019. Plasma levels of TCA cycle metabolites were measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) protocol. A composite TCA index was constructed using five specific intermediates: α-ketoglutarate, methylmalonate, succinate, fumarate, and malate. Multivariable Cox regression models were employed to evaluate independent associations and estimate population attributable fractions (PAFs) for clinical outcomes. The incremental predictive value beyond the GRACE score and cardiac biomarkers was assessed using the C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: During a median follow-up of 6.2 years, 1263 (31.0%) major adverse cardiovascular events (MACE), 672 (16.5%) all-cause deaths, 373 (9.2%) cardiovascular deaths, and 561 (13.8%) heart failure events were documented. Each standard deviation (SD) increase in the TCA index was independently associated with a higher risk of MACE (HR: 1.20; 95% CI: 1.13-1.27), all-cause death (HR: 1.22; 95% CI: 1.13-1.32), cardiovascular death (HR: 1.28; 95% CI: 1.16-1.42), and heart failure (HR: 1.21; 95% CI: 1.11-1.31). Notably, PAF analysis revealed distinct patterns: while relative risks were robust in males, the TCA index accounted for a substantially higher mortality burden in females (24.70% vs. 10.05% in males) and younger individuals (≤ 60 years; 25.10%), suggesting these subgroups are particularly vulnerable to metabolic dysregulation. Adding the TCA index to the GRACE score provided incremental prognostic value, evidenced by improved reclassification metrics. CONCLUSIONS: The TCA index serves as a novel indicator of ischemic mitochondrial stress and a robust independent predictor of adverse outcomes in AMI. This metabolic algorithm offers complementary prognostic value to existing clinical models, aiding risk stratification for post-infarction care.