Prognostic impact of the combined effects of lipoprotein(a) and homocysteine in patients with premature myocardial infarction: a prospective cohort study

Background Lipoprotein(a) [Lp(a)] is a causal driver of atherosclerosis, yet the interaction between Lp(a)-driven lipid accumulation and a prothrombotic state induced by hyperhomocysteinemia has not been systematically investigated in this high-risk population. From a clinical nutrition perspective, homocysteine (HCY) is a critical modifiable metabolite influenced by B vitamins and folate, making this interaction particularly relevant for dietary or supplementation strategies. This study aims to systematically evaluate the independent and combined prognostic significance of Lp(a) and homocysteine (HCY) in premature myocardial infarction (PMI). Methods This prospective cohort study enrolled 1741 PMI patients (aged ≤55 years) at Tianjin Chest Hospital (January 2018–June 2023). Restricted cubic spline (RCS) was used to explore nonlinearity between Lp(a)/HCY and major adverse cardiovascular events (MACE). HCY was analyzed both as a continuous variable and, for exploratory stratification, dichotomized at the clinically referenced threshold of 15 μmol/L. The cutoff for Lp(a) was pre-specified as 50 mg/dL based on clinical guidelines and further validated by maximally selected rank statistics (MSRS). Survival analyses assessed the effects of these factors on MACE. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) quantified incremental model value. Results During a median follow-up of 19.6 months, 224 (12.87%) patients experienced MACE. RCS revealed a nonlinear association between Lp(a) and MACE ( p = 0.003), whereas HCY showed no significant nonlinear trend. High Lp(a; HR = 2.266, 95% CI: 1.685–3.046, p < 0.001) and high HCY (HR = 1.597, 95% CI: 1.204–2.117, p = 0.001) are independent MACE risk factors. Compared with the low Lp(a) + low HCY group, the high Lp(a) + high HCY group had a 3.566-fold greater MACE risk (95% CI, 2.427–5.239, p < 0.001). Additive interaction analysis revealed a statistically significant interaction: RERI = 1.630 (95% CI, 0.314–2.945, p = 0.015), AP = 0.456 (95% CI, 0.197–0.716, p < 0.001), SI = 1.840 (95% CI, 0.960–2.719, p = 0.061). Conclusion This study systematically characterizes the combined prognostic role of Lp(a) and HCY in PMI patients, validating a pragmatic “50–15” dual-threshold strategy for MACE risk stratification. The findings support a precision nutrition approach, suggesting that patients with dual elevation may benefit from targeted B-vitamin or folate supplementation as a low-cost adjunctive strategy.