Association of free fatty acids with long-term adverse outcomes in patients with premature myocardial infarction: a prospective cohort study

Background The dose-response relationship and independent prognostic value of free fatty acids (FFA) on major adverse cardiovascular events (MACE) in patients with premature myocardial infarction (PMI) are not well defined. This study aims to explore the significance of FFA levels on long-term prognostic in patients with PMI and the combined effects of FFA with inflammatory markers, obesity, and insulin resistance (IR) on clinical outcomes. Methods This single-center prospective cohort study enrolled 1,168 consecutive patients with PMI admitted to the CCU ward of Tianjin Chest Hospital from March 2017 to December 2024. Participants were stratified into four groups (Q1-Q4) based on the quartiles of baseline FFA levels. With a median follow-up of 2.83 years (IQR: 2.58–3.10), the primary endpoint was MACE. Cox proportional hazard models assessed the association between FFA levels and long-term outcomes, while the restricted cubic spline plot evaluated the nonlinear relationship between FFA levels and MACE risk. Results 216 (18.50%) MACE were recorded during a median follow-up of 2.83 years. FFA levels showed a non-linear U-shaped association with long-term prognosis in patients with PMI. When the second quartile of FFA levels (Q2: 0.43-0.61 mmol/L) was used as the reference group, after multifactorial correction, the association between FFA levels in the Q1 (<0.43 mmol/L) [HR=1.888 (95% CI: 1.109-2.956), p =0.009], Q3 (0.61-0.83 mmol/L) [HR=2.466 (95% CI: 1.548-3.928), p <0.001] and Q4 (≥0.83 mmol/L) [HR=2.944 (95% CI: 1.862-4.654), p <0.001] had significantly higher risk of MACE. Subgroup analyses showed that the U-shaped association between FFA and MACE remained significant in PMI patients with comorbid metabolic syndrome or type 2 diabetes mellitus. Subsequent joint analyses demonstrated that patients with PMI exhibited a significantly elevated risk of MACE if they had abnormal levels of FFA and a metabolic disorder with a hypersensitive C-reactive protein (hs-CRP) >5 mg/L, body mass index (BMI) >28 kg/m², or TyG >9.21 mmol/L. Conclusions Elevated and decreased levels of FFA, when surpassing a certain threshold, independently increase the risk of MACE in patients with PMI. Consequently, dynamic monitoring of FFA and combined assessment of inflammation, obesity, and IR in patients with PMI are essential for risk stratification and clinical management.