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

Abstract Background With the prevalence of unhealthy lifestyles and metabolic disorders, the incidence of premature myocardial infarction (PMI) has increased significantly.1, 2 Free fatty acids (FFA), a central regulator of myocardial energy metabolism, are abnormally accumulated and may drive atherosclerosis progression and plaque destabilization through insulin resistance, oxidative stress, inflammatory response, and lipotoxic injury.3 However,the dose-response associations and independent prognostic value of FFA about major adverse cardiovascular events (MACE) in patients with PMI have not been elucidated. Purpose To explore the prognostic value of FFA levels for long-term MACE in PMI patients and to examine the synergistic effects of FFA with inflammatory markers, obesity, and remnant cholesterol (RC) on clinical outcomes. Methods This single-center prospective cohort study enrolled 1,168 consecutive patients with PMI admitted to the CCU ward of a hospital from March 2017 to December 2024. Participants were stratified into four groups (Q1-Q4) according to 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 restricted cubic spline (RCS) evaluated the nonlinear relationship between FFA levels and MACE risk. Results A total of 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 group HR=1.888 (95% CI: 1.109-2.956), p=0.009, Q3 group HR=2.466 (95% CI: 1.548-3.928), p0.001 and Q4 group HR=2.944 (95% CI: 1.862-4.654), p0.001 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 (MS) or type 2 diabetes mellitus (T2DM). Further joint analyses showed that the risk of MACE was significantly increased with high-sensitivity C-reactive protein (hs-CRP)5 mg/L, body mass index (BMI)28 kg/m², and RC≥0.8 mmol/L. Conclusions Elevated and reduced FFA levels, when exceeding a certain threshold, have been shown to independently increase the risk of MACE in patients with PMI. This threshold effect remains evident in patients with PMI who also have metabolic syndrome or type 2 diabetes mellitus. The findings indicate the necessity for dynamic monitoring of FFA in patients with metabolically impaired PMI, as well as a comprehensive assessment of systemic inflammation and adiposity. This approach aims to optimize risk stratification and personalized clinical management.