Angiopoietin-like protein 4 identifies residual risk for atherothrombotic events in stable post-acute coronary syndrome patients: insights from the SPUM-ACS study

Background Angiopoietin-like protein 4 (ANGPTL4) regulates lipid metabolism and inflammation and has been linked to plaque vulnerability and thrombosis. However, its prognostic value in stable post-ACS patients is unclear, and clinical data on its association with recurrent atherothrombotic events, independent of traditional risk factors, are lacking. Aim To investigate the association between ANGPTL4 levels measured one-year post-acute coronary syndrome (ACS) and the long-term risk of recurrent myocardial infarction (MI) and ischemic stroke, and independently of conventional cardiometabolic risk factors, including triglycerides. Methods Serum ANGPTL4 levels were measured by ELISA in 900 ACS patients from the SPUM-ACS registry one year post-event. Patients were grouped by ANGPTL4 tertiles (T1: ≤7.55, T2: 7.55–18.23, T3: ≥18.23 ng/mL). The primary endpoint was MI or ischemic stroke from day 365 onward. Associations were assessed via Kaplan-Meier curves and multivariable Cox regression adjusted for age, sex, diabetes, triglycerides, obesity, statins, hypertension, and smoking. Baseline characteristics are shown in Table 1. Results For the composite outcome of myocardial infarction or ischemic stroke occurring from one year post-ACS onward, the adjusted event-free survival analyses demonstrated a clear gradient across ANGPTL4 tertiles. ANGPTL4 tertile 3 had the lowest event-free survival over 2920 days post-1year-landmark, tertile 2 showed an intermediate pattern, and tertile 1 had the most favourable event-free survival (T2 vs T1, p = 0.114; and T3 vs T1, p = 0.002), independent of age, sex, and 1-year diabetes, triglycerides, obesity (BMI), statin use, hypertension, and smoking (Figure 1). In an adjusted hazard ratio for composite MI or ischemic stroke from one year post-ACS onward, higher ANGPTL4 levels were significantly associated with an increased risk of myocardial infarction or ischemic stroke during follow-up to day 2920 after multivariable adjustment. Compared with the lowest ANGPTL4 tertile (T1), the adjusted HR for the composite outcome was 1.35 (95% CI 1.15–1.59; p = 0.0003) for the middle tertile (T2) and 1.49 (95% CI 1.26–1.75; p = 2.0×10⁻⁶) for the highest tertile (T3). Among the covariates, higher 1-year triglyceride levels were also associated with a higher risk of myocardial infarction or ischemic stroke (HR 1.11; 95% CI 1.02–1.20; p = 0.012), whereas age, sex, diabetes, obesity, statin use, hypertension, and smoking at 1 year were not significantly associated with the composite endpoint in this model (all p > 0.05) (Figure 2). Conclusion In stable post-ACS patients, elevated ANGPTL4 levels at one year emerged as an independent predictor of long-term recurrent myocardial infarction and ischemic stroke, after adjustment for traditional risk factors, including triglycerides, positioning ANGPTL4 as a biomarker of residual atherothrombotic risk.