Discrimination and net-reclassification of cardiovascular disease risk with Lipoprotein(a) levels: the ATTICA study (2002-2022)

Background Lipoprotein(a) [Lp(a)] is a recognized as risk factor for atherosclerotic cardiovascular disease (ASCVD). However, its influence on clinical risk evaluations remains unclear. Objective This study aimed to determine whether Lp(a) improves CVD risk prediction among apparently healthy adults from the general population. Methods In 2002, n=3,042 adults free of CVD, residing in Athens metropolitan area, in Greece, were recruited. A 20-year follow-up was conducted in 2022, comprising n=2,169 participants, of which n=1,988 had complete data for CVD incidence. Results Lp(a) levels were significantly associated with 20-year ASCVD incidence in the crude model (Hazard Ratio per 1 mg/dL: 1.004, p=0.048), but not in multi-adjusted models considering demographic, lifestyle, and clinical factors. Adding Lp(a) to the Reynolds Risk Score (RRS) and Framingham Risk Score (FRS) models resulted in positive Net Reclassification Improvement (NRI) values (0.329 and 0.365 respectively), indicating improved risk classification. Mediation analysis suggested that C-reactive protein, Interleukin-6, and Fibrinogen mediate the relationship between Lp(a) and ASCVD. No significant interaction was observed between Lp(a) and potential moderators. Conclusion Lp(a) levels can predict 20-year CVD outcomes and improve CVD risk prediction within the general population, possibly via the intricate relationship between Lp(a), systemic inflammation, atherothrombosis.