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) variables resulted in positive Net Reclassification Improvement (NRI) values (0.159 and 0.160 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.