The interplay of fibrinogen and lipoprotein(a) with 20-year atherosclerotic cardiovascular disease risk: a path analysis within the ATTICA study (2002–2022)

AIMS: Elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen are known risk factors for atherosclerotic cardiovascular disease (ASCVD), and their combined elevation in high-risk individuals may amplify risk. However, the long-term impact of this combination on ASCVD incidence in a primary prevention setting remains unclear. This study sought to examine the association between the combination of Lp(a) and fibrinogen with long-term ASCVD risk, in apparently healthy adults from the general population. METHODS AND RESULTS: A cohort of 3042 CVD-free adults residing in greater Athens, Greece, was recruited in 2002. A 20-year follow-up was conducted in 2022, comprising n = 2169 participants, of which n = 1988 had complete data for cardiovascular disease incidence. Participants were divided into four groups, using a recommended threshold of 30 mg/dL for Lp(a) and the median value of 303 mg/dL for fibrinogen. In the overall cohort, fibrinogen was associated with higher ASCVD risk [hazard ratio (HR) per 10 mg/dL: 1.040, 95%CI:1.009-1.072]. Upon stratification by Lp(a) levels, the significant association was retained and amplified only in individuals with elevated Lp(a) levels (HR 1.083, 95%CI:1.009-1.162) (P for interaction=0.041). Participants with both elevated Lp(a) and fibrinogen levels demonstrated the highest 20-year ASCVD risk (HR 1.904, 95%CI [1.023, 3.547]). Path analysis revealed a mediating role of fibrinogen in the inflammation [i.e. interleukin-6 (IL-6)]-ASCVD risk association, which become more pronounced at higher Lp(a) concentrations. CONCLUSION: In this general population study, elevated levels of Lp(a) and fibrinogen jointly conferred a higher long-term risk of ASCVD than either marker alone, potentially through the complex involvement of inflammation.