Lipoprotein(a) and vascular function in pre- and postmenopausal women

Abstract

Intro. Lipoprotein(a) [Lp(a)] is a newly appreciated risk factor for cardiovascular disease (CVD), yet its contribution to subclinical disease, particularly vascular endothelial dysfunction, is not fully elucidated. Fibrinogen may represent an important pathway by which Lp(a) may contribute to vascular endothelial dysfunction. Additionally, menopausal status has been shown to alter both Lp(a) and FMD. We therefore assessed, in pre- and postmenopausal women, whether: 1) Lp(a) is associated with FMD, 2) Lp(a) is associated with fibrinogen, and 3) Lp(a) and FMD collectively influence CVD risk. Methods. 1,379 women from the Framingham Offspring cohort at exam 7 were included in the analysis. We stratified by menopausal status (114 premenopausal, 1,265 postmenopausal), and excluded individuals with current CVD or missing data for Lp(a), FMD, or CVD. Associations between Lp(a) and FMD were evaluated using both categorical (generalized linear) and continuous (linear regression) models. Associations between Lp(a) and fibrinogen and fibrinogen and FMD were evaluated using linear regression. Mediation analysis was performed to evaluate the mediating role of fibrinogen in the association between Lp(a) and FMD. Cox proportional hazards models evaluated the effect of Lp(a) and FMD on incident CVD risk. Results. Premenopausal women with elevated Lp(a) (≥65 mg/dL) exhibited significantly reduced FMD compared to those with lower levels. This association persisted after multivariable adjustment. In postmenopausal women, no significant difference in FMD was observed between Lp(a) groups. Lp(a) was positively associated with fibrinogen in both pre- and postmenopausal women. However, fibrinogen was not associated with FMD. Mediation analysis confirmed that the association between Lp(a) and FMD was not mediated through the effects of fibrinogen. Compared to individuals with normal FMD and low Lp(a), those with high Lp(a) alone (and normal FMD) faced a 115% increased risk of CVD (HR 2.15), while low FMD alone (and low Lp(a)) was associated with a 43% increased risk (HR 1.43). The joint association of high Lp(a) and low FMD conferred a significant two-fold increase in CVD risk (HR 2.00; 95% CI: 1.31-3.05, p=0.001) after adjusting for traditional cardiovascular risk factors. Conclusions. Elevated Lp(a) is associated with impaired endothelial function in premenopausal women, suggesting early vascular effects prior to menopause. The assessment of Lp(a) and FMD modified CVD risk, highlighting the importance of integrating genetic, lipid, and functional vascular markers in women.