Abstract Aims Hypercholesterolaemia has been associated with earlier menarche and menopause; however, these observations may reflect reverse causation or confounding. Familial Hypercholesterolaemia (FH) provides a model to investigate these associations. This study compared reproductive characteristics and pregnancy outcomes in women with FH vs. women without FH. Methods and results Between November 2023 and April 2025, women with FH aged ≥40 years were recruited from two university hospital outpatient clinics in the Netherlands and Norway. Women without FH were selected from the Rotterdam Study and Norwegian population-based cohorts. FH cases were matched 1:2 to women without FH on age, smoking status, body mass index, and ethnicity using nearest-neighbour matching. Information on reproductive factors and pregnancy outcomes were obtained via an online survey. 484 women with FH and 968 matched women without FH (median age 55 years [IQR 48–62]; 93% North-Western European) were included. Cardiovascular disease prevalence was higher in women with FH (22% vs. 4%; P < 0.001). Most women with FH (95%) used lipid-lowering therapy, LDL cholesterol levels were lower compared to controls (2.5 vs. 3.5 mmol/L; P < 0.001). Women with FH more often had been pregnant (91% vs. 84%; P < 0.001). Prevalence of gestational diabetes (4% vs. 4%; P = 0.70) and hypertensive disorders of pregnancy (16% vs. 13%; P = 0.10) was similar; however, preeclampsia was more frequent in FH (11% vs. 7%; P = 0.030). Age at menarche (13.2 vs. 13.1 years; P = 0.43), age at menopause (50 years; P = 0.92), and reproductive lifespan (36 years; P = 0.98) were similar between groups. Conclusion Reproductive lifespan is comparable between women with and without FH, but FH was associated with a higher prevalence of preeclampsia, highlighting the importance of targeted pregnancy monitoring and prevention.
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.
Abstract Aims Familial hypercholesterolaemia (FH) leads to lifelong elevated low-density lipoprotein (LDL) cholesterol and increased risk of coronary artery disease. We tested the hypothesis that elevated remnant cholesterol additionally increases cardiovascular risk in FH. Methods and results In the Copenhagen General Population Study (CGPS) and UK Biobank, 108 751 and 428 625 individuals were classified as with or without FH according to clinical scores and genetic mutations. In the two cohorts, 7708 and 50 997 experienced coronary artery disease, respectively. In CGPS and UK Biobank, remnant cholesterol ≥1 mmol/L (39 mg/dL) was observed in 12% and 11% of individuals without FH (n = 104 226 and 403 172), in 33% and 40% with Simon Broome FH (n = 3923 and 23 860), in 44% and 78% with MEDPED FH (n = 1005 and 2465), in 33% and 34% with DLCN FH (n = 744 and 1207), and in 12% and 21% of individuals with genetic FH (n = 188 and 875). Likewise in the CGPS and UK Biobank, the multivariable adjusted hazard ratios for coronary artery disease by remnant cholesterol ≥1 vs. < 1 mmol/L (39 mg/dL) were 1.49 (95% CI: 1.39–1.59) and 1.47 (1.43–1.52) in individuals without FH, 1.59 (1.31–1.93) and 1.18 (1.10–1.27) in Simon Broome FH, 1.50 (1.08–2.08) and 1.14 (0.89–1.45) in MEDPED FH, 1.60 (1.17–2.21) and 1.59 (1.20–2.09) in DLCN FH, and 1.48 (0.59–3.69) and 1.39 (0.88–2.19) in genetic FH. Conclusion In familial hypercholesterolaemia, remnant cholesterol ≥1 mmol/L (39 mg/dL) vs. below is associated with ≈50% higher risk of coronary artery disease, that is, above the already high risk due to lifelong genetically elevated LDL cholesterol.
