Familial hypercholesterolaemia patients face nearly 4-fold higher risk of needing aortic valve replacement, driven partly by elevated Lp(a), in 5,022 SAFEHEART participants (Eur Heart J 2021)

Original title: Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia

Eur Heart J · 7 June 2021 · 8

Pérez de Isla L, Watts GF, Alonso R, Díaz-Díaz JL, Muñiz-Grijalvo O, Zambón D, Fuentes F, de Andrés R, Padró T, López-Miranda J, Mata P

In the SAFEHEART cohort of 5,022 subjects (3,712 with familial hypercholesterolaemia, FH; 1,310 unaffected relatives), followed a mean 7.48 years, 50 FH patients (1.48%) and 3 unaffected relatives (0.27%) required aortic valve replacement (AVR) for aortic valve stenosis (OR 5.71, 95% CI 1.78-18.4, P=0.003). FH was independently associated with need for AVR (HR 3.89, 95% CI 1.20-12.63, P=0.024), and older age, prior atherosclerotic cardiovascular disease, hypertension, cumulative LDL-C-Lp(a)-years exposure, and elevated Lp(a) independently predicted the need for AVR. The findings show FH substantially raises the risk of needing aortic valve replacement, and suggest that reducing LDL-C and Lp(a) alongside controlling hypertension might slow aortic stenosis progression in FH, a hypothesis the authors say requires testing in clinical trials.

Original abstract

Aims: Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH.

Methods And Results: SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR [odds ratio 5.71; 95% confidence interval (CI): 1.78-18.4; P = 0.003] after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20-12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event.

Conclusion: The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials.ClinicalTrials.gov number NCT02693548.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.