Maternal Inheritance of Familial Hypercholesterolemia Gene Mutation Predisposes to Coronary Atherosclerosis as Assessed by Calcium Score in Adulthood

Abstract

Background: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis. Methods: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score. Results: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P <0.0001) and were 2 years older (46.9±16.8 versus 44.7±15.9 years old, P =0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%–170%; P =0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06–3.11; P =0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39–5.51; P =0.004) when compared with paternal inheritance in multivariate analysis. Conclusions: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor.

Dyslipidaemia management in pregnant patients: a 2024 update

“…In a multivariate analysis of the French National Registry of FH, it was shown that maternal inheritance of the FH gene is associated with an increase in CAC scores by 86% (95% CI, 23–170%; P = 0.003), a 1.81-fold higher risk of having a CAC score ≥ 100 Agatston units (95% CI, 1.06–3.11; P = 0.03), and a 2.72-fold risk of having a CAC score ≥ 400 Agatston units (95% CI, 1.39–5.51; P = 0.004) compared with paternal inheritance. 99 Given the apparent safety of statins in pregnancy, Graham and Raal 100 have recommended that women homozygous for FH or with a defined atherosclerotic vessel or aortic disease be treated with statins during pregnancy if lipoprotein apheresis is not a therapeutic option.…”

Lipid metabolism during pregnancy: consequences for mother and child

“…On the other hand, a significant association between maternal inheritance and increased coronary artery calcium scores was observed in 1350 French patients, but no difference in prevalence of cardiovascular events [ 48 ▪ ]. Surprisingly, a Canadian study found a younger age at first event and a 1.5-fold increased risk of ASCVD adjusted for confounders with paternal inheritance compared to maternal inheritance [ 49 ].…”

Familial Hypercholesterolemia in Children. The Current State of the Problem

“…Схожие данные были получены в другом ретроспективном исследовании с участием более чем 1300 пациентов, занесенных во французский регистр семейной гиперхолестеринемии. Пациенты с материнским наследованием дефектного гена семейной гиперхолестеринемии реже имели семейный анамнез преждевременных сердечно-сосудистых событий [30]. Механизмы, лежащие в основе данного феномена, неизвестны [29].…”