Sex differences in atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia have been reported but are not fully established. We aimed to assess sex differences in the risk of ASCVD and life-time burden of ASCVD in patients with heterozygous familial hypercholesterolaemia. SAFEHEART is a nationwide, multicentre, long-term prospective cohort study conducted in 25 tertiary care hospitals and one regional hospital in Spain. Participants in the SAFEHEART study aged 18 years or older with genetically confirmed familial hypercholesterolaemia were included in our analysis. Data were obtained between Jan 26, 2004, and Nov 30, 2022. ASCVD and age at onset were documented at enrolment and at follow-up. Our aim was to investigate the differences by sex in the risk and burden of ASCVD in patients with heterozygous familial hypercholesterolaemia, over the study follow-up and over the life course. The SAFEHEART study is registered with , . Of the 5262 participants in SAFEHEART at the time of analysis, 3506 (1898 [54·1%] female and 1608 [45·9%] male participants) met the inclusion criteria and were included in the current study. Mean age was 46·1 years (SD 15·5) and median follow-up was 10·3 years (IQR 6·4–13·0). Mean on-treatment LDL-cholesterol at follow-up was 3·1 mmol/L (SD 1·4) in females and 3·0 mmol/L (1·5) in males. LDL-cholesterol reductions over time were similar in both sexes (1·39 mmol/L [95% CI 1·30–1·47] absolute reduction in females 1·39 mmol/L [1·29–1·48] in males; p=0·98). At enrolment, 130 (6·8%) females and 304 (18·9%) males (p<0·0001) had cardiovascular disease. During follow-up, 134 (7·1%) females and 222 (13·8%) males (p<0·0001) had incident cardiovascular events. Median age at first ASCVD event (mostly due to coronary artery disease) was 61·6 years (IQR 50·0–71·4) in females and 50·6 years (42·0–58·6) in males (p<0·0001). The adjusted hazard ratio for ASCVD in males compared with females during follow-up was 1·90 (95% CI 1·49–2·42) and for cardiovascular death was 1·74 (1·11–2·73). Major adverse cardiovascular disease event (MACE)-free survival from birth was lower in males than females (hazard ratio 3·52 [95% CI 2·98–4·16]; p<0·0001). Median MACE-free survival time was 90·1 years (95% CI 86·5–not estimable) in females and 71·0 years (69·2–74·6) in males. The age at which 25% of female participants have had a MACE event was 74·9 years, this figure was 55·5 years in male participants. Our findings suggest that the burden and risk of ASCVD are markedly lower in females than males with familial hypercholesterolaemia. The impact of sex needs to be considered to improve risk stratification and personalised management in patients with heterozygous familial hypercholesterolaemia. Fundación Hipercolesterolemia Familiar, the Instituto de Salud Carlos III, and Next Generation EU funds from the Recovery and Resilience Mechanism Program. For the Spanish translation of the abstract see Supplementary Materials section.

中文翻译：

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西班牙杂合子家族性高胆固醇血症患者动脉粥样硬化性心血管疾病的长期性别差异：一项使用 SAFEHEART（一项全国性、多中心、前瞻性队列研究）数据的研究


家族性高胆固醇血症中动脉粥样硬化性心血管疾病（ASCVD）的性别差异已有报道，但尚未完全确定。我们的目的是评估杂合子家族性高胆固醇血症患者 ASCVD 风险和 ASCVD 终生负担的性别差异。 SAFEHEART 是一项全国性、多中心、长期前瞻性队列研究，在西班牙 25 家三级医院和一家地区医院进行。我们的分析中包括年龄 18 岁或以上且经基因证实患有家族性高胆固醇血症的 SAFEHEART 研究参与者。数据于2004年1月26日至2022年11月30日期间获得。ASCVD和发病年龄在入组和随访时记录。我们的目的是调查杂合子家族性高胆固醇血症患者在研究随访和生命历程中 ASCVD 风险和负担的性别差异。 SAFEHEART 研究已在 , 注册。在分析时 SAFEHEART 的 5262 名参与者中，有 3506 名（1898 [54·1%] 女性和 1608 [45·9%] 男性参与者）符合纳入标准并被纳入当前研究。平均年龄为 46·1 岁 (SD 15·5)，中位随访时间为 10·3 年 (IQR 6·4–13·0)。随访时治疗中的平均 LDL-胆固醇女性为 3·1 mmol/L (SD 1·4)，男性为 3·0 mmol/L (1·5)。随着时间的推移，两性 LDL 胆固醇的降低程度相似（1·39 mmol/L [95% CI 1·30–1·47]，女性绝对降低 1·39 mmol/L [1·29–1·48]）男性；p=0·98)。入组时，130 名 (6·8%) 女性和 304 名 (18·9%) 男性 (p<0·0001) 患有心血管疾病。在随访期间，134 名 (7·1%) 女性和 222 名 (13·8%) 男性 (p<0·0001) 发生了心血管事件。 首次 ASCVD 事件（主要由于冠状动脉疾病）的中位年龄女性为 61·6 岁 (IQR 50·0–71·4)，男性为 50·6 岁 (42·0–58·6) (p% 3C0·0001）。与女性相比，随访期间男性 ASCVD 的调整后风险比为 1·90 (95% CI 1·49–2·42)，心血管死亡风险比为 1·74 (1·11–2·73)。男性的无主要不良心血管疾病事件 (MACE) 出生后生存率低于女性（风险比 3·52 [95% CI 2·98–4·16]；p<0·0001）。女性中位无 MACE 生存时间为 90·1 年（95% CI 86·5 – 不可估计），男性为 71·0 年（69·2–74·6）。 25% 的女性参与者发生过 MACE 事件的年龄为 74·9 岁，男性参与者的这一数字为 55·5 岁。我们的研究结果表明，患有家族性高胆固醇血症的女性的 ASCVD 负担和风险明显低于男性。需要考虑性别的影响，以改善杂合子家族性高胆固醇血症患者的风险分层和个性化管理。 Fundación Hipercolesterolemia Familiar、Instituto de Salud Carlos III 和来自恢复和复原机制计划的下一代欧盟资金。有关摘要的西班牙语翻译，请参阅补充材料部分。