Department of Paediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Lancet Child Adolesc Health. 2024 Jul;8(7):491-499. doi: 10.1016/S2352-4642(24)00073-7. Epub 2024 May 14.
Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence.
In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis.
The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037).
Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life.
Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.
家族性高胆固醇血症（HoFH）是一种罕见的遗传性疾病，其特征是从出生起血浆 LDL 胆固醇极高，导致年轻时发生动脉粥样硬化性心血管疾病。脂蛋白吸附联合降脂药物可有效降低 LDL 胆固醇，但这种治疗的长期健康结果尚不清楚。本研究旨在调查儿童或青少年期开始的脂蛋白吸附治疗的长期心血管结局。
在这项队列研究中，数据来自 HoFH 国际临床协作组（HICC）和国际儿童纯合子高胆固醇血症脂蛋白吸附治疗登记处（CHAIN）。总体队列包括在 2010 年 1 月 1 日至 2021 年 11 月 8 日期间确诊为 HoFH 且年龄为 0-18 岁的患者，这些患者存活且正在接受随访，其高血浆 LDL 胆固醇浓度使其有资格接受脂蛋白吸附治疗。为了比较心血管结局，将在儿童期开始脂蛋白吸附治疗的患者（脂蛋白吸附组）和仅接受降脂药物治疗的患者（药物治疗组）按性别和未治疗的血浆 LDL 胆固醇浓度进行匹配。主要结局是心血管死亡、心肌梗死、缺血性卒、经皮冠状动脉介入、冠状动脉旁路移植、主动脉瓣置换、外周动脉疾病、颈动脉内膜切除术、心绞痛、以及升主动脉或主动脉瓣狭窄（统称为动脉粥样硬化性心血管疾病）的复合结局，在匹配队列中进行生存分析。使用 Cox 回归分析比较两组的无病生存率，并计算调整性别、诊断时年龄、未治疗的血浆 LDL 胆固醇浓度和除脂蛋白吸附以外的降脂治疗次数后的危险比（HR）和 95%置信区间。
总体队列包括 404 名患者，中位诊断年龄为 6.0 岁（IQR 3.0-9.5），中位未治疗的血浆 LDL 胆固醇为 17.8mmol/L（14.7-20.8）。匹配的队列包括 250 名患者（每组 125 名患者），中位未治疗的 LDL 胆固醇为 17.2mmol/L（14.8-19.7）。与基线相比，脂蛋白吸附组的血浆 LDL 胆固醇浓度平均降低幅度更大（-55%[95%CI -60 至-51]比-31%[-36 至-25]；p<0·0001）。脂蛋白吸附组的动脉粥样硬化性心血管疾病无病生存率更长（调整后的 HR 0.52[95%CI 0.32-0.85]），心血管死亡无病生存率更长（0.0301[0.0021-0.4295]）。药物治疗组的心血管死亡更常见（10 例[8%]比 1 例[1%]；p=0.010），而脂蛋白吸附组的冠状动脉旁路移植中位年龄较低（15.0 岁[IQR 12.0-24.0]比 30.5 岁[19.0-33.8]；p=0.037）。
在 HoFH 患者中，儿童和青少年期开始的脂蛋白吸附治疗与降低长期发生动脉粥样硬化性心血管疾病和死亡的风险相关，并且发现早期开始高频治疗降低血浆胆固醇的明确益处。现在需要共识建议来指导更广泛和及时地使用脂蛋白吸附治疗 HoFH 儿童，还需要研究进一步优化治疗方法，并确保早期和积极治疗的益处与生活质量的影响之间达到平衡。
阿姆斯特丹大学医学中心，学术医学中心分部；宾夕法尼亚大学佩雷尔曼医学院；欧洲动脉粥样硬化学会；以及美国国立卫生研究院国家心肺血液研究所，国立卫生研究院。
