Department of Cardiovascular Medicine National Cerebral and Cardiovascular Center Suita Japan.
Department of Cardiovascular Medicine Kyorin University Faculty of Medicine Mitaka Japan.
J Am Heart Assoc. 2024 Aug 6;13(15):e033972. doi: 10.1161/JAHA.123.033972. Epub 2024 Jul 16.
The atherogenic characteristics of heterozygous familial hypercholesterolemia (HeFH) increase the risk of premature atherosclerotic cardiovascular disease including not only coronary artery disease but ischemic stroke. Asymptomatic intracranial artery stenosis/occlusion (IASO) is a major cause of ischemic stroke, but it has not yet been fully characterized in patients with HeFH.
This study analyzed 147 clinically diagnosed subjects with HeFH who underwent magnetic resonance imaging/magnetic resonance angiography imaging for evaluation of IASO (≥50% diameter stenosis). Major adverse cerebrovascular and cardiovascular events (cardiac death, ischemic stroke, and acute coronary syndrome) were compared in patients with HeFH with and without asymptomatic IASO. Asymptomatic IASO was observed in 13.6% of patients with HeFH. The untreated low-density lipoprotein cholesterol level (240±95 versus 244±75 mg/dL; =0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, =0.71; high-intensity statin, =0.81; ezetimibe, =0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, =0.39; low-density lipoprotein apheresis, =0.14), on-treatment low-density lipoprotein cholesterol level in patients with both HeFH and IASO was still suboptimally controlled (97±62 versus 105±50 mg/dL; =0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; =0.001). During the 12.4-year observational period (interquartile range, 6.2-24.6 years), asymptomatic IASO exhibited a 4.04-fold greater likelihood of experiencing a major adverse cardiovascular event (95% CI, 1.71-9.55; =0.001) in patients with HeFH. This increased risk of a major adverse cardiovascular event was consistently observed in a multivariate Cox proportional hazards model adjusting clinical characteristics (hazard ratio, 4.32 [95% CI, 1.71-10.9]; =0.002).
A total of 13.6% of Japanese subjects with HeFH presented with asymptomatic IASO. Despite lipid-lowering therapies, patients with both HeFH and IASO more likely had elevated risk of cerebrovascular and cardiovascular events. Our findings highlight asymptomatic IASO as a phenotypic feature of HeFH-related atherosclerosis, which ultimately affects future outcomes.
杂合子家族性高胆固醇血症（HeFH）的动脉粥样硬化特征增加了发生早发性动脉粥样硬化性心血管疾病的风险，包括不仅是冠心病，还有缺血性脑卒中。无症状性颅内动脉狭窄/闭塞（IASO）是缺血性脑卒中的主要原因，但尚未在 HeFH 患者中得到充分描述。
本研究分析了 147 例经临床诊断为 HeFH 的患者，他们接受了磁共振成像/磁共振血管造影成像评估 IASO（≥50%直径狭窄）。比较 HeFH 患者有无症状性 IASO 时的主要不良脑血管和心血管事件（心源性死亡、缺血性卒中和急性冠脉综合征）。HeFH 患者中无症状性 IASO 的发生率为 13.6%。两组患者的未治疗低密度脂蛋白胆固醇水平（240±95 与 244±75mg/dL；=0.67）无差异。尽管使用了降脂治疗（他汀类药物，=0.71；高强度他汀类药物，=0.81；依折麦布，=0.33；前蛋白转化酶枯草溶菌素 9 抑制剂，=0.39；低密度脂蛋白吸咐法，=0.14），但伴有 IASO 的 HeFH 患者的治疗后低密度脂蛋白胆固醇水平仍未得到理想控制（97±62 与 105±50mg/dL；=0.17），且甘油三酯水平更高（中位数，109 与 79mg/dL；=0.001）。在 12.4 年的观察期（四分位间距，6.2-24.6 年）内，伴有 IASO 的无症状性 HeFH 患者发生主要不良心血管事件的可能性增加了 4.04 倍（95%CI，1.71-9.55；=0.001）。在调整临床特征的多变量 Cox 比例风险模型中，这种主要不良心血管事件的风险增加一直存在（风险比，4.32[95%CI，1.71-10.9]；=0.002）。
日本 HeFH 患者中共有 13.6%出现无症状性 IASO。尽管进行了降脂治疗，但同时患有 HeFH 和 IASO 的患者发生脑血管和心血管事件的风险更高。我们的研究结果强调了无症状性 IASO 是 HeFH 相关动脉粥样硬化的表型特征，最终会影响未来的结果。
