背景: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过早发生动脉粥样硬化性心血管疾病的风险,不仅包括冠状动脉疾病,还包括缺血性卒中。无症状颅内动脉狭窄/闭塞(IASO)是缺血性卒中的主要原因,但尚未在HeFH患者中得到充分表征。
结果:本研究分析了147名临床诊断为HeFH的受试者,他们接受了磁共振成像/磁共振血管造影成像,以评估IASO(直径狭窄≥50%)。主要不良脑血管和心血管事件(心源性死亡,缺血性卒中,和急性冠状动脉综合征)在有和没有无症状IASO的HeFH患者中进行了比较。在13.6%的HeFH患者中观察到无症状IASO。未治疗的低密度脂蛋白胆固醇水平(240±95对244±75mg/dL;P=0.67)在两组之间没有差异。尽管使用了降脂治疗(他汀类药物,P=0.71;高强度他汀类药物,P=0.81;依泽替米贝,P=0.33;前蛋白转化酶subxilisin/kexin9型抑制剂,P=0.39;低密度脂蛋白单采术,P=0.14),HeFH和IASO患者的治疗中低密度脂蛋白胆固醇水平仍未得到最佳控制(97±62对105±50mg/dL;P=0.17),伴有更高的甘油三酯水平(中位数,109对79mg/dL;P=0.001)。在12.4年的观测期内(四分位间距,6.2-24.6年),在HeFH患者中,无症状IASO出现重大不良心血管事件的可能性增加4.04倍(95%CI,1.71~9.55;P=0.001).在调整临床特征(风险比,4.32[95%CI,1.71-10.9];P=0.002)。
结论:共有13.6%的日本HeFH患者出现无症状IASO。尽管有降脂治疗,同时患有HeFH和IASO的患者发生脑血管和心血管事件的风险较高.我们的发现强调无症状IASO是HeFH相关动脉粥样硬化的表型特征,最终影响未来的结果。
BACKGROUND: 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.
RESULTS: 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; P=0.67) did not differ between the 2 groups. Despite the use of lipid-lowering therapies (statin, P=0.71; high-intensity statin, P=0.81; ezetimibe, P=0.33; proprotein convertase subxilisin/kexin type 9 inhibitor, P=0.39; low-density lipoprotein apheresis, P=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; P=0.17), accompanied by a higher triglyceride level (median, 109 versus 79 mg/dL; P=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; P=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]; P=0.002).
CONCLUSIONS: 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.