Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks.
Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks.
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DOI：
10.1161/atvbaha.113.301373
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Hazen SL
中科院分区：
文献类型：
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作者：
Li XM;Tang WH;Mosior MK;Huang Y;Wu Y;Matter W;Gao V;Schmitt D;Didonato JA;Fisher EA;Smith JD;Hazen SL
载脂蛋白B（apo B）去除血清胆固醇流出活性降低与冠状动脉疾病的流行有关，但其对心血管事件的预后价值尚不清楚。我们研究了胆固醇流出活性与冠状动脉疾病和主要不良心血管事件（死亡、心肌梗死或卒中）的关系。在2个病例对照队列中测量游离胆固醇富集巨噬细胞的胆固醇流出活性：（1）血管造影队列（n=1150），包括接受择期诊断性冠状动脉造影术的稳定受试者和（2）门诊队列（n=577）。对胆固醇流出试验的培养基分析显示，高密度脂蛋白组分（1.063<d<1.21）仅含有少量（约40%）释放的[14 C]胆固醇，大部分在脂蛋白颗粒去除组分中发现，其中约60%在载脂蛋白A1免疫沉淀后回收。白蛋白免疫沉淀法在该馏分中回收了另外约30%的放射性标记胆固醇。在两个队列的未校正模型中，ATP结合盒转运体A1刺激的巨噬细胞的胆固醇外排活性增强与流行性冠状动脉疾病风险降低相关;然而，仅在门诊队列中校正传统冠状动脉疾病风险因素后，反向风险关系仍显着。令人惊讶的是，较高的胆固醇外排活性与心肌梗死/卒中（校正风险比，2.19; 95%置信区间，1.02-4.74）和主要不良心血管事件（校正风险比，1.85; 95%置信区间，1.11-3.06）的前瞻性（3年）风险增加相关。胆固醇流出到apoB耗竭血清的增加与心肌梗死、卒中和死亡的预期风险增加矛盾相关。在胆固醇外排活性测定中，巨噬细胞释放的大多数放射性标记胆固醇不存在于高密度脂蛋白颗粒内。
Diminished cholesterol efflux activity of apolipoprotein B (apoB)–depleted serum is associated with prevalent coronary artery disease, but its prognostic value for incident cardiovascular events is unclear. We investigated the relationship of cholesterol efflux activity with both prevalent coronary artery disease and incident development of major adverse cardiovascular events (death, myocardial infarction, or stroke). Cholesterol efflux activity from free cholesterol–enriched macrophages was measured in 2 case– control cohorts: (1) an angiographic cohort (n=1150) comprising stable subjects undergoing elective diagnostic coronary angiography and (2) an outpatient cohort (n=577). Analysis of media from cholesterol efflux assays revealed that the high-density lipoprotein fraction (1.063<d<1.21) contained only a minority (≈40%) of [14C]cholesterol released, with the majority found within the lipoprotein particle–depleted fraction, where ≈60% was recovered after apolipoprotein A1 immunoprecipitation. Albumin immunoprecipitation recovered another ≈30% of radiolabeled cholesterol within this fraction. Enhanced cholesterol efflux activity from ATP-binding cassette transporter A1–stimulated macrophages was associated with reduced risk of prevalent coronary artery disease in unadjusted models within both cohorts; however, the inverse risk relationship remained significant after adjustment for traditional coronary artery disease risk factors only within the outpatient cohort. Surprisingly, higher cholesterol efflux activity was associated with increase in prospective (3 years) risk of myocardial infarction/stroke (adjusted hazard ratio, 2.19; 95% confidence interval, 1.02–4.74) and major adverse cardiovascular events (adjusted hazard ratio, 1.85; 95% confidence interval, 1.11–3.06). Heightened cholesterol efflux to apoB-depleted serum was paradoxically associated with increased prospective risk for myocardial infarction, stroke, and death. The majority of released radiolabeled cholesterol from macrophages in cholesterol efflux activity assays does not reside within a high-density lipoprotein particle.