Objective

Patients undergoing carotid endarterectomy (CEA) maintain a substantial residual risk of major cardiovascular events (MACE). Improved risk stratification is warranted to select high risk patients qualifying for secondary add on therapy. Plasma extracellular vesicles (EVs) are involved in atherothrombotic processes and their content has been related to the presence and recurrence of cardiovascular events. The association between pre-operative levels of five cardiovascular disease related proteins in plasma EVs and the post-operative risk of MACE was assessed.

Methods

In 864 patients undergoing CEA from 2002 to 2016 included in the Athero-Express biobank, three plasma EV subfractions (low density lipoprotein [LDL], high density lipoprotein [HDL], and tiny extracellular vesicles [TEX]) were isolated from pre-operative blood samples. Using an electrochemiluminescence immunoassay, five proteins were quantified in each EV subfraction: cystatin C, serpin C1, serpin G1, serpin F2, and CD14. The association between EV protein levels and the three year post-operative risk of MACE (any stroke, myocardial infarction, or cardiovascular death) was evaluated using multivariable Cox proportional hazard regression analyses.

Results

During a median follow up of three years (interquartile range 2.2 – 3.0), 137 (16%) patients developed MACE. In the HDL-EV subfraction, increased levels of CD14, cystatin C, serpin F2, and serpin C1 were associated with an increased risk of MACE (adjusted hazard ratios per one standard deviation increase of 1.30, 95% confidence interval [CI] 1.15–1.48; 1.22, 95% CI 1.06–1.42; 1.36, 95% CI 1.16–1.61; and 1.29, 95% CI 1.10–1.51; respectively), independently of cardiovascular risk factors. No significant associations were found for serpin G1. CD14 improved the predictive value of the clinical model encompassing cardiovascular risk factors (net re-classification index = 0.16, 95% CI 0.08–0.21).

Conclusion

EV derived pre-operative plasma levels of cystatin C, serpin C1, CD14, and serpin F2 were independently associated with an increased long term risk of MACE after CEA and are thus markers for residual cardiovascular risk. EV derived CD14 levels could improve the identification of high risk patients who may benefit from secondary preventive add on therapy in order to reduce future risk of MACE.

中文翻译：

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在接受颈动脉内膜切除术的患者中，术前血浆细胞外囊泡蛋白与长期继发性主要心血管事件的高风险相关

客观的

接受颈动脉内膜切除术 (CEA) 的患者仍有发生主要心血管事件 (MACE) 的大量残余风险。有必要改进风险分层，以选择有资格进行二次附加治疗的高风险患者。血浆细胞外囊泡 (EV) 参与动脉粥样硬化血栓形成过程，其含量与心血管事件的存在和复发有关。评估了血浆 EV 中五种心血管疾病相关蛋白的术前水平与 MACE 术后风险之间的关联。

方法

在 Athero-Express 生物库中 2002 年至 2016 年接受 CEA 的 864 名患者中，从术前分离出三种血浆 EV 亚组分（低密度脂蛋白 [LDL]、高密度脂蛋白 [HDL] 和微小的细胞外囊泡 [TEX]）血液样本。使用电化学发光免疫测定法，在每个 EV 亚组分中量化了五种蛋白质：胱抑素 C、丝氨酸蛋白酶抑制剂 C1、丝氨酸蛋白酶抑制剂 G1、丝氨酸蛋白酶抑制剂 F2 和 CD14。使用多变量 Cox 比例风险回归分析评估 EV 蛋白水平与术后三年 MACE（任何中风、心肌梗死或心血管死亡）风险之间的关联。

结果

在三年的中位随访期间（四分位距 2.2 – 3.0），137 名 (16%) 患者发生了 MACE。在 HDL-EV 亚组分中，CD14、胱抑素 C、丝氨酸蛋白酶抑制剂 F2 和丝氨酸蛋白酶抑制剂 C1 水平升高与 MACE 风险增加有关（调整后的风险比每增加 1.30 个标准差，95% 置信区间 [CI] 1.15– 1.48；1.22，95% CI 1.06–1.42；1.36，95% CI 1.16–1.61；和 1.29，95% CI 1.10–1.51；独立于心血管危险因素。未发现 serpin G1 的显着关联。CD14 提高了包含心血管危险因素的临床模型的预测价值（净重新分类指数 = 0.16，95% CI 0.08–0.21）。

结论

EV 衍生的术前血浆半胱氨酸蛋白酶抑制剂 C、丝氨酸蛋白酶抑制剂 C1、CD14 和丝氨酸蛋白酶抑制剂 F2 水平与 CEA 后长期 MACE 风险增加独立相关，因此是残余心血管风险的标志物。EV 衍生的 CD14 水平可以提高对可能受益于二级预防附加治疗的高危患者的识别，以降低未来发生 MACE 的风险。