载脂蛋白 2 和钙卫蛋白可能成为外周动脉疾病的预后生物标志物。

Lipocalin-2 and Calprotectin Potential Prognosis Biomarkers in Peripheral Arterial Disease.

机构信息

Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Spain; IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain.

IdiSNA, Instituto de Investigación Sanitaria de Navarra, Spain; Laboratory of Heart Failure, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Pamplona, Spain; CIBERCV, Madrid, Spain.

出版信息

Eur J Vasc Endovasc Surg. 2022 Apr;63(4):648-656. doi: 10.1016/j.ejvs.2022.01.012. Epub 2022 Mar 17.

DOI:10.1016/j.ejvs.2022.01.012

PMID:35307155

Abstract

OBJECTIVE

Peripheral arterial disease (PAD) is the most prevalent cardiovascular (CV) condition globally. Despite the high CV risk of PAD patients, no reliable predictors of adverse clinical evolution are yet available. In this regard, previous transcriptomic analyses revealed increased expression of calprotectin (S100A8/A9) and lipocalin-2 (LCN2) in circulating extracellular vesicles (EVs) of patients with PAD. The aim of this study was to determine the prognostic value of LCN2 and calprotectin for CV risk assessment in PAD.

METHODS

LCN2 and the S100A9 subunit of calprotectin were examined in human femoral plaques by immunohistochemistry and qPCR. LCN2 and calprotectin were determined by ELISA in PAD (CHN cohort, n = 331, Fontaine II-IV, serum), and PAD diagnosed by population based screening (VIVA trial, n = 413, the majority Fontaine 0-I, plasma). Patients were followed up for a mean of four years, recording the primary outcomes; CV death or amputation in the CHN cohort and CV death or major lower limb events (MALE) in the VIVA population. Secondary outcomes were all cause death or amputation, and all cause death or MALE, respectively.

RESULTS

LCN2 and S100A9 were detected in human plaques in regions rich in inflammatory cells. LCN2 and calprotectin levels were 70% and 64% lower in plasma than in serum. In the CHN cohort, high serum levels of LCN2 and calprotectin increased the risk of primary and secondary outcomes 5.6 fold (p < .001) and 1.8 fold (p = .034), respectively, after covariable adjustment. Similarly, elevated plasma levels of LCN2 and calprotectin increased by three fold the risk of primary and secondary outcomes (p < .001) in the VIVA cohort. Moreover, addition of the combined variable to basal models, considering clinically relevant risk factors, improved reclassification for the primary outcome in both cohorts (p ≤ .024).

CONCLUSION

Combined assessment of the inflammatory biomarkers LCN2 and calprotectin might be useful for risk stratification in advanced and early PAD.

摘要

目的

外周动脉疾病（PAD）是全球最常见的心血管（CV）疾病。尽管 PAD 患者的 CV 风险很高，但目前还没有可靠的不良临床转归预测指标。在这方面，先前的转录组分析显示 PAD 患者循环细胞外囊泡（EVs）中钙卫蛋白（S100A8/A9）和脂钙蛋白-2（LCN2）的表达增加。本研究旨在确定 LCN2 和钙卫蛋白对 PAD 患者 CV 风险评估的预后价值。

方法

通过免疫组织化学和 qPCR 检测人股动脉斑块中的 LCN2 和钙卫蛋白的 S100A9 亚基。通过 ELISA 法检测 PAD（CHN 队列，n=331，Fontaine II-IV，血清）和基于人群筛查诊断的 PAD（VIVA 试验，n=413，大多数为 Fontaine 0-I，血浆）中的 LCN2 和钙卫蛋白。对患者进行平均 4 年的随访，记录主要结局；CHN 队列的 CV 死亡或截肢，VIVA 人群的 CV 死亡或主要下肢事件（MALE）。次要结局分别为全因死亡或截肢，以及全因死亡或 MALE。

结果

LCN2 和 S100A9 在富含炎症细胞的斑块区域中被检测到。与血清相比，血浆中 LCN2 和钙卫蛋白的水平分别降低了 70%和 64%。在 CHN 队列中，高血清 LCN2 和钙卫蛋白水平使主要和次要结局的风险分别增加了 5.6 倍（p<0.001）和 1.8 倍（p=0.034），在调整协变量后。同样，在 VIVA 队列中，升高的血浆 LCN2 和钙卫蛋白水平使主要和次要结局的风险增加了 3 倍（p<0.001）。此外，在两个队列中，将联合变量添加到考虑临床相关危险因素的基础模型中，可改善主要结局的重新分类（p≤0.024）。