PURPOSE

Clinical models to identify patients at high risk of primary graft dysfunction (PGD) after heart transplantation (HT) are limited, and the underlying pathophysiology of this common post-transplant complication remains poorly understood. We sought to identify whether pre-transplant levels of circulating proteins reporting on immune activation and inflammation are associated with incident PGD.

METHODS

The study population consisted of 219 adult heart transplant recipients identified between 2016 and 2020 at Duke University Medical Center, randomly divided into derivation (n = 131) and validation (n = 88) sets. PGD was defined using modified ISHLT criteria. Proteomic profiling was performed using Olink panels (n = 354 proteins) with serum samples collected immediately prior to transplantation. Association between normalized relative protein expression and PGD was tested using univariate and multivariable (recipient age, creatinine, mechanical circulatory support, and sex; donor age; ischemic time) models. Significant proteins identified in the derivation set (p < 0.05 in univariate models), were then tested in the validation set. Pathway enrichment analysis was used to test candidate biological processes. The predictive performance of proteins was compared to that of the RADIAL score.

RESULTS

Nine proteins were associated with PGD in univariate models in the derivation set. Of these, only CLEC4C remained associated with PGD in the validation set after Bonferroni correction (OR [95% CI] = 3.04 [1.74,5.82], p = 2.8 × 10⁻⁴). Patterns of association were consistent for CLEC4C in analyses stratified by biventricular/left ventricular and isolated right ventricular PGD. Pathway analysis identified interferon-alpha response and C-type lectin signaling as significantly enriched biologic processes. The RADIAL score was a poor predictor of PGD (AUC = 0.55). CLEC4C alone (AUC = 0.66, p = 0.048) and in combination with the clinical covariates from the multivariable model (AUC = 0.69, p = 0.018) improved discrimination for the primary outcome.

CONCLUSIONS

Pre-transplantation circulating levels of CLEC4C, a protein marker of plasmacytoid dendritic cells (pDCs), may identify HT recipients at risk for PGD. Further studies are needed to better understand the potential role pDCs and the innate immune response in PGD.

中文翻译：

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蛋白质组学分析将 CLEC4C 表达鉴定为心脏移植后原发性移植物功能障碍的新生物标志物

目的

用于识别心脏移植(HT)后原发性移植物功能障碍 (PGD) 高风险患者的临床模型是有限的，而且这种常见的移植后并发症的潜在病理生理学仍然知之甚少。我们试图确定报告免疫激活和炎症的循环蛋白的移植前水平是否与事件 PGD 相关。

方法

研究人群由 2016 年至 2020 年间在杜克大学医学中心确定的 219 名成年心脏移植受者组成，随机分为推导组 ( n  = 131) 和验证组 ( n  = 88)。PGD​​ 是使用修改后的 ISHLT 标准定义的。使用 Olink 面板 ( n  = 354 蛋白质) 进行蛋白质组学分析，并在移植前立即收集血清样本。使用单变量和多变量（受体年龄、肌酐、机械循环支持和性别；供体年龄；缺血时间）模型测试标准化相对蛋白表达与 PGD 之间的关联。在派生集中鉴定的重要蛋白质 ( p< 0.05 在单变量模型中），然后在验证集中进行测试。通路富集分析用于测试候选生物过程。将蛋白质的预测性能与 RADIAL 评分的预测性能进行比较。

结果

在推导集中的单变量模型中，九种蛋白质与 PGD 相关。其中，在 Bonferroni 校正后，验证集中只有 CLEC4C 仍与 PGD 相关（OR [95% CI] = 3.04 [1.74,5.82]，p  = 2.8 × 10 ^-4）。在按双心室/左心室和孤立的右心室 PGD 分层的分析中，CLEC4C 的关联模式是一致的。通路分析将干扰素-α 反应和 C 型凝集素信号确定为显着丰富的生物过程。RADIAL 评分不能很好地预测 PGD（AUC = 0.55）。单独使用 CLEC4C (AUC = 0.66, p  = 0.048) 并结合多变量模型的临床协变量 (AUC = 0.69, p = 0.018) 提高了对主要结果的区分度。

结论

CLEC4C 是浆细胞样树突状细胞 (pDC) 的一种蛋白质标志物，移植前循环水平可以识别 HT 受体的 PGD 风险。需要进一步研究以更好地了解 pDCs 和 PGD 中的先天免疫反应的潜在作用。