Grupo de investigación en Cardiología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), SERGAS, Universidade da Coruña (UDC), Spain.
Servicio de Cardiología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), CIBERCV, SERGAS, Universidade da Coruña (UDC), Spain.
J Heart Lung Transplant. 2020 Oct;39(10):1100-1108. doi: 10.1016/j.healun.2020.05.018. Epub 2020 Jun 7.
Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx.
This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0R → 2R → 0R). Relative expression (2) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx.
A total of 21 ACR episodes (0R → 2R → 0R) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%.
miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.
急性细胞排斥（ACR）是心脏移植（HTx）的主要并发症。心内膜心肌活检是早期检测 ACR 的参考方法，但需要一种新的非侵入性方法。候选者可能是循环 microRNAs。本研究旨在发现和验证 HTx 后用于 ACR 检测的血清中的 microRNAs。
这是一项前瞻性、观察性、单中心研究，纳入了 121 例 HTx 患者。根据国际心肺移植学会（ISHLT）分类（0R-3R）对 ACR 进行分级。首先，在发现阶段，对排斥前、排斥时和排斥后时间点（0R→2R→0R）的患者血清样本进行 microRNA 表达谱分析。通过逆转录定量聚合酶链反应（qPCR）分析每个样本中 179 个 microRNAs 的相对表达量（2）。其次，选择在 ACR 期间呈显著上升和下降模式的 microRNA 进入下一个验证阶段，在该阶段分析 2 组患者的血清样本：无 ACR 组（0R 级）和 ACR 组（≥2R 级）。最后，进行敏感性分析（受试者工作特征曲线）以评估 microRNA 检测 HTx 中 ACR 的准确性。
共纳入 21 例 ACR 发作（0R→2R→0R）及其相应的血清样本（n=63）进行发现阶段分析。在分析的 179 个 microRNAs 中，只有 miR-181a-5p 符合上升和下降标准。在验证阶段，ACR 组（n=45）的 miR-181a-5p 相对表达量（2）明显升高（p<0.0001）与无 ACR 组（n=45）。miR-181a-5p 的曲线下面积为 0.804（95%置信区间：0.707-0.880）；灵敏度和特异性分别为 78%和 76%，阴性预测值为 98%。
血清中的 miR-181a-5p 是一种潜在的非侵入性 ACR 生物标志物（曲线下面积=0.80，阴性预测值=98%）。因此，该生物标志物可以减少对心内膜心肌活检的需求以及这种有创性操作的相关风险和成本。
