Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain and CIBERCV, Madrid, Spain.
Heart Failure and Transplantation Unit, Cardiology Department, University and Polytechnic La Fe Hospital, Valencia, Spain.
Transplantation. 2023 Feb 1;107(2):466-474. doi: 10.1097/TP.0000000000004273. Epub 2023 Jan 26.
Given the central role of sarcomeric dysfunction in cardiomyocyte biology and sarcomere alterations described in endomyocardial biopsies of transplant patients with rejection, we hypothesized that the serum expression levels of genes encoding sarcomeric proteins were altered in acute cellular rejection (ACR). The aim of this study is to identify altered sarcomere-related molecules in serum and to evaluate their diagnostic accuracy for detecting rejection episodes.
Serum samples from transplant recipients undergoing routine endomyocardial biopsies were included in an RNA sequencing analysis (n = 40). Protein concentrations of alpha-cardiac actin were determined using a specific enzyme-linked immunoassay (n = 80).
We identified 17 sarcomeric genes differentially expressed in patients with clinically relevant rejection (grade ≥2R ACR). A receiver operating characteristic curve was done to assess their accuracy for ACR detection and found that 6 relevant actins, myosins, and other sarcomere-related genes showed great diagnostic capacity with an area under the curve (AUC) > 0.800. Specifically, the gene encoding alpha-cardiac actin ( ACTC1 ) showed the best results (AUC = 1.000, P < 0.0001). We determine ACTC1 protein levels in a larger patient cohort, corroborating its overexpression and obtaining a significant diagnostic capacity for clinically relevant rejection (AUC = 0.702, P < 0.05).
Sarcomeric alterations are reflected in peripheral blood of patients with allograft rejection. Because of their precision to detect ACR, we propose sarcomere ACTC1 serum expression levels as potential candidate for to be included in the development of molecular panel testing for noninvasive ACR detection.
由于肌节功能障碍在心肌细胞生物学中的核心作用以及移植患者排斥反应的心肌活检中描述的肌节改变，我们假设编码肌节蛋白的基因在急性细胞排斥（ACR）中的血清表达水平发生改变。本研究的目的是鉴定血清中改变的肌节相关分子，并评估其检测排斥发作的诊断准确性。
纳入接受常规心肌活检的移植受者的血清样本进行 RNA 测序分析（n = 40）。使用特定的酶联免疫吸附测定法（n = 80）测定α-心肌肌动蛋白的蛋白浓度。
我们在具有临床相关排斥（≥2R ACR）的患者中鉴定出 17 个肌节基因差异表达。绘制了接受者操作特征曲线以评估其检测 ACR 的准确性，并发现 6 个相关肌动蛋白、肌球蛋白和其他肌节相关基因的 AUC > 0.800，具有很好的诊断能力。特别是编码α-心肌肌动蛋白（ACTC1）的基因表现出最佳结果（AUC = 1.000，P < 0.0001）。我们在更大的患者队列中确定了 ACTC1 蛋白水平，证实了其过表达，并获得了用于检测临床相关排斥的显著诊断能力（AUC = 0.702，P < 0.05）。
肌节改变反映在同种异体移植排斥患者的外周血中。由于其精确性可检测 ACR，我们提出肌节 ACTC1 血清表达水平作为潜在候选物，以包含在用于非侵入性 ACR 检测的分子面板检测的开发中。
