Heart Transplant Program, Transplant Institute, Tampa General Hospital, Tampa, Florida; Heart Failure Center, Heart & Vascular Institute, Tampa General Hospital, Tampa, Florida; Division of Cardiovascular Science, Department of Internal Medicine, Unversity of South Florida Morsani College of Medicine, Tampa, Florida.
Division of Cardiovascular Science, Department of Internal Medicine, Unversity of South Florida Morsani College of Medicine, Tampa, Florida; Morsani College of Medicine, University of South Florida, Tampa, Florida.
J Heart Lung Transplant. 2024 Mar;43(3):359-368. doi: 10.1016/j.healun.2023.09.009. Epub 2023 Sep 18.
The purpose of the study is to investigate the relationship between blood and tissue-derived rejection-related transcripts from blood gene expression profiling (GEP) and molecular microscope in the setting of allograft rejection in heart transplant.
All heart transplant patients from August 2021 to May 2022 with both circulating blood GEP (AlloMap) and endomyocardial biopsy with molecular microscope diagnostic system (MMDx) within 4 weeks were included (N = 173 samples). We obtained individual blood GEP-based messenger RNA transcript expression levels of the 11 target genes from CareDx. Student's t-test was performed to compare blood GEP transcript expression levels between no rejection and rejection as assessed by MMDx. A Scatter plot with Spearman correlation analysis was performed to compare the relationship between transcript expression levels from AlloMap and MMDx, with and without allograft rejection.
There were 52 samples (30.1%) with antibody-mediated rejection (ABMR) and 15 samples (8.7%) with T-cell-mediated rejection (TCMR), as assessed by MMDx. Expression of one of the blood ITGA4 (Integrin alpha 4) expression level was elevated in ABMR, compared to no ABMR (4,607.5 vs 4,217.5; p = 0.019). Most tissue rejection-associated transcript expression levels were elevated in ABMR, and tissue ROBO4 expression correlated with the blood ITGA4 expression with moderate or greater effect size in all samples (Spearman's R = 0.31; p < 0.001). There was also a positive correlation between blood ITGA4 and tissue ROBO4 expression in samples without ABMR (Spearman's R = 0.33; p < 0.001), but no correlation between blood ITGA4 and tissue ROBO4 expression in samples with ABMR (Spearman's R = 0.009; p = 0.513).
Circulating blood ITGA4 expression is elevated in antibody-mediated rejection (AMR) and correlates with myocardial expression of ROBO4. The knowledge of individual transcript expression levels in blood and in tissue may provide insights into various disease processes in heart transplant patients. Taken together, the results of our study reveal an overlap between 2 objective post-heart transplant rejection surveillance methods, identify potential novel markers for ABMR, and reveal the need for a deeper understanding of molecular mechanisms underlying allograft rejection.
本研究旨在探讨血液基因表达谱（GEP）和分子显微镜检查中血液和组织来源的排斥相关转录物与同种异体移植排斥之间的关系。
纳入 2021 年 8 月至 2022 年 5 月间接受心脏移植的患者，在 4 周内同时进行循环血液 GEP（AlloMap）和分子显微镜诊断系统（MMDx）检查（N=173 个样本）。我们从 CareDx 获得了 11 个靶基因的个体血液 GEP 信使 RNA 转录表达水平。采用学生 t 检验比较 MMDx 评估的无排斥和排斥患者的血液 GEP 转录表达水平。采用散点图和 Spearman 相关性分析比较 AlloMap 和 MMDx 中转录表达水平与有无同种异体移植排斥的关系。
根据 MMDx 评估，52 个样本（30.1%）存在抗体介导的排斥（ABMR），15 个样本（8.7%）存在 T 细胞介导的排斥（TCMR）。与无 ABMR 相比，ABMR 中血液 ITGA4（整合素 alpha 4）表达水平升高（4607.5 比 4217.5；p=0.019）。大多数组织排斥相关转录物表达水平在 ABMR 中升高，并且组织 ROBO4 表达与所有样本中血液 ITGA4 表达具有中等或更大的效应大小相关（Spearman's R=0.31；p<0.001）。在无 ABMR 的样本中，血液 ITGA4 与组织 ROBO4 表达之间也存在正相关（Spearman's R=0.33；p<0.001），但在有 ABMR 的样本中，血液 ITGA4 与组织 ROBO4 表达之间无相关性（Spearman's R=0.009；p=0.513）。
循环血液 ITGA4 表达在抗体介导的排斥（ABMR）中升高，并与心肌中 ROBO4 的表达相关。血液和组织中个体转录表达水平的知识可能为心脏移植患者的各种疾病过程提供深入了解。总之，本研究结果揭示了两种客观的心脏移植后排斥监测方法之间的重叠，确定了潜在的 ABMR 新标志物，并揭示了深入了解同种异体移植排斥分子机制的必要性。
