Alberta Transplant Applied Genomics Center, Edmonton, AB, Canada.
Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Transplantation. 2024 Sep 1;108(9):1931-1942. doi: 10.1097/TP.0000000000004986. Epub 2024 Aug 20.
Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart study ( ClinicalTrials.gov No. NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study ( ClinicalTrials.gov No. NCT04239703).
We analyzed 137 consecutive dd-cfDNA-EMB pairs from 70 patients. Plasma %dd-cfDNA was measured by the Prospera test (Natera Inc), and gene expression in EMBs was assessed by Molecular Microscope Diagnostic System using machine-learning algorithms to interpret rejection and injury states.
Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as interferon gamma-inducible genes (eg, HLA-DMA ) but also with genes induced by injury and expressed in macrophages (eg, SERPINA1 and HMOX1 ). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts.
In this first analysis of Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in clinical management of heart transplant recipients.
血浆供体来源的无细胞 DNA（dd-cfDNA）用于筛查心脏移植中的排斥反应。我们开展了 Trifecta-Heart 研究（ClinicalTrials.gov 编号：NCT04707872），这是一项由研究者发起的前瞻性试验，旨在研究心内膜活检（EMB）中全基因组分子变化与血浆 dd-cfDNA 之间的相关性。本报告分析了来自 4 个先锋中心的 EMB 中血浆 dd-cfDNA 与基因表达的相关性，并将这些相关性与 Trifecta-Kidney 研究（ClinicalTrials.gov 编号：NCT04239703）中的 604 例肾脏移植活检进行了比较。
我们分析了来自 70 例患者的 137 对连续的 dd-cfDNA-EMB 样本。通过 Prospera 试验（Natera Inc）测量血浆%dd-cfDNA，使用机器学习算法通过分子显微镜诊断系统评估 EMB 中的基因表达，以解释排斥和损伤状态。
与 dd-cfDNA 相关性最高的转录本与排斥反应中增加的基因有关，如干扰素γ诱导基因（如 HLA-DMA），但也与损伤诱导并在巨噬细胞中表达的基因有关（如 SERPINA1 和 HMOX1）。在基因富集分析中，与 dd-cfDNA 相关性最高的基因反映了炎症和排斥反应途径。EMB 中与排斥反应基因的 dd-cfDNA 相关性与肾脏移植活检中的相关性相似，但心脏中的 TCMR 基因和肾脏中的 ABMR 基因的相关性更强。然而，与实质损伤诱导基因和巨噬细胞基因的相关性在心脏中要强得多。
在 Trifecta-Heart 研究的首次分析中，dd-cfDNA 与分子排斥反应显著相关，但也与损伤和巨噬细胞浸润相关，反映了受损心肌细胞的促炎特性。这种关系支持了 dd-cfDNA 在心脏移植受者临床管理中的应用。
