Investigation of hub genes and immune status in heart transplant rejection using endomyocardial biopsies

Abstract

Over the last 5 decades, heart transplantation (HTx) has become the definitive gold standard surgical approach for patients with end-stage heart disease, such as heart failure. 1,2 However, even with immunosuppressive treatments, allograft rejection remains a major cause of morbidity and mortality because the pathogenesis, diagnosis and management of rejection remain highly undefined. 3,4 According to the International Society for Heart and Lung Transplantation (ISHLT) guidelines, HTx rejection can be divided into T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), the diagnoses of which are based on the histology of the endomyocardial biopsies (EMBs). 5-9 Recently, molecular examination of EMBs has been proposed to improve the precision and accuracy of HTx rejection diagnosis. A new diagnostic system, the Molecular Microscope™ Diagnostic System

Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection

“…We assessed overlap of the AR signature with other previously identified signatures. This includes the antibody mediated rejection (AbMR) signature previously identified in Loupy et al 17 as well as t-cell mediated rejection (TCMR) and AbMR signatures curated from large datasets by Xiu et al 18 For the former, we observed that »30% of genes in the Loupy et al signature, as well as »20% of the genes in the TCMR signature, are present in our AR signature (Figure S1A). Furthermore, »36% of the genes in the AbMR signature from Xiu et al (Figure S1B) are present in our AR signature, indicating that while a subset of the characterized genes are novel, there is concordance with prior studies in this area.…”

“…17 Additional recent work by Xiu et al utilized prior expression array datasets to identify signatures associated with tcell mediated and antibody-mediated rejection. 18 While these prior studies have advanced our knowledge of rejection-associated transcriptional regulation, array-based expression platforms have a large of number of limitations vs RNA-seq including smaller dynamic range and inability to detect novel transcripts and splicing isoforms. 19,20 In this current study, we performed the first RNA-sequencing (RNA-seq) study on 125 longitudinal EMB samples prospectively collected as part of the Clinical Trials of Transplantation (CTOT)-03 study with the aim of assessing the sensitivity and specificity of acute rejection diagnoses.…”

Subtyping based on immune cell fractions reveal heterogeneity of cardiac fibrosis in end-stage heart failure

“…We envision that the 30-gene biomarker panel derived from ventricular tissue samples could provide a key reference for patient stratification, facilitating personalised therapeutic strategies based on drugs targeting fibrotic pathways (especially those related to subtype-specific pro-fibrotic gene sets, such as endothelin inhibitors, anti-TGFβ drugs, and anti-inflammation drugs), and reduce the adverse symptoms caused by drug treatments (such as inflammatory response ( 21 )). Although ventricular tissue samples can be obtained with endomyocardial biopsy ( 99 ), the procedure increases mortality risk, cost and inconveniences the patient. Routine screening and assessment of patient subtypes would be more feasible through minimally invasive methods such as cardiovascular magnetic resonance (CMR), which is non-invasive and is the primary technology for stratifying patients with cardiac fibrosis ( 19 , 100 ).…”

Long noncoding RNA NEAT1 promotes cardiac fibrosis in heart failure through increased recruitment of EZH2 to the Smad7 promoter region

“…There has been increasing interest in the link between Neat1-related pathways and fibrotic diseases, but there are still no detailed reports on the role of Neat1 in cardiac fibrosis. Cardiac fibrosis is a crucial hallmark of heart failure [ 42 ] that, ultimately, irreversibly accelerates its clinical progression [ 43 ]. Thus, understanding the specific pathogenesis of cardiac fibrosis is essential for designing new therapeutic strategies to prevent heart failure.…”