title: Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.
abstract: Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.|Institute for Pathology, University of Duisburg-Essen, Essen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Afzali
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Chapman
authors.affiliation: Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Racapé
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: B
authors.identifier: http://orcid.org/0000-0003-1908-1739
authors.initials: B
authors.lastname: Adam
authors.affiliation: Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Gil
authors.affiliation: Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Hidalgo
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Sis
authors.affiliation: Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, Paris, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Duong Van Huyen
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Mengel
mesh_terms: D000328:Adult; D064591:Allografts; D015415:Biomarkers / Q000032:analysis*; D001706:Biopsy; D005260:Female; D005500:Follow-Up Studies; D005557:Formaldehyde / Q000737:chemistry*; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology; D006085:Graft Survival; D006333:Heart Failure / Q000601:surgery; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000235:genetics*; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D014019:Tissue Donors
chemical_list: D015415:Biomarkers; D007518:Isoantibodies; D005557:Formaldehyde
keywords: biopsy; clinical research/practice; heart transplantation/cardiology; molecular biology; pathology/histopathology; rejection: antibody-mediated (ABMR)