title: MicroRNAs as non-invasive biomarkers of heart transplant rejection.
abstract: OBJECTIVE
  Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.
  
  
  METHODS
  We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity.
  
  
  RESULTS
  We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant.
  
  
  CONCLUSIONS
  This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France Université Sorbonne Paris Cité, France Department of Pathology, Necker Hospital, APHP, Paris F-75015, France jp.dvh@wanadoo.fr.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Duong Van Huyen
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France Université Sorbonne Paris Cité, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Tible
authors.affiliation: Cardio-Thoracic Surgery Unit and Pathology Department, Rouen University Hospital, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gay
authors.affiliation: Department of Pathology and Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, APHP, Paris F-75015, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guillemain
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Aubert
authors.affiliation: Cardio-Thoracic Surgery Unit and Pathology Department, La Pitié-Salpétrière, APHP, Paris F-75013, France.
authors.forename: Shaida
authors.initials: S
authors.lastname: Varnous
authors.affiliation: Departement of Cardiology, Necker Hospital, APHP, Paris F-75015, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Iserin
authors.affiliation: Cardio-Thoracic Surgery Unit and Pathology Department, La Pitié-Salpétrière, APHP, Paris F-75013, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rouvier
authors.affiliation: Cardio-Thoracic Surgery Unit and Pathology Department, Rouen University Hospital, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: François
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France.
authors.forename: Dewi
authors.initials: D
authors.lastname: Vernerey
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.affiliation: Cardio-Thoracic Surgery Unit and Pathology Department, La Pitié-Salpétrière, APHP, Paris F-75013, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leprince
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Empana
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France Université Sorbonne Paris Cité, France Department of Pathology and Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, APHP, Paris F-75015, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France Université Sorbonne Paris Cité, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Loupy
authors.affiliation: Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France Université Sorbonne Paris Cité, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jouven
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D006084:Graft Rejection / Q000175:diagnosis*; D006331:Heart Diseases / Q000601:surgery*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D057285:Precision Medicine; D012372:ROC Curve; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D035683:MicroRNAs
keywords: Biomarker; Heart transplantation; MicroRNA; Molecular medicine; Non-invasive; Personalized medicine; Transplant rejection