Jean-Paul Duong Van Huyen1, Marion Tible2, Arnaud Gay3, Romain Guillemain4, Olivier Aubert5, Shaida Varnous6, Franck Iserin7, Philippe Rouvier6, Arnaud François3, Dewi Vernerey5, Xavier Loyer5, Pascal Leprince6, Jean-Philippe Empana5, Patrick Bruneval8, Alexandre Loupy2, Xavier Jouven2. 1. 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. 2. 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. 3. Cardio-Thoracic Surgery Unit and Pathology Department, Rouen University Hospital, France. 4. Department of Pathology and Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, APHP, Paris F-75015, France. 5. Paris Translational Research Center for Organ Transplantation, INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris F-75015, France. 6. Cardio-Thoracic Surgery Unit and Pathology Department, La Pitié-Salpétrière, APHP, Paris F-75013, France. 7. Departement of Cardiology, Necker Hospital, APHP, Paris F-75015, France. 8. 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.
Abstract
AIM: 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
RCT Entities:
AIM: 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.