Circulating microRNAs in cellular and antibody-mediated heart transplant rejection

Palak Shah, Heart Failure, Mechanical Circulatory Support & Transplant, Inova Heart and Vascular Institute, Falls Church, Virginia; Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland. Electronic address: palak.shah@inova.org.
Sean Agbor-Enoh, Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; Applied Precision Genomics, National Heart, Lung and Blood Institute, Bethesda, Maryland.
Pramita Bagchi, Volgenau School of Engineering, George Mason University, Fairfax, Virginia.
Christopher R. deFilippi, Cardiovascular Medicine, Inova Heart and Vascular Institute, Falls Church, Virginia.
Angela Mercado, Heart Failure, Mechanical Circulatory Support & Transplant, Inova Heart and Vascular Institute, Falls Church, Virginia.
Gouqing Diao, Milken Institute School of Public Health, The George Washington University, Washington, District of Columbia.
Dave Jp Morales, Heart Failure & Transplantation, Stanford University, Palo Alto, California.
Keyur B. Shah, The Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.
Samer S. Najjar, Advanced Heart Failure Program, Medstar Heart and Vascular Institute, Washington Hospital Center, Washington, District of Columbia.
Erika Feller, Heart Failure & Transplantation, University of Maryland, Baltimore, Maryland.
Steven Hsu, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
Maria E. Rodrigo, The Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.
Sabra C. Lewsey, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
Moon Kyoo Jang, Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Applied Precision Genomics, National Heart, Lung and Blood Institute, Bethesda, Maryland.
Charles Marboe, Department of Pathology, New York Presbyterian University Hospital of Cornell and Columbia, New York, New York, New York.
Gerald J. Berry, Stanford University School of Medicine, Palo Alto, California.
Kiran K. Khush, Stanford University School of Medicine, Palo Alto, California.
Hannah A. Valantine, Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Stanford University School of Medicine, Palo Alto, California.

Document Type

Journal Article

Publication Date

10-1-2022

Journal

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

Volume

41

Issue

10

DOI

10.1016/j.healun.2022.06.019

Keywords

allograft rejection; biomarker; heart transplantation; microRNA

Abstract

BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection. METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use. RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively. CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

Department

Biostatistics and Bioinformatics

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