Circulating microRNAs in cellular and antibody-mediated heart transplant rejection.
allograft rejection
biomarker
heart transplantation
microRNA
Journal
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
ISSN: 1557-3117
Titre abrégé: J Heart Lung Transplant
Pays: United States
ID NLM: 9102703
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
13
12
2021
revised:
17
06
2022
accepted:
22
06
2022
pubmed:
26
7
2022
medline:
5
10
2022
entrez:
25
7
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 35872109
pii: S1053-2498(22)02018-6
doi: 10.1016/j.healun.2022.06.019
pmc: PMC9529890
mid: NIHMS1826987
pii:
doi:
Substances chimiques
Antibodies
0
Biomarkers
0
Circulating MicroRNA
0
MicroRNAs
0
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1401-1413Subventions
Organisme : American Heart Association-American Stroke Association
ID : 17SDG33660431
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201300001C
Pays : United States
Organisme : NHLBI NIH HHS
ID : K23 HL143179
Pays : United States
Organisme : NIAID NIH HHS
ID : RC4 AI092673
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 International Society for Heart and Lung Transplantation. All rights reserved.
Références
Am J Transplant. 2013 Apr;13(4):1069-1074
pubmed: 23414257
Nucleic Acids Res. 2020 Jan 8;48(D1):D148-D154
pubmed: 31647101
Genome Biol. 2014;15(12):550
pubmed: 25516281
Circ Res. 2012 Feb 3;110(3):483-95
pubmed: 22302755
Cell. 1993 Dec 3;75(5):843-54
pubmed: 8252621
J Heart Lung Transplant. 2020 Oct;39(10):1100-1108
pubmed: 32654912
Circulation. 2017 Mar 7;135(10):917-935
pubmed: 28148598
Int J Oncol. 2012 Dec;41(6):1897-912
pubmed: 23026890
Eur Heart J. 2014 Dec 1;35(45):3194-202
pubmed: 25176944
Am J Transplant. 2019 Oct;19(10):2889-2899
pubmed: 30835940
Transplantation. 2012 Dec 15;94(11):1172-7
pubmed: 23222738
J Heart Lung Transplant. 2020 Oct;39(10):1003-1015
pubmed: 32811772
J Heart Lung Transplant. 2013 Dec;32(12):1147-62
pubmed: 24263017
J Stat Softw. 2010;33(1):1-22
pubmed: 20808728
Circulation. 2015 May 5;131(18):1608-39
pubmed: 25838326
J Heart Lung Transplant. 2009 May;28(5):417-22
pubmed: 19416767
Circulation. 2021 Mar 23;143(12):1184-1197
pubmed: 33435695
Am J Cardiol. 2010 Apr 1;105(7):1024-9
pubmed: 20346325
Curr Heart Fail Rep. 2017 Dec;14(6):454-464
pubmed: 28940102
Curr Opin Cardiol. 2021 May 1;36(3):320-328
pubmed: 33741769
Lab Invest. 2019 Apr;99(4):452-469
pubmed: 30542067
Transplantation. 2017 Mar;101(3):524-530
pubmed: 27893611
J Heart Lung Transplant. 2010 May;29(5):504-8
pubmed: 20133166
Br J Biomed Sci. 2017 Oct;74(4):187-192
pubmed: 28745139
Sci Transl Med. 2014 Jun 18;6(241):241ra77
pubmed: 24944192
BMC Genomics. 2019 Jun 21;20(1):513
pubmed: 31226924
Am J Transplant. 2006 Jan;6(1):150-60
pubmed: 16433769
J Heart Lung Transplant. 2015 Jul;34(7):970-7
pubmed: 25840504
J Heart Lung Transplant. 2013 Apr;32(4):463-6
pubmed: 23384889
Transplant Direct. 2020 Oct 19;6(11):e615
pubmed: 33134491
Biom J. 2005 Aug;47(4):458-72
pubmed: 16161804
Circulation. 2015 Mar 10;131(10):882-9
pubmed: 25673669
Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6229-34
pubmed: 21444804
Front Genet. 2020 Jun 03;11:442
pubmed: 32582273
J Heart Lung Transplant. 2018 Apr;37(4):503-512
pubmed: 29198929
J Heart Lung Transplant. 2016 Aug;35(8):953-61
pubmed: 27080415
J Heart Lung Transplant. 2005 Nov;24(11):1710-20
pubmed: 16297770
Am J Transplant. 2012 May;12(5):1113-23
pubmed: 22300508
J Heart Lung Transplant. 2018 Nov;37(11):1329-1340
pubmed: 30174164