title: Multicenter Analysis of Immune Biomarkers and Heart Transplant Outcomes: Results of the Clinical Trials in Organ Transplantation-05 Study.
abstract: Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.
authors.affiliation: Kaufman Center for Heart Failure, Cleveland Clinic and the Cleveland Clinic Lerner College of Medicine, Cleveland, OH.
authors.forename: R C
authors.initials: RC
authors.lastname: Starling
authors.affiliation: Division of Cardiovascular Medicine, University of Utah Health Sciences Center, Salt Lake City, UT.
authors.forename: J
authors.initials: J
authors.lastname: Stehlik
authors.affiliation: Transplant Center, Newark Beth Israel Medical Center, Newark, NJ.
authors.forename: D A
authors.initials: DA
authors.lastname: Baran
authors.affiliation: Rho, Chapel Hill, NC.
authors.forename: B
authors.initials: B
authors.lastname: Armstrong
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: J R
authors.initials: JR
authors.lastname: Stone
authors.affiliation: Rho, Chapel Hill, NC.
authors.forename: D
authors.initials: D
authors.lastname: Ikle
authors.affiliation: Transplantation Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD.
authors.forename: Y
authors.initials: Y
authors.lastname: Morrison
authors.affiliation: Transplantation Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD.
authors.forename: N D
authors.initials: ND
authors.lastname: Bridges
authors.affiliation: Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: P
authors.initials: P
authors.lastname: Putheti
authors.affiliation: Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
authors.affiliation: Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA.|Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: M
authors.initials: M
authors.lastname: Bhasin
authors.affiliation: Department of Medicine, Schuster Family Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: I
authors.initials: I
authors.lastname: Guleria
authors.affiliation: Department of Medicine, Schuster Family Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: Chandraker
authors.affiliation: Department of Medicine, Schuster Family Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: M
authors.initials: M
authors.lastname: Sayegh
authors.affiliation: Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: K P
authors.initials: KP
authors.lastname: Daly
authors.affiliation: Department of Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: D M
authors.initials: DM
authors.lastname: Briscoe
authors.affiliation: Translational Transplant Research Center, Department of Medicine, Immunology Institute and Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: P S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002986:Clinical Trials as Topic; D003324:Coronary Artery Disease / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D006331:Heart Diseases / Q000601:surgery*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A
chemical_list: D015415:Biomarkers; D019332:Endothelin-1; D012333:RNA, Messenger; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Biomarker; heart transplantation/cardiology; monitoring: immune; rejection: acute; translational research/science; vasculopathy