The diagnosis of heart transplant rejection by histology in endomyocardial biopsies (EMB) is challenging. A molecular system (MMDx) has been developed to assess both T cell-mediated (TCMR) and antibody-mediated (ABMR) rejection in kidney transplant biopsies. The present project adapted the MMDx derived in kidney transplant biopsies to heart transplant EMBs. We collected a single bite from 331 standard-of-care EMBs from three centers and processed them on Affymetrix microarrays. EMB diagnoses were assessed by histology using ISHLT guidelines. To develop rejection tests for heart, the genes most highly associated with Rejection, ABMR, and TCMR in kidney transplants were used to perform semi-supervised clustering on the EMBs. Two-thirds of the biopsies were used as a discovery set, and the remaining third as a validation set. The biopsies segregated into three overlapping molecular clusters in the discovery set (fig 1A), roughly corresponding to histologic diagnoses of TCMR (A3), ABMR (A2), and No Rejection (A1) (fig 1B). Some histology ABMR and TCMR biopsies were molecularly No Rejection. Cluster scores in the validation set were assigned using a predictive model based on the molecular distribution of biopsies in the discovery set. Diagnostic performance was similar in the discovery and validation sets. Biopsies designated as ABMR by the molecular test showed reasonably good agreement with histology, and were highly associated with HLA antibody. There was less agreement between molecular and histologic TCMR, supporting concerns that the current histologic assessment of EMBs is poorly predictive of true TCMR. We conclude that the MMDx can provide a new basis for classifying endomyocardial biopsies and a new reference point for improving the assessment by histology. (Kidney biopsies from Clinicaltrials.govNCT#01299168).

CITATION INFORMATION: Halloran P, Kim D, Loupy A, Duong Van-Huyen J.-P, Bruneval P, Potena L, Leone O, Reeve J. Development and Validation of a Molecular Microscope Diagnostic System (MMDx) for Heart Transplant Biopsies. Am J Transplant. 2016;16 (suppl 3).

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