The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Advanced Heart Failure and Heart Transplant Unit Complexo Hospitalario Universitario A Coruña A Coruña Spain

Baylor Scott and White Health Dallas Texas USA

Department of Cardiac Surgery Medical University of Vienna Vienna Austria

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cardiology Virginia Commonwealth University Richmond Virginia USA

Department of Medicine University of Alberta Edmonton Alberta Canada

Department of Medicine University of Utah Salt Lake City Utah USA

Heart Failure and Transplant Unit IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Ronald Reagan UCLA Medical Center Los Angeles California USA

Smidt Heart Institute Cedars Sinai Medical Center Los Angeles California USA

The Victor Chang Cardiac Research Institute Sydney Australia

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ClinicalTrials.gov
NCT02670408