MMDx-Heart System

Investigators: Dr. Philip F Halloran, and the MMDx-Heart Study Group (ClinicalTrials.gov NCT02670408)

The current standard for assessment of rejection in heart transplants is an endomyocardial biopsy (EMB) interpreted by histology according to ISHLT guidelines. In kidney transplantation, a microarray assessment of rejection and injury has been developed, the Molecular Microscope® Diagnostic System (MMDx-Kidney). MMDx-Kidney measures global gene expression by microarrays, and by using unsupervised and supervised methods provides molecular scores of probability of rejection, acute and chronic tissue injury, and the risk of graft loss. MMDx-Kidney was verified as a real-time assay in the INTERCOMEX study (ClinicalTrials.gov NCT01299168). The present project adapts the MMDx-Kidney for interpreting EMB to create MMDx-Heart, aiming to assess both rejection and injury. In the initial phase, a first-generation MMDx system for EMB has been developed, based on rejection molecules defined in MMDx-Kidney.

There are four phenotypes that guide the assessment of heart transplants: clinical and imaging data, HLA antibody, and EMB. The EMB is regarded as the gold standard to detect rejection in heart transplants. However, histologic EMB assessment is flawed even with expert pathologist reads, both for T cell- and antibody-mediated rejection (TCMR and ABMR). It has been reported that there is a Kappa value of 0.28 in pathology reads of ISHLT grade 2R rejection, the threshold to treat TCMR in many centers. Therefore, a more accurate means to assess the EMB is needed. Moreover, assessment of parenchymal injury is desirable.

Using both supervised and unsupervised assessment of gene expression in a large cohort of single EMB collected in eight centers (Canada, US, Europe, and Australia), we found three principal molecular groups of EMB: no rejection, TCMR, and ABMR. Additionally, the unsupervised analysis identified an additional molecular group that corresponded to parenchymal injury. Molecular biopsy assessment of rejection correlates with histology assessment but with many disparities, suggesting considerable error in conventional standard-of-care diagnoses. Additionally, molecular assessment outlines a novel parenchymal injury phenotype that is common after transplant and in rejection and is associated with parenchymal dedifferentiation and the heart function depression. Thus the MMDx-Heart has the potential to diagnose types of heart transplant rejection and transplant tissue injury, beyond what histology cannot assess.

MMDx-Heart Publications:

  1. Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, et al. Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System. J Heart Lung Transplant. 2017;36(11):1192-200.
  2. Halloran PF, Reeve J, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, Deng M, et al. Exploring the cardiac response to injury in heart transplant biopsies. JCI Insight. 2018;3(20):e123674.
  3. Loupy A, Duong Van Huyen JP, Hidalgo LG, Reeve J, Racape M, Venner J, et al. Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection. Circulation. 2017;135(10):917-35.
  4. Parkes MD, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, Deng M, Depasquale EC, et al. An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms. J Heart Lung Transplant. 2019;38(6):636-46.
  5. Halloran PF, Madill-Thomsen KS, Aliabadi-Zuckermann A, Cadeiras M, Crespo-Leiro M, DePasquale E, et al. Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes Journal of Heart and Lung Transplantation. 2022 Mar;41(3):334-344.
  6. Madill-Thomsen KS, Reeve J, Aliabadi AZ, Cadeiras M, Crespo-Leiro M, Depasquale EC, et al. Assessing the relationship between molecular rejection and parenchymal injury in heart transplant biopsies. Transplantation. 2022 Nov 1;106(11):2205-2216.
  7. Halloran PF, Madill-Thomsen K. The Molecular Microscope® Diagnostic System: assessment of rejection and injury in heart transplant biopsies. Transplantation. 2023 Jan 1;107(1):27-44.
  8. Halloran PF, Madill-Thomsen K, Mackova M, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, et al. Molecular states associated with dysfunction and graft loss in heart transplants. J Heart Lung Transplant. 2023;2023 Nov 30:S1053-2498(23)02132-0. doi: 10.1016/j.healun.2023.11.013. Online ahead of print.