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Demonstrate the impact of the Molecular Microscope Diagnostic System as the standard of care for heart transplant patients.
The current standard for biopsy-based diagnoses of rejection of heart transplants is the ISHLT classification from 2004, which represents a widely-used international consensus, based on morphological criteria of the cellular infiltrate within the myocardial specimen system with certainties and some arbitrary and blurred parameters. Recent data-driven approaches using molecular and conventional technologies indicate that this system produces incorrect diagnoses with potential harm to patients due to inappropriate treatment. To address this unmet need and improve diagnostics in the area of organ transplantation, the Alberta Transplant Applied Genomics Centre (ATAGC, University of Alberta) has developed a new diagnostic system - the Molecular Microscope® Diagnostic System (MMDx) that interprets biopsies in terms of their molecular phenotype, and combines the molecular and histopathological features of transplant biopsies, plus clinical and laboratory parameters, to create the first Integrated Diagnostic System. The MMDx developed first in kidney transplant biopsies because phenotypes are well established, will now be adapted to heart transplant endomyocardial biopsies (EMBs). The present study will develop a Reference Set of EMB, adapt the MMDx system to assess and report EMBs; and validate and refine this system in 900 unselected prospectively collected for clinical indications and a standard of care EMBs from North American and European Centers. In addition to demonstrating the real-time feasibility and potential value of this System in patient care, the study will develop and optimize a transparent and user-friendly reporting format to communicate this information to clinicians and obtain detailed feedback to improve its utility. We refine now our MMDx system using a new type of analysis (see primary outcome) and the resulting MMDx report. Currently, INTERHEART recruited 1912 biopsies from 1279 patients.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Endomyocardial biopsy | Procedure | One of several endomyocardial biopsy bites taken as the standard of care. We are asking now for two endomyocardial biopsy bites, to determine tissue sampling variability. |
| Measure | Description | Time Frame |
|---|---|---|
| Assign molecular scores (probability) of T cell mediated rejection, antibody mediated rejection in heart transplant biopsies, in a reference set of 200 biopsies | Create a molecular classifier that predicts antibody mediated and T cell mediated rejection, based on the archetypal analysis. | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Assign in real time (three working days upon biopsy receipt) molecular scores (probability) of T cell mediated rejection and antibody mediated rejection. | The molecular phenotype of a newly acquired sample predicts the histologic and clinical features of this sample when compared to the reference set. | 1 year |
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Inclusion Criteria:
Exclusion Criteria:
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This study aims to recruit 1200 biopsies from heart transplant patients for clinical indications and the standard of care biopsies.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Konrad S Famulski, PhD | Contact | 1 7804921725 | konrad@ualberta.ca | |
| Robert Polakowski, PhD | Contact | 1780 492 5091 | polakows@ualberta.ca |
| Name | Affiliation | Role |
|---|---|---|
| Philip F Halloran, MD PhD | University of Alberta | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UCLA Medical Centre | Completed | Los Angeles | California | 90024 | United States | |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38819301 | Background | Madill-Thomsen KS, Halloran PF. Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope(R) Diagnostic System (MMDx). Clin Sci (Lond). 2024 Jun 5;138(11):663-685. doi: 10.1042/CS20220530. | |
| 28148598 | Result | Loupy A, Duong Van Huyen JP, Hidalgo L, Reeve J, Racape M, Aubert O, Venner JM, Falmuski K, Bories MC, Beuscart T, Guillemain R, Francois A, Pattier S, Toquet C, Gay A, Rouvier P, Varnous S, Leprince P, Empana JP, Lefaucheur C, Bruneval P, Jouven X, Halloran PF. Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection. Circulation. 2017 Mar 7;135(10):917-935. doi: 10.1161/CIRCULATIONAHA.116.022907. Epub 2017 Feb 1. |
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Biopsy extract containing RNA
| Cedars-Sinai Heart Institute |
| Completed |
| Los Angeles |
| California |
| 90048 |
| United States |
| Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&White Research Institute | Completed | Dallas | Texas | 75246 | United States |
| Cardiovascular Medicine, University of Utah Health | Completed | Salt Lake City | Utah | 84132 | United States |
| Virginia Commonwealth University, Division of Cardiology | Completed | Richmond | Virginia | 23298 | United States |
| Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute | Recruiting | Darlinghurst | NSW 2010 | Australia |
|
| Department of Cardiac Surgery, Medical University of Vienna | Recruiting | Vienna | A-1090 | Austria |
|
| Alberta Transplant Applied Genomics Center, University of Alberta | Recruiting | Edmonton | Alberta | T6G 2E1 | Canada |
|
| Division of Cardiology, University of Alberta | Completed | Edmonton | Alberta | T6G 2R7 | Canada |
| Institute for Clinical and Experimental Medicine - IKEM | Recruiting | Prague | 14021 | Czechia |
|
| Service de Néphrologie-Dialyse Adultes , Hôpital Necker-Enfants Malades | Completed | Paris | 75015 | France |
| Heart Failure and Heart Transplant Unit, University of Bologna | Completed | Bologna | 40138 | Italy |
| Advanced Heart Failure Transplant Unit | Completed | A Coruña | Spain |
| 28662985 | Result | Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A. Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System. J Heart Lung Transplant. 2017 Nov;36(11):1192-1200. doi: 10.1016/j.healun.2017.05.029. Epub 2017 May 29. |
| 30333303 | Result | Halloran PF, Reeve J, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, Deng M, Depasquale EC, Goekler J, Jouven X, Kim DH, Kobashigawa J, Loupy A, Macdonald P, Potena L, Zuckermann A, Parkes MD. Exploring the cardiac response to injury in heart transplant biopsies. JCI Insight. 2018 Oct 18;3(20):e123674. doi: 10.1172/jci.insight.123674. |
| 30795962 | Result | Parkes MD, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, Deng M, Depasquale EC, Goekler J, Kim DH, Kobashigawa J, Loupy A, Macdonald P, Potena L, Zuckermann A, Halloran PF. An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms. J Heart Lung Transplant. 2019 Jun;38(6):636-646. doi: 10.1016/j.healun.2019.01.1318. Epub 2019 Feb 6. |
| 36508644 | Result | Halloran PF, Madill-Thomsen KS. The Molecular Microscope Diagnostic System: Assessment of Rejection and Injury in Heart Transplant Biopsies. Transplantation. 2023 Jan 1;107(1):27-44. doi: 10.1097/TP.0000000000004323. Epub 2022 Dec 8. |
| 38042442 | Result | Halloran PF, Madill-Thomsen K, Mackova M, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Gokler J, Hall SA, Kim DH, Kobashigawa J, Macdonald P, Potena L, Shah K, Stehlik J, Zuckermann A, Reeve J. Molecular states associated with dysfunction and graft loss in heart transplants. J Heart Lung Transplant. 2024 Mar;43(3):508-518. doi: 10.1016/j.healun.2023.11.013. Epub 2023 Nov 30. |
| 34548198 | Result | Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Gokler J, Kim DH, Kobashigawa J, Macdonald P, Potena L, Shah K, Stehlik J, Zuckermann A. Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes. J Heart Lung Transplant. 2022 Mar;41(3):334-344. doi: 10.1016/j.healun.2021.08.004. Epub 2021 Aug 26. |
| 38527588 | Result | Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Gokler J, Hall S, Jamil A, Kim DH, Kobashigawa J, Macdonald P, Melenovsky V, Patel J, Potena L, Shah K, Stehlik J, Zuckermann A. Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival. Am J Transplant. 2024 Aug;24(8):1414-1426. doi: 10.1016/j.ajt.2024.03.031. Epub 2024 Mar 26. |
| 35968995 | Derived | Madill-Thomsen KS, Reeve J, Aliabadi-Zuckermann A, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Goekler J, Kim DH, Kobashigawa J, Macdonald P, Potena L, Shah K, Stehlik J, Zuckermann A, Halloran PF. Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies. Transplantation. 2022 Nov 1;106(11):2205-2216. doi: 10.1097/TP.0000000000004231. Epub 2022 Oct 21. |
| 33595110 | Derived | Halloran PF. Integrating molecular and histologic interpretation of transplant biopsies. Clin Transplant. 2021 Apr;35(4):e14244. doi: 10.1111/ctr.14244. Epub 2021 Feb 17. No abstract available. |