Molecular Diagnosis of Heart Allograft Rejection Using Intra-Graft Targeted Gene Expression Profiling.

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

496 participants

Study Classification

OBSERVATIONAL

Study Start Date

2021-11-10

Study Completion Date

2023-12-15

Brief Summary

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The goal of this observational study is to develop and validate a molecular heart rejection diagnostic system based on targeted transcriptome as a novel monitoring companion tool for heart allograft precision diagnostics applicable to formalin-fixed paraffin-embedded endomyocardial biopsies.

The primary outcome will be the biopsy-proven rejection, that will be predicted with molecular classifiers (cellular and antibody-mediated rejection scores).

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Detailed Description

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Heart transplantation (HTx) remains the most valuable therapeutic option for patients with end-stage heart failure refractory to optimal medical therapy. Despite major improvements in immunosuppression and transplant care, acute and chronic rejection-induced allograft injuries remain one of the leading causes of mortality and morbidity after heart transplantation, thus limiting recipients' life expectancy. An improvement in the overall management of rejection remains an unmet medical need. As a first step, a precise diagnosis of rejection is crucial to guide patient care and optimize management.

Nowadays, the diagnosis of cardiac rejection relies exclusively on the pathological assessment of endomyocardial biopsies (EMBs) by identifying and grading cellular infiltrates and myocardial damage. While important advances have been made in the standardization of the rejection diagnosis, pathology remains an imperfect gold-standard, particularly due to the inter-observer variability, sample bias and the use of qualitative or semi-quantitative scales that oversimplify complex phenotypes. Additionally, disease severity, degree of myocardial injury and progression stage are crucial pieces of information poorly captured by the current working formulations. All these limits represent major barriers to achieve a precise and reliable diagnosis of rejection.

In this context, gene expression profiling analysis of fresh myocardial samples retrieved during an extra-core biopsy and using a whole transcriptome approach arose as a potential objective companion tool of pathology to refine the diagnosis of rejection. However, important drawbacks have limited the routine clinical applicability of whole-transcriptome based molecular diagnosis including extra-core sampling bias, low reproducibility, technical and analytical heaviness, with costs and sample turn-around that is not compatible with a clinical setting.

Recent technologies may overcome this limitation by allowing analysis of the same tissue used for histology assessment. Targeted molecular profiling applicable to formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies may allow the implementation of molecular diagnosis into the clinical routine. Recently, we have shown that the Banff Human Organ Transplant Panel (B-HOT) panel, a consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group, accurately captured key molecular patterns of antibody-mediated rejection (AMR) in heart allograft biopsies and may serve as a proxy to whole transcriptome-based analysis.

The aim of the present study is therefore to identify gene expression signatures for AMR and acute cellular rejection in heart transplantation and to develop and validate a molecular heart rejection diagnostic system based on targeted transcriptome as a novel monitoring companion tool for heart allograft precision diagnostics applicable to FFPE-EMB.

Conditions

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Heart Transplant Rejection

Study Design

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Observational Model Type

COHORT

Study Time Perspective

RETROSPECTIVE

Study Groups

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Development cohort

Random selection of 80% of the overall cohort.

Nano-Heart tool: Intra-Graft Targeted Gene Expression Profiling

Intervention Type DIAGNOSTIC_TEST

Targeted molecular profiling will be performed on formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies using the NanoString nCounter technology. A consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group (MDWG) will be used.

Validation cohort

Random selection of 20% of the overall cohort.

Nano-Heart tool: Intra-Graft Targeted Gene Expression Profiling

Intervention Type DIAGNOSTIC_TEST

Targeted molecular profiling will be performed on formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies using the NanoString nCounter technology. A consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group (MDWG) will be used.

Interventions

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Nano-Heart tool: Intra-Graft Targeted Gene Expression Profiling

Targeted molecular profiling will be performed on formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies using the NanoString nCounter technology. A consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group (MDWG) will be used.

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Inclusion Criteria

* heart transplant recipients ≥ 18 years old
* at least one endomyocardial biopsy performed as part of routine clinical care
* biopsy performed at least ≥ 1 month post transplant and less that 10-year post-transplant
* written informed consent