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PLoS One. 2016 Nov 29;11(11):e0167213. doi: 10.1371/journal.pone.0167213. eCollection 2016.

Myocardial Gene Expression Profiling to Predict and Identify Cardiac Allograft Acute Cellular Rejection: The GET-Study.

Bodez D1,2,3,4, Hocini H2,3,5, Tchitchek N6,7, Tisserand P2,3,5, Benhaiem N8, Barau C2,3,9, Kharoubi M1,10, Guellich A1,2,3,4,10, Guendouz S1,2,4,10, Radu C11, Couetil JP2,3,11, Ghaleh B2,3,9, Dubois-Randé JL1,2,3,4, Teiger E1,2,3,4, Hittinger L1,2,3,4, Levy Y2,3,5,12, Damy T1,2,3,4,10.

Author information

1
AP-HP, Department of Cardiology, Henri Mondor Teaching Hospital, Créteil, France.
2
School of Medicine, Paris-Est-Créteil University (UPEC), Créteil, France.
3
IMRB INSERM U955, Paris-Est-Créteil University (UPEC), Créteil F-94000, France`.
4
DHU ATVB, Henri Mondor Teaching Hospital, Creteil, France.
5
Vaccine Research Institute (VRI), Henri Mondor Teaching Hospital, Créteil, France.
6
CEA, DSV/iMETI, Immunology of viral infections and autoimmune diseases research unit, Fontenay-aux-Roses, France.
7
UMR1184, IDMIT infrastructure, Fontenay-aux-Roses, France.
8
AP-HP, Department of Pathology, Henri Mondor Teaching Hospital, Créteil, France.
9
AP-HP, Platform of Biological Resources, Henri Mondor Teaching Hospital, Créteil, France.
10
GRC Amyloid Research Institute, Henri Mondor Teaching Hospital, Créteil, France.
11
AP-HP, Department of Cardiac Surgery, Henri Mondor Teaching Hospital, Créteil, France.
12
AP-HP, Clinical Immunology, Henri Mondor Teaching Hospital, Créteil, France.

Abstract

AIMS:

Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR.

METHODS:

A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41-57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or ≥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n = 13); rejection ≥3A (RISHLT, n = 13); 0 one month before ACR (BRISHLT, n = 10).

RESULTS:

We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples.

CONCLUSION:

Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipients' care.

PMID:
27898719
PMCID:
PMC5127573
DOI:
10.1371/journal.pone.0167213
[Indexed for MEDLINE]
Free PMC Article

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