Background

ABMR is a major cause of heart transplant failure. The diagnosis of ABMR in heart transplantation is based on the 2013 ISHLT pAMR classification. We hypothesized that a molecular microscope approach of ABMR could be useful for better estimating disease activity and stage.

Methods

We selected heart transplant recipients from four French centres with a diagnosis of biopsy proven ABMR and adequate endomyocardial (EMB) material for microarray studies (n=71). ABMR diagnosis was based on histopathology evidence of intra-vascular mononuclear cells and/or C4d/CD68 IHC positivity (ISHLT 2013). We assessed allograft gene expression using diagnostic classifier equations (ABMR molecular Score) and pathogenesis-based transcript sets (http://atagc.med.ualberta.ca/Pages/default.aspx) reflecting endothelial activation (DSAST), macrophage burden (QCMAT), gamma-interferon response (GRIT), cardiac injury response genes (IRIT), T-cell burden (TCB). We used a matched control group of heart transplant recipients without rejection (pAMR0 & ACR 0R, n=32).

Results

The histopathological features of ABMR revealed 44 pAMR1 biopsies (including 20 pAMR1(I+) cases and 24 pAMR1(H+) cases) and 27 pAMR2/3 biopsies (pAMR2 and pAMR3, n=25 and n=2 respectively). All patients with pAMR+ diagnosis had circulating DSA at the time of biopsy with a mean immunodominant DSA MFI of 4940 ± 718.

The gene expression analysis revealed that pAMR+ EMB showed higher ABMR molecular Score (p<0.0001), higher expression of DSAST (p<0.0001), QCMAT (p<0.0001), GRIT (p<0.0001), IRIT (p<0.0001) and TCB (p=0.0001) as compared to EMB without rejection. We found that pAMR1(I+) and pAMR1(H+) demonstrated distinct molecular profiles, with pAMR1(H+) cases showing higher expression of endothelial genes (DSAST, p=0.0032), GRIT (p=0.009), IRIT (p=0.0026), T-cell burden (p=0.0026), and ABMR molecular score reflecting interferon-effects, microcirculation stress and NK burden (p=0.0006) as compared to pAMR1(I+) cases. The group of patients with pAMR1(H+) had a similar ABMR-related gene expression levels as compared to pAMR2/3 cases.

Conclusion

A gene expression analysis reveals that ISHLT “suspicious heart ABMR” category actually contains many cases with overt ABMR, which may be currently being suboptomally managed due to the uncertainty in the diagnosis. The molecular microscope approach provides clues for improving disease activity and stage in heart ABMR.

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