Clinical and Pathological Insights of Myocardial Molecular Profiling: Time to Revise ISHLT Grading System?

Purpose Gene expression profiling (GEP) of endomyocardial biopsies (EMB) by the MMDx system has been shown to estimate the probability of T-cell mediated (TCMR) and antibody-mediated rejection (AMR), improving the histology-based diagnoses in heart transplant (HT) recipients. Second generation analysis allowed to identify an additional phenotype characterised by molecules related to tissue injury (INJ), such as de-differentiation pathways, macrophages transcripts, and heart transcripts. The clinical correlates of this novel profile and its association with ISHLT pathology grading is under development. In this study we analyse the association of MMDx novel profiles with cardiac function and with ISHLT grades for TCMR and AMR. Methods 254 EMBs from 121 patients were analysed with MMDx platform. EMBs were performed according to standard protocol during the first 5 years after transplant and by clinical indication later on. Right heart catheretization was performed at the time of EMB, which were graded by 1990 and 2006 ISHLT classifications for TCMR and 2014 guidelines for AMR. Results Prevalence of molecular phenotypes varied during time course: INJ was frequent in the first months, absent during the first 5 years, and rose again in late for-cause EMBs; AMR peaked early and late after transplant, in line with DSA time-course; TCMR probability was meaningful in the early months only. Cardiac function also varied across the three profiles: INJ was significantly associated with low cardiac index (CI) and high right atrial pressure, AMR with elevated wedge pressure and low CI, and TCMR with low CI only. Overall, GEP was in agreement with pathology readings in most cases, being normal in 90% of the 0 graded EMB, and abnormal in over 70% of the 2R or pAMR2. While current 1R grade showed abnormal GEP only in 37% of cases, the old 1B grade had abnormal GEP in 60% of cases, mostly associated with AMR profile. INJ profile was found in 54% of the 2R or greater EMBs. Conclusion GEP reveals variable molecular patterns during transplant time course; INJ phenotype appears associated mainly with low CI in the context of post-operative injury and severe mixed rejection, while AMR seems to increase markers of graft stiffness. Despite good overall agreement with pathology readings, current ISHLT grading is inaccurate, with the “old” 1B grade being highly associated with AMR molecular profiling.