Abstract 4147345: Sex differences in cardiac allograft rejection states using Tissue gene-expression profiling (MMDx)

Introduction: Limited knowledge exists regarding the influence of sex on rejection-related gene-expression profiling using the Molecular Microscope (MMDx). Methods: We prospectively included all heart transplant recipients who underwent endomyocardial biopsy for clinical indication from November 2022 to May 2024 at New York Presbyterian. During the biopsy procedure, four samples were sent for histologic evaluation, and two for molecular analysis. Donor-derived cell-free DNA levels (dd-cfDNA%), peripheral gene-expression profiling (pGEP) scores, MMDx rejection scores, and rejection rates on histology and MMDx were compared based on sex. Results: A total of 414 samples were included, 130 (31.4%) were from female recipients. dd-cfDNA levels were higher in females compared to male recipients ( 0.30% [0.15-0.80] vs. 0.22% [0.11-0.45]; p=0.02). Despite similar rates of pGEP scores (32 [28-34] vs. 32 [29-35]; p=0.70) or pGEP positivity (14.6% vs 17.0%; p=0.18), there was a trend towards a higher prevalence of donor-specific antibodies in female recipients (51.5% vs. 44.4%; p=0.20). Overall, rejection rates on MMDx (30.8% vs. 19.1%; p=0.01) and MMDx rejection scores ( 0.40 [0.17-0.63] vs. 0.27 [0.11-0.55]; p=0.005) were higher in female recipients ( Figure 1 ), primarily due to increased rates of antibody-mediated rejection ( ABMR ) diagnosis in this group ( 21.5% vs. 10.8% ; p=0.003). No differences in rejection rates were noted when assessed by histology (6.9% vs 8.0%; p=0.37). Conclusion: In a cohort of heart transplant recipients biopsied due to suspected rejection, female recipients were associated with increased MMDX-rejection scores and higher rejection rates, primarily driven by a twofold higher frequency of ABMR detection by MMDx compared to males.