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Gene expression profiling (GEP) is a reliable monitoring tool for rejection surveillance following heart transplantation (HT), but may also be helpful in assessing degree of immunosuppression. We aimed to evaluate changes in GEP with modern, rapid steroid weaning. GEP results collected on HT patients from January 2020-August 2022 were reviewed. At our center, a score ≥ 30 is considered high 2-6 months post-HT and ≥ 34 is considered high after 6-months post-HT. In patients without concern for clinical rejection or new donor specific antibody, steroids are weaned off by month 5-6 post-HT. A total of 561 GEP samples were obtained during the study period from patients 2 months to > 24 months post-transplant. The highest percentage of samples (42%) were collected between months 4-6 post-HT. There was a steady increase in mean GEP score from month 3 (22.5) to month 5 (32.5) as steroids were being quickly weaned (Figure 1a). Utilizing a threshold score of 30 in patients < 6 months post-transplant yielded approximately 60% of samples that would have been abnormal (above threshold). In contrast, only 31.3% would be considered abnormal (above threshold) if a threshold value of 34 were used during this time frame to reflect reduced steroid dosing from our modern taper (Figure 1b). GEP scores rise steadily during the first few months post-transplant as steroids are aggressively weaned. Lowering the threshold score within the first 6 months can help decrease the number of positive (above threshold) results and potentially decrease the need for unnecessary endomyocardial biopsies. [ABSTRACT FROM AUTHOR]

Cardiac allograft rejection (AR) diagnosis has historically relied on endomyocardial biopsy (EMBx) and histopathology (HP). Quantifying donor-derived cell free DNA (ddcfDNA) has recently offered a non-invasive alternative for detecting graft injury. EMBx mRNA analysis via the molecular microscope profiles (MMP) quantifies AR probability not subject to HP interpretation. Our aim was to evaluate the clinical role of MMP in cardiac transplant recipients (HTx) with positive ddcfDNA. We identified 39 patients with ddcfDNA testing and subsequent EMBx for HP (n=36) and MMP (n=39) analysis. MMP was conducted by the molecular microscope diagnostic system (MMDX™). Patients with multi-organ transplantation or coronary allograft vasculopathy were excluded. MMP, HP, echo and ddcfDNA association were assessed using logistical regression (SPSS™). Average time post-transplant was 1585 ±1435 days, average LVEF 55%, and average ddcfDNA 0.81 ± 1.1. Donor specific antibodies were present in 14/39 of patients. MMP was abnormal in 18/39 patients and correlated with ddcfDNA levels (p=0.007) and HP (p=0.05), but not with LVEF (p=0.71). MMP abnormalities included 9 antibody mediated rejection (AMR), 5 acute cellular rejection (ACR), and 4 injury patterns. By HP, biopsies were abnormal in 18/36 patients: 18 ACR (grade 1) and 1 AMR (grade 2). Abnormal HP did not correlate with ddcfDNA levels (p= 0.07). HP and MMP are often discordant, Table 1. Abnormal MMP correlated with both ddcfDNA and HP, but not with LVEF. Large prospective clinical trials are needed to define clinical outcomes from treatment strategies based on biopsy results. Multi-modality testing may be necessary to monitor cardiac transplant patients for rejection and avoid misclassification. [ABSTRACT FROM AUTHOR]