Multimodal molecular testing provides prognostic value for heart transplant recipients

BACKGROUND: Multimodal molecular testing with gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used for rejection surveillance, but less is known about their joint ability to predict future clinical events. METHODS: We evaluated 1934 heart transplant recipients from the Surveillance HeartCare Outcomes Registry. Risk was assessed two ways. First, based on the most abnormal GEP/dd-cfDNA result during months 2-6 post-transplant, the incidence of graft dysfunction (GD) and cardiovascular (CV) death was assessed in the subsequent 12 months. Second, we analyzed the 30-day incidence of GD and CV death following individual GEP/dd-cfDNA results between 2-months and 5-years post-transplant. RESULTS: GD and CV death occurred in 166 and 19 patients during the 12-month follow-up period, respectively. In months 2 to 6 post-transplant, those with GEP+/dd-cfDNA+ had the highest incidence of GD or CV death (15.5%) in the following year, with a HR of 1.59 (1.08-2.32; p=0.017) versus those without GEP+/dd-cfDNA+. When limited to those without evidence of rejection in months 2 to 6, the GEP+/dd-cfDNA+ group had the highest incidence of GD or CV death (14.6% vs 5.1-8.7%; p=0.039). A single GEP+/dd-cfDNA+, versus a GEP-/dd-cfDNA- result, conferred a 3-fold increase in the 30-day incidence rate of GD or CV death (adjusted IRR 3.12; 95% CI 1.37-7.10; p=0.007). CONCLUSIONS: Patients with dual positive GEP and dd-cfDNA are at increased risk for subsequent GD and CV death, even in the absence of histological evidence of rejection, indicating circulating multimodal molecular evidence of rejection provides prognostic information not detected by histology.