*Purpose: We hypothesize that subclinical inflammation, resulting in molecular injury of the cardiac allograft, may contribute to sensitization of the recipients’ immune system. Antigenic presentation of donor-derived nucleic acids, as reflected by elevated donor derived cell free DNA (dd-cfDNA) levels, may lead to leukocyte activation, promoting cytokine release and donor specific antibody (DSA) formation, with elevated dd-cfDNA levels previously seen prior to detection of de-novo DSAs in kidney and lung transplantation. We aimed to assess this relationship in cardiac transplantation.

*Methods: This was a retrospective cohort analysis examining a subset of the Donor‐Derived Cell‐Free DNA‐Outcomes AlloMap Registry (D‐OAR) data, focusing on dd‐cfDNA and DSA results. 67 patients were identified, providing 284 samples, with corresponding dd-cfDNA (AlloSure) and DSA results. Samples that that had associated rejection were excluded.

*Results: 28 patients (42%) had negative DSA, with a median dd-cfDNA = 0.06% (IQR 0.03% – 0.08%), 27 patients (40%) had pre-formed DSA with a median dd-cfDNA = 0.09% (IQR 0.06% – 0.18%). 12 patients (18%) had de-novo DSA formation, median dd-cfDNA = 0.24%, (IQR 0.11% – 0.45%). DSA negative patients had significantly lower dd-cfDNA levels than patients who were DSA positive (p< 0.001), while patients with de-novo DSA had significantly higher dd-cfDNA than patients who had pre-formed DSA. (p= 0.001). Elevations in dd-cfDNA appeared a median of 12 days (range 2-28) prior to DSA testing. Multivariate logistic regression analysis identified dd-cfDNA an independent predictor of de-novo DSA formation, when controlling for recipient race, age, donor demographics and HLA mismatch (1-6) (p < 0.001).

*Conclusions: Higher dd-cfDNA levels are associated with de-novo DSA formation. Further mechanistic studies and the clinical significance of this observation remain to be determined, as not all DSA are associated with poor outcomes.

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