DEFINE-HT cohort study: The prognostic value of dd-cfDNA in heart transplantation

Results from the prospective, multicenter, observational DEFINE-HT cohort study (NCT05309382), evaluating donor-derived cell-free DNA (dd-cfDNA) as a prognostic biomarker in 110 adult heart transplant recipients, were published in JACC: Heart Failure by Shah et al. The primary composite endpoint was the incidence of treated rejection, graft dysfunction, re-transplantation, and death at 1-year post-transplant. 

Key data: At 1-year post-heart transplantation (HT), 34.5% (95% confidence interval [CI], 26.0–43.5) of patients met the primary composite endpoint, with treated rejection, graft dysfunction, re-transplantation, and death occurring in 20.0%, 10.9%, 0.0%, and 3.6% of patients, respectively. Elevated dd-cfDNA levels (dd-cfDNA ≥0.26% and/or donor quantity score [DQS] ≥18 copies/mL) were associated with increased risk of meeting the composite endpoint (hazard ratio [HR], 4.42; 95% CI, 1.99–9.80; p < 0.001). A 1-intrapatient-standard deviation (SD) increase in dd-cfDNA% and DQS was associated with 19% and 12% higher risk of the composite endpoint, respectively (both p < 0.001).  

Key learning: dd-cfDNA demonstrates prognostic value beyond biopsy-defined rejection in heart transplant recipients, distinguishing clinically actionable rejection from histologic-only rejection and identifying graft dysfunction in the absence of histopathology, supporting its potential role in biopsy-sparing strategies.