Circulation. Heart failure · 2025
Significance of Elevated Donor-Derived Cell-Free DNA in Heart Transplant Recipients With Negative Endomyocardial Biopsies: A Dawn of a New Era.
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Moeller Cathrine M, Fernandez Valledor Andrea, Oren Daniel, Rahman Salwa, Baranowska Julia, Hertz Adi, DeFilippis Ersilia M, Lee Changhee, Regan Matthew C, Oren Amit, Rahman Afsana, Hennecken Carolyn, Salazar Ruben, Donald Elena M, Lotan Dor, Majure David T, Yuzefpolskaya Melana, Colombo Paolo C, Raikhelkar Jayant K, Fried Justin A, Clerkin Kevin J, Latif Farhana, Sayer Gabriel T, Uriel Nir
Аннотация
BACKGROUND: The purpose of the current study was to investigate the clinical implications of elevated donor-derived cell-free DNA (dd-cfDNA) levels in heart transplantation recipients without evidence of rejection observed on endomyocardial biopsy.
METHODS: We retrospectively analyzed dd-cfDNA samples from all consecutive heart transplantation recipients between 2019 and 2023, excluding those with multiorgan transplants. Each sample was paired with an endomyocardial biopsy (<30 days). A positive biopsy was defined based on International Society for Heart and Lung Transplantation criteria of ≥1R/1B or antibody-mediated rejection >0. Elevated dd-cfDNA was defined as ≥0.12%, with a subanalysis using a threshold of 0.20%. Graft dysfunction was defined as an ejection fraction<50%. We excluded dd-cfDNA samples with concurrent histologically positive biopsy results, focusing on those with positive dd-cfDNA and negative biopsy findings. A mixed model Cox regression approach was applied to assess for mortality and graft dysfunction.
RESULTS: Of 643 dd-cfDNA samples from 227 patients, 238 samples (37%) from 110 patients showed positive dd-cfDNA results with negative endomyocardial biopsy. The median age was 56 years, with 27% females and 53% White patients. The median time from heart transplantation to sample collection was 5 months (interquartile range, 3-12). Among the positive samples, the median dd-cfDNA level was 0.24% (interquartile range, 0.16%-0.53%) with 63% exceeding 0.20%. A higher prevalence of prior treated antibody-mediated rejection was observed in the dd-cfDNA positive group (15% versus 5%; P=0.002). Patients with elevated dd-cfDNA results ≥ 0.20% demonstrated a near 5-fold increased risk of mortality (hazard ratio, 4.6 [95% CI, 1.6-13.4]; P=0.005) and a 3-fold risk of graft dysfunction (hazard ratio, 3.4 [95% CI, 1.0-11.9]; P=0.054) compared with those with negative dd-cfDNA.
CONCLUSIONS: In our cohort, patients with positive dd-cfDNA levels and negative biopsy results had higher rates of adverse outcomes, including graft dysfunction and mortality.
METHODS: We retrospectively analyzed dd-cfDNA samples from all consecutive heart transplantation recipients between 2019 and 2023, excluding those with multiorgan transplants. Each sample was paired with an endomyocardial biopsy (<30 days). A positive biopsy was defined based on International Society for Heart and Lung Transplantation criteria of ≥1R/1B or antibody-mediated rejection >0. Elevated dd-cfDNA was defined as ≥0.12%, with a subanalysis using a threshold of 0.20%. Graft dysfunction was defined as an ejection fraction<50%. We excluded dd-cfDNA samples with concurrent histologically positive biopsy results, focusing on those with positive dd-cfDNA and negative biopsy findings. A mixed model Cox regression approach was applied to assess for mortality and graft dysfunction.
RESULTS: Of 643 dd-cfDNA samples from 227 patients, 238 samples (37%) from 110 patients showed positive dd-cfDNA results with negative endomyocardial biopsy. The median age was 56 years, with 27% females and 53% White patients. The median time from heart transplantation to sample collection was 5 months (interquartile range, 3-12). Among the positive samples, the median dd-cfDNA level was 0.24% (interquartile range, 0.16%-0.53%) with 63% exceeding 0.20%. A higher prevalence of prior treated antibody-mediated rejection was observed in the dd-cfDNA positive group (15% versus 5%; P=0.002). Patients with elevated dd-cfDNA results ≥ 0.20% demonstrated a near 5-fold increased risk of mortality (hazard ratio, 4.6 [95% CI, 1.6-13.4]; P=0.005) and a 3-fold risk of graft dysfunction (hazard ratio, 3.4 [95% CI, 1.0-11.9]; P=0.054) compared with those with negative dd-cfDNA.
CONCLUSIONS: In our cohort, patients with positive dd-cfDNA levels and negative biopsy results had higher rates of adverse outcomes, including graft dysfunction and mortality.