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Updated: Jul 2, 2025
A High-Fidelity Porcine Model of Orthotopic Heart Transplantation Following Donation after Circulatory Death
Published on: June 6, 2025
Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the
Palak Shah1,2, Sean Agbor-Enoh2,3,4, Seiyon Lee5
1Heart Failure, Mechanical Circulatory Support & Transplant, Inova Schar Heart and Vascular, Falls Church, VA (P.S., S.S.S., L.H., E.M.).
Insights
Black heart transplant recipients face higher risks of acute rejection and death. Elevated donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA may explain these disparities, highlighting potential biomarkers for improved outcomes.
Area of Science:
- Cardiovascular Surgery
- Transplant Immunology
- Genomics
Background:
- Black heart transplant recipients exhibit a higher incidence of acute rejection (AR) and mortality compared to White recipients.
- This disparity is hypothesized to be linked to elevated levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA.
Purpose of the Study:
- To investigate the association between dd-cfDNA, cell-free mitochondrial DNA, and clinical outcomes in Black versus White heart transplant recipients.
- To identify potential biomarkers contributing to racial disparities in heart transplant outcomes.
Main Methods:
- A prospective, longitudinal cohort study involving 148 heart transplant patients (65 Black, 83 White).
- Quantification of plasma dd-cfDNA using sequencing and cell-free mitochondrial DNA via PCR.
- AR defined by cellular or antibody-mediated rejection; primary outcome included AR, graft dysfunction, or death.
Main Results:
- Black patients showed a significantly higher incidence of AR (43% vs. 19%) and antibody-mediated rejection (20% vs. 2%).
- Elevated levels of both dd-cfDNA and cell-free mitochondrial DNA were observed in Black patients post-transplant.
- Black race and higher dd-cfDNA levels were independently associated with adverse composite outcomes (AR, graft dysfunction, or death).
Conclusions:
- Increased dd-cfDNA and cell-free mitochondrial DNA levels may be mechanistically involved in the heightened AR and poorer outcomes seen in Black heart transplant recipients.
- These cell-free DNA markers could serve as crucial indicators for monitoring and potentially mitigating risks in this patient population.
Background:
Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA.
Methods:
The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death.
Results:
We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome.
Conclusions:
Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
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