Donor-Derived Cell-Free DNA is Associated with Cardiac Allograft Vasculopathy

Abstract

There is mounting evidence on the use of donor-derived cell-free DNA (dd-cfDNA) as a non-invasive tool to detect acute antibody and cellular mediated rejection. However the role of dd-cfDNA in detecting and monitoring cardiac allograft vasculopathy (CAV) in the absence of acute rejection remains unknown. We hypothesized that dd-cfDNA levels would correlate with the presence of CAV. 65 clinically stable heart transplant recipients ≥ 2 years post-transplant, with no rejection episodes in the preceding 6 months were enrolled. CAV was assessed by routine coronary angiogram and intravascular ultrasound. Patients were stratified by time since transplant (2-5, 5-10 and ≥ 10 years post transplant) and high versus low levels of dd-cfDNA defined as above and below the median. Significant CAV was defined as Stanford III-IV or angiographic disease. A targeted amplification, next generation-sequencing assay (AlloSure®; CareDx, Inc.) was used to detect dd-cfDNA. Of 58 patients with known CAV status, 30 had high levels of ddcf-DNA (≥0.14%) and 28 had low levels (<0.14%). There was no difference in left ventricular ejection fraction between the groups but CAV was present in 63% of patients with high levels of ddcf-DNA compared to 36% in the low ddcf-DNA group (p 0.047). Donor-specific antibodies were present in 27% of the high ddcf-DNA group compared to 3.6% of the low ddcf-DNA group (p 0.026) (Table). There were no differences in the frequency of cellular and antibody medicated rejection episodes between the groups. Importantly, there were also no differences in time post-transplant between patients with high versus low ddcf-DNA. dd-cfDNA levels were associated with CAV in a cohort of stable transplant recipients >2 years post HT and thus might help to identify those in need for invasive assessment. Further studies should investigate if there is an association between dd-cfDNA levels and CAV severity and whether dd-cfDNA levels can predict CAV progression.