Lack of Usefulness of Donor-Derived Cell-Free DNA as a Biomarker for Cardiac Allograft Vasculopathy: A Prospective Study

Abstract

BackgroundCardiac allograft vasculopathy (CAV) remains a major cause of morbidity and mortality among long-term heart transplant recipients. There is an unmet need for a non-invasive biomarker of CAV that could obviate the need to perform surveillance coronary angiograms in these patients. Our aim was to evaluate the performance of Donor-derived Cell Free DNA (dd-cfDNA) as a biomarker of CAV.MethodsWe prospectively measured dd-cfDNA levels in all patients undergoing routine coronary angiography >1 year after heart transplant at a single center. Endpoints included the association between dd-cfDNA levels and the presence CAV, according to several prespecified criteria.ResultsWe included 94 heart transplant recipients, a median of 10.9 years after transplant. Coronary angiogram revealed CAV0, CAV1, CAV2, and CAV3 in 61, 19, 14, and 6% of patients, respectively. Comparison of dd-cfDNA levels in patients with CAV0 and CAV1–2–3 (primary end-point) did not show significant differences (0.92%, IQR 0.46–2.0 vs. 0.46%, IQR 0.075–1.5, p = 0.059), nor did the comparison between patients with stable CAV (no new coronary lesions since previous angiogram, n = 77) and progressive CAV (n = 17); dd-cfDNA values 0.735% (IQR 0.195–2.0) vs. 0.9% (IQR 0.12–1.8), p = 0.76. However, we found an association between NTproBNP levels and CAV degree (p = 0.017). Dd-cfDNA levels did not correlate with NTproBNP (ρ = −0.095).ConclusionIn this study, dd-cfDNA did not perform as a useful biomarker to avoid surveillance coronary angiograms for CAV diagnosis.Clinical Trial NotationPotential Role of Donor-derived Cell Free DNA as a Biomarker in Cardiac Allograft Vasculopathy, NCT 04791852.

New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation

“…One small single center study did find an association after 2 years post-heart transplant, where a majority of patients with established CAV had higher levels of dd-cfDNA, compared with a minority of patients without CAV ( 131 ). In contrast, in a Spanish cohort, there was no significant difference in levels of dd-cfDNA comparing heart transplant patients with and without CAV on concurrent angiogram >1 year after transplant ( 132 ). Therefore, the utility of dd-cfDNA to indicate chronic vascular changes within the graft warrants more investigation.…”

“…Further, higher levels of dd-cfDNA averaged over the first three months post-transplant conferred a 6.6-fold higher risk of severe CLAD (130). One small single center study did find an association after 2 years postheart transplant, where a majority of patients with established CAV had higher levels of dd-cfDNA, compared with a minority of patients without CAV (131). In contrast, in a Spanish cohort, there was no significant difference in levels of dd-cfDNA comparing heart transplant patients with and without CAV on concurrent angiogram >1 year after transplant (132).…”

European Society for Organ Transplantation (ESOT) Consensus Statement on the Use of Non-invasive Biomarkers for Cardiothoracic Transplant Rejection Surveillance

“…A small single-center pilot study performed in the US showed that dd-cfDNA is elevated in cardiac allograft vasculopathy (CAV) and suggested endothelial injury and ischemia as possible mechanisms [12]. However, another study from Spain using different dd-cfDNA detection methods and thresholds did not confirm the association between dd-cfDNA and CAV [13].…”

“…A small single-center pilot study performed in the US showed that dd-cfDNA is elevated in cardiac allograft vasculopathy (CAV) and suggested endothelial injury and ischemia as possible mechanisms [ 12 ]. However, another study from Spain using different dd-cfDNA detection methods and thresholds did not confirm the association between dd-cfDNA and CAV [ 13 ]. These divergent findings underscore the need for larger prospective studies to define the role of dd-cfDNA in screening for CAV (the SHORE registry is exploring this question).…”

Selection and Interpretation of Molecular Diagnostics in Heart Transplantation

“…A single-center study from Madrid, Spain, evaluated dd-cfDNA of 94 recipients at time of angiography and showed no association between dd-cfDNA and presence of CAV. 90 In another study using proteomics, aptamer-based protein expression profiling identified a signature that discriminated patients with mild to moderate CAV, including proteins related to cellular injury, inflammation, and platelet activation. 91 As investigations continue to evaluate molecular methodologies as markers of CAR, it will be important to assess their ability to predict these other posttransplant outcomes.…”