CMR characteristics in pediatric heart transplant recipients with chronically elevated serum donor derived cell-free DNA (RF_TH_243)

Graft rejection is a common and morbid complication in pediatric heart transplant recipients (PHTR). While endomyocardial biopsy (EMB) remains the gold standard for diagnosis, non-invasive methods are being increasingly employed for rejection surveillance including serum donor derived cell-free DNA (ddcfDNA) with high negative predictive value for acute rejection. A subset of PHTR demonstrate chronically elevated ddcfDNA in the absence of significant histopathological rejection by EMB, and the cause of this elevation is unclear. Multiparametric CMR also has a growing role in graft surveillance and may provide insights into pathologic myocardial processes in those instances.

Methods: This is a retrospective, single-center analysis of PHTR who underwent EMB, serial ddcfDNA testing, and CMR for post-transplant monitoring between July 2021 and January 2024. At least 3 ddcfDNA results had to be obtained over the study period for inclusion. PHTR were identified as having chronically elevated ddcfDNA when greater than 50% of all tests were greater than or equal to 0.2%, compared to a control group with entirely normal (< 0.2%) ddcfDNA. Incidence of acute cellular (ACR) and antibody mediated (AMR) rejection by EMB during the study period was evaluated, with rejection defined as ACR and/or AMR grade 2 or higher. CMR findings were compared between the two groups including parametric mapping (T1/ECV, T2), presence of LGE, and myocardial perfusion reserve index (MPRI).

Results: We identified 18 PHTR with chronically elevated and 40 with entirely normal ddcfDNA. Elevated ddcfDNA was associated with increased incidence of significant rejection (10/18, 56% vs 1/40, 2.5%; p=< 0.00001). Of all 11 patients with rejection by EMB during the study period, 6 demonstrated AMR, 2 demonstrated ACR, and the remaining 3 had both AMR and ACR. PHTR with elevated ddcfDNA demonstrated significantly elevated mean native T1 (1036 vs 1065ms, p = 0.047), mean T2 (48.3 vs 51.1ms, p=0.009), and presence of LGE (13% vs 39%, p=0.022). In a subset analysis of the 39 control and 8 elevated ddcfDNA patients without rejection by EMB, patients with chronically elevated ddcfDNA demonstrated lower MPRI (1.24 vs 1.48, p=0.071) and higher incidence of LGE (38% vs 13%; p=0.091), with no difference in T1/ECV or T2.

Conclusion: PHTR with chronically elevated ddcfDNA had high incidence of EMB-proven rejection and demonstrated elevated native T1, T2, and presence of LGE. However, in the subset of PHTR with elevated ddcfDNA in the absence of rejection, there was a distinct pattern of low MPRI and increased incidence of LGE without differences in T1 and T2 parameters. These findings suggest a possible perfusion-based etiology of graft injury that is distinct from rejection in some patients with elevated ddcfDNA testing.