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

Marta Jiménez-Blanco Bravo, Laura Pérez-Gómez, Francisco J Hernández-Pérez, Carlos Arellano-Serrano, Mario Torres-Sanabria, Manuel Gómez-Bueno, Juan F Oteo-Domínguez, Susana Mingo-Santos, Javier Segovia-Cubero, Marta Jiménez-Blanco Bravo, Laura Pérez-Gómez, Francisco J Hernández-Pérez, Carlos Arellano-Serrano, Mario Torres-Sanabria, Manuel Gómez-Bueno, Juan F Oteo-Domínguez, Susana Mingo-Santos, Javier Segovia-Cubero

Abstract

Background: Cardiac 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.

Methods: We 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.

Results: We 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).

Conclusion: In this study, dd-cfDNA did not perform as a useful biomarker to avoid surveillance coronary angiograms for CAV diagnosis.

Clinical trial notation: Potential Role of Donor-derived Cell Free DNA as a Biomarker in Cardiac Allograft Vasculopathy, NCT04791852.

Keywords: NTproBNP; biomarker; cardiac allograft vasculopathy; cardiac troponin; coronariography; donor-derived cell free DNA.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Jiménez-Blanco Bravo, Pérez-Gómez, Hernández-Pérez, Arellano-Serrano, Torres-Sanabria, Gómez-Bueno, Oteo-Domínguez, Mingo-Santos and Segovia-Cubero.

Figures

FIGURE 1
FIGURE 1
Study flow-chart.
FIGURE 2
FIGURE 2
(A) Box-plot of Donor-derived Cell Free DNA levels according to CAV degree. Numerical data represent median dd-cfDNA values and their interquartile range. (B) Box-plot of Donor-derived Cell Free DNA levels according to CAV presence (CAV0 vs. CAV 1, 2, or 3). Numerical data represent median dd-cfDNA values and their interquartile range.
FIGURE 3
FIGURE 3
Area Under the Curve Receiver Operating Characteristics (AUC ROC) curve for the diagnosis of CAV0 vs. CAV123.
FIGURE 4
FIGURE 4
(A) Box-plot of Donor-derived Cell Free DNA levels according to time after heart transplant. (B) Box-plot of Donor-derived Cell-Free DNA according to CAV progression. Numerical data represent median dd-cfDNA values and their interquartile range.
FIGURE 5
FIGURE 5
Box-plot of NTproBNP levels according to CAV degree. Numerical data represent median NTproBNP values (pg/ml) and their interquartile range. An outlier value of NTproBNP 26 350 pg/ml in the CAV0 group was excluded from the figure but included in the analysis.

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