Redefining Cardiac Antibody-Mediated Rejection With Donor-Specific Antibodies and Graft Dysfunction

Jason F. Goldberg, Inova Schar Heart and Vascular, Falls Church, VA (J.F.G., P.S.).
Xin Tian, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Ann Bon, Brown University, Providence, RI (A.B.).
Yifei Xu, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Heath, Bethesda, MD (X.T., Y.X., R.B., M.K.J., H.K., T.E.A., W.P., S.A.-E.).
Eleanor Gerhard, Weill Cornell Medical College, New York, NY (E.G.).
Ruth Brower, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Moon Kyoo Jang, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Hyesik Kong, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Temesgen E. Andargie, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Woojin Park, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Heath, Bethesda, MD (X.T., Y.X., R.B., M.K.J., H.K., T.E.A., W.P., S.A.-E.).
Samer S. Najjar, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Inna Tchoukina, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Keyur B. Shah, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Steven Hsu, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Maria E. Rodrigo, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Charles Marboe, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Gerald J. Berry, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Hannah A. Valantine, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).
Palak Shah, Inova Schar Heart and Vascular, Falls Church, VA (J.F.G., P.S.).
Sean Agbor-Enoh, Genomic Research Alliance for Transplantation (J.F.G., X.T., R.B., M.K.J., H.K., T.E.A., S.S.N., I.T., K.B.S., S.H., M.E.R., C.M., G.J.B., H.A.V., P.S., S.A.-E.).

Document Type

Journal Article

Publication Date

12-1-2024

Journal

Circulation. Heart failure

Volume

17

Issue

12

DOI

10.1161/CIRCHEARTFAILURE.124.011592

Keywords

antibodies; biomarkers; cell-free nucleic acids; heart transplantation

Abstract

BACKGROUND: Heart transplant recipients with donor-specific antibodies (DSAs) have an increased risk for antibody-mediated rejection. However, many patients with graft dysfunction and DSA do not have evidence of antibody-mediated rejection by endomyocardial biopsy (EMB). METHODS: Participants from this prospective, multicenter study underwent serial EMB, echocardiogram, DSA, and donor-derived cell-free DNA evaluations. Outcomes were defined as pAMR+ (pAMR≥1) or DSA+/left ventricle (LV) dysfunction (DSA presence+LVEF drop ≥10% to an LVEF≤50%). Cox regression evaluated the association between antibody-mediated rejection categories and death or sustained (for 3 months) reduction of LVEF to <50%. RESULTS: Two hundred sixteen patients (29% women, 39% Black race, median age 55 [interquartile range, 47-62] years) had 1488 EMB, 2792 DSA, 1821 echocardiograms, and 1190 donor-derived cell-free DNA evaluations. DSAs were present in 86 patients (40%). Fourteen patients had isolated pAMR+ episodes and 8 patients had isolated DSA+/LV dysfunction episodes; 2 patients had pAMR+ and then subsequently DSA+/LV dysfunction with pAMR+. Median %dd-cfDNA was significantly higher at diagnosis of pAMR+ (0.63% [interquartile range, 0.23-2.0]; P=0.0002), or DSA+/LV dysfunction (0.40% [interquartile range, 0.36-1.24]; P<0.0001), compared with patients without these outcomes (0.01% [interquartile range, 0.0001-0.10]). Both pAMR+ and DSA+/LV dysfunction were associated with long-term clinical outcome of death (n=18) or prolonged LV dysfunction (n=10): pAMR+ (hazard ratio, 2.8 [95% CI, 1.03-7.4]; P=0.043); DSA+/LV dysfunction (hazard ratio, 26.2 [95% CI, 9.6-71.3]; P<0.001); composite of both definitions (hazard ratio, 6.5 [95% CI, 2.9-14.3]; P<0.001). Patients who developed pAMR+ or DSA+/LV dysfunction within the first 6 months of transplant were more likely to die within 3 years posttransplant (hazard ratio, 3.9 [95% CI, 1.03-14.6]; P=0.031). CONCLUSIONS: Expanding the characterization of antibody-mediated rejection to include patients with DSA and concurrent allograft dysfunction identified DSA+ patients at risk for death and prolonged LV dysfunction.

Department

Medicine

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