Circulating Donor-Specific Anti–Human Leukocyte Antigen Antibodies and Complement C4d Deposition Are Associated With the Development of Cardiac Allograft Vasculopathy

BACKGROUND: Cardiac allograft vasculopathy (CAV) continues to be a limiting factor in long-term survival of heart transplant recipients (HTRs). Pathophysiologic and immunologic factors affecting CAV are complex, and criteria for early diagnosis remain elusive. METHODS: We performed a retrospective analysis of the relationship between donor-specific antibody (DSA), C4d immunofluorescence, and the development of CAV. RESULTS: We evaluated 330 endomyocardial biopsy (EMB) specimens from 112 cardiac grafts. Twenty-four (21%) of 112 grafts developed CAV, and 18 (75%) of 24 were positive for C4d. Patients with DSA (n = 51) against human leukocyte antigen class I (n = 5), II (n = 26), or both (n = 20) developed CAV at a rate of 40%, 38%, and 20% and a mean time to CAV of 89, 47, and 25 months, respectively. Of 61 grafts without DSA, only 13% developed CAV, with a mean time to CAV of 116 months. CONCLUSIONS: Compared with the general HTR population, patients with graft dysfunction and DSA or positive C4d on EMB show a statistically significant increased incidence of CAV and allograft failure, suggesting an antibody-mediated injury. The presence of pre- and posttransplant DSA, even in the absence of positive C4d immunofluorescence, may identify a group of HTRs at increased risk of developing CAV.