Deposition of C4d and C3d in cardiac transplants: A factor in the development of coronary artery vasculopathy

Background: Coronary artery vasculopathy (CAV) is the major life-limiting factor in cardiac transplantation, after 1 year. Antibody-mediated rejection (AMR) has been associated with development of both acute and chronic rejection. We analyzed endomyocardial biopsies for pathologic markers of AMR (C4d and C3d), from the first 2 years post-transplantation, to determine complement deposition in relation to the development of CAV. Methods: A retrospective, matched-pair study was used. Group 1 subjects (n = 26) were CAV-negative at 8 years, and Group 2 (n = 26) had angiographically detectable CAV at 4 years. Biopsies from six time-points were studied (total = 282). Immunohistochemistry was performed for C4d, C3d and CD68. Biopsies were graded for rejection using ISHLT criteria. Results: Although CAV was not significantly associated with C4d deposition, it was associated with C3d deposition (p = 0.043). Only 4% of C4d and 5% of C3d biopsies were completely negative. Group 1 had 6 AMR-positive biopsies, with Group 2 having 8. There was no significant relationship between acute cellular rejection or AMR events and CAV. Conclusions: This study demonstrates that complement deposition is a frequent occurrence in the first 2 years post-transplantation. Although acute rejection is a known risk factor for CAV, in this study the relationship was found not to be significant. No relationship was found with the development of CAV and histologic features of AMR, when assessed by C4d deposition alone. However, an association between C3d deposition and the development of CAV was determined in this study group, suggesting that complement activation may play a role in the pathogenesis of CAV.