Complement deposition in early cardiac transplant biopsies is associated with ischemic injury and subsequent rejection episodes.

Background. Prolonged warm or cold ischemia is associated with poor survival of cardiac transplants, and ischemic changes in early posttransplantation endomyocardial biopsies correlate with the later development of chronic rejection. In animal models, tissue ischemia has been shown to activate complement. Methods. To determine whether ischemic changes in endomyocardial biopsies were associated with complement deposition, biopsies obtained 1‐3 weeks after transplantation from 33 patients were evaluated immunohistologically for C4d and C3d deposition as well as for IgM, IgG, and IgA. The histological changes associated with ischemic injury were scored independently, using previously reported criteria without knowledge of the immunohistochemical results. Results. Diffuse capillary and pericapillary deposition of C4d or C3d were detected in endomyocardial biopsies of 14 of the 33 patients. The majority of biopsies (79%) with C4d or C3d deposits had histological evidence of ischemic injury, including eight of the nine biopsies containing both C4d and C3d deposition. In contrast, only 8 of 18 (45%) of the biopsies without C4d or C3d deposition had ischemic injury. Only trace amounts of IgM and no IgG or IgA were demonstrable in the biopsies. Only 2 of the 14 biopsies with C4d or C3d deposition had evidence of moderate acute rejection, whereas 5 of the 18 biopsies without C4d or C3d deposition had moderate acute rejection. However, C4d and C3d deposition did correlate with repeated acute rejection episodes on subsequent biopsies. Conclusions. Thus, ischemic changes are associated with the activation of complement. Complement activation may in turn promote tissue injury and provide a potential target for future treatment. Warm and cold ischemia have been implicated clinically and experimentally as risk factors for the development of acute and chronic graft dysfunction (1‐ 8). The link between ischemia and complement was made in experimental models, in which the arterial supply to the myocardium, skeletal muscle, or renal tissue is occluded temporarily. This warm ischemic injury initiates a series of events including complement deposition, inflammatory cell infiltration, and cytokine release (9 ‐13). The capacity of complement inhibitors to decrease ischemia-related tissue injury indicates that complement has a causal role in this process (9, 10). We and others have shown the effects of ischemic injury are not short-lived, but rather ischemic injury can progress to a chronic inflammatory response that continues to increase months later (14 ‐17). On the basis of the experimental animal models, we predicted that evidence of ischemic damage in clinical endomyocardial biopsies obtained in the early posttransplantation period would correlate with complement deposition. PATIENTS AND METHODS