Development of a Combined Heart and Carotid Artery Transplant Model to Investigate the Impact of Acute Rejection on Cardiac Allograft Vasculopathy

Background: Cardiac allograft vasculopathy (CAV) is the leading cause of late allograft loss after heart transplantation. Although clinical studies are suggestive of an association between episodes of acute rejection and subsequent emergence of CAV, direct experimental evidence in support of a causal relationship is lacking. Methods: We developed a new murine model of CAV in which a carotid artery and a heart graft are simultaneously transplanted into a single recipient. Transplants were performed across full or partial major histocompatibility complex (MHC) mismatched strain combinations. The heart grafts were either syngeneic with the carotid graft or from a third-party strain. Carotid arteries were harvested after 30 days and evaluated by morphometry and immunohistochemistry. Results: In the fully mismatched combination, all heart grafts were rejected within 7 days, as determined by loss of pulsation. At 30 days, carotid allografts in the combined transplant group had significantly more intimal hyperplasia compared with isolated carotid allografts. The neointima consisted of abundant smooth muscle cells and leukocytes. Intimal hyperplasia was also significantly enhanced by acute rejection of the third-party donor heart. In the partial MHC mismatched combination, the heart graft survived indefinitely, and this was associated with diminished intimal hyperplasia in the cotransplanted carotid artery compared with the isolated carotid allograft. Conclusion: We present direct experimental evidence that CAV is promoted by acute parenchymal rejection of the heart. This interaction between acute rejection and CAV is mediated by both allospecific and non-allospecific processes. Effective therapeutic strategy against CAV should therefore target non-allospecific mediators as well as prevent episodes of acute rejection.