Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome

OBJECTIVES: We sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome. BACKGROUND: Allograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia. METHODS: One hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n = 32), ischemia (n = 24), fibrosis (n = 62) or vascular rejection (n = 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up. RESULTS: Patients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p = 0.008) and lowest average episodes of cellular rejection (1.7 ± 1.4, p = 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness = 0.59 ± 0.28 mm, p < 0.0001) and poor seven-year event-free survival (49%, p = 0.01). CONCLUSIONS: The development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy.