Background: Little has been reported on the clinical significance of mixed cellular and AMR in heart transplantation. It remains unclear whether mix rejection (MR) has unique clinicopathologic findings beyond those of pure acute cellular rejection (ACR) and AMR. We aimed to show whether MR has a differential impact on the development of CAV and CVM.
Methods: Patients classified as ACR (n=24), AMR (n=20), or MR (n=26) based on their rejection type in the first 3-months post-transplant. Biopsies stained with Ki-67, CD68, and  HLA-DR. Loss of DR expression on capillaries accepted as microvascular destruction. Apoptotic cells detected by the TUNEL method. The degree of macrophages and neutrophils in capillaries and interstitium graded. The presence of endothelitis in small vessels evaluated. Patients analyzed for the development of CAV via angiography.
Results: Endothelitis, apoptotic cell death of myocytes, interstitial and capillary macrophage and neutrophil infiltration were significantly higher in cases with MR compared to cases with ACR and AMR (p<.01). Ki-67 proliferation index was also found to be higher in cases with MR than patients with ACR and AMR (p<.001). Compared to patients with ACR and AMR, recipients with MR showed higher degrees of myocyte DR expression and lower degrees of capillary DR expression which means higher degrees of capillary destruction (p<.01).  The mean time of the development of CAV found significantly early in recipients with MR (22±12) than patients with ACR (78±13) and AMR (50±21) (p<.001). Overall 10-year patient survival was 100%, 75% and 54% for ACR, AHR, and MR respectively (p<.001).
Conclusion: MR occurred within 3-months after transplant and should be recognized because of its worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity. Another point that we must underline is the endothelitis of small arteries and capillary destruction which may be a sign of severe rejection.