Impact of donor benign intimal thickening on cardiac allograft vasculopathy.

BACKGROUND: Epicardial cardiac allograft vasculopathy (CAV) is commonly described as a homogeneous smooth muscle cell (SMC)-rich inward intimal lesion with the SMC oriented circumferentially around the vessel. Recent findings have called this description into question. In this study we aimed to clarify the clinical presentation of epicardial CAV. METHODS: Autopsied samples of the 3 major coronaries were analyzed from patients fitting cardiac donor criteria (n = 10) and patients who had undergone cardiac transplantation (n = 34). Histology and immunohistochemistry were performed to identify cellular components of CAV, and image analysis was used to measure the various vascular compartments. RESULTS: Of the 34 cases examined, 28 of the epicardial intimal lesions contained 2 clearly definable layers overlying the media. The layer most adjacent to the media was SMC-rich, with the SMC oriented longitudinally along the vessel length and containing few macrophages, both characteristics of donor-derived benign intimal thickening (BIT). Transplants harvested at 1, 4 or 10 days post-transplant confirmed retention of BIT after transplantation. Image analysis of later transplants supported a hypothesis of carry-over BIT in CAV. The more lumenal CAV layer more closely resembled naturally occurring atherosclerosis. CONCLUSIONS: We propose that retention of the SMC-rich BIT layer after transplantation accounts, to a large extent, for the donor-derived, SMC-rich nature of human CAV, and that perturbation of the BIT provides the inflammatory foundation for the development of an accelerated atherosclerosis in the epicardial coronaries of transplant patients. This expanding accelerated atherosclerosis along with the underlying BIT demonstrates the characteristics ascribed to CAV.

Early innate immune events induced by prolonged cold ischemia exacerbate allograft vasculopathy.

BACKGROUND: Ischemia/reperfusion induced innate immune injury is inescapable in solid organ transplantation. Prolonged cold ischemia exacerbates the primary manifestation of late graft rejection, allograft vasculopathy (AV). The relationship between prolonged cold ischemia and late graft events is unclear and the subject of this study. METHODS: Aortic interposition transplants were performed between fully disparate mice treated with CyclosporineA. Allografts were exposed to 20 min or 60 min of cold ischemia and harvested between 1 d-6 wk. Lesion size, smooth muscle cells (SMC), neutrophils (NØ), and CD8+ T cells were quantified. RESULTS: Early SMC loss was identical in both groups. When compared to 20 min cold ischemia, grafts exposed to 60 min exhibited greater early NØ influx, greater SMC proliferation but fewer medial SMC at 1 wk and 2 wk. Subsequently, earlier and greater CD8+ T cell infiltration were seen in the 60 min group with larger lesions at every time point. CONCLUSIONS: These data suggest that the larger neointimal lesions in grafts exposed to 60 min cold ischemia result from enhanced early innate immune events resulting in impaired SMC recovery and subsequent increased adaptive immune response.

Neutrophil mediated smooth muscle cell loss precedes allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (AV) is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation. While there is consensus that AV is alloimmune mediated, and evidence that the most important alloimmune target is medial smooth muscle cells (SMC), the role of the innate immune response in the initiation of this disease is still being elucidated. As ischemia reperfusion (IR) injury plays a pivotal role in the initiation of AV, we hypothesize that IR enhances the early innate response to cardiac allografts. METHODS: Aortic transplants were performed between fully disparate mouse strains (C3H/HeJ and C57BL/6), in the presence of therapeutic levels of Cyclosporine A, as a model for cardiac AV. Neutrophils were depleted from some recipients using anti-PMN serum. Grafts were harvested at 1,2,3,5d and 1,2wk post-transplant. Ultrastructural integrity was examined by transmission electron microscopy. SMC and neutrophils were quantified from histological sections in a blinded manner. RESULTS: Grafts exposed to cold ischemia, but not transplanted, showed no medial SMC loss and normal ultrastructural integrity. In comparison, allografts harvested 1d post-transplant exhibited > 90% loss of SMC (p < 0.0001). SMC partially recovered by 5d but a second loss of SMC was observed at 1wk. SMC loss at 1d and 1wk post-transplant correlated with neutrophil influx. SMC loss was significantly reduced in neutrophil depleted recipients (p < 0.01). CONCLUSIONS: These novel data show that there is extensive damage to medial SMC at 1d post-transplant. By depleting neutrophils from recipients it was demonstrated that a portion of the SMC loss was mediated by neutrophils. These results provide evidence that IR activation of early innate events contributes to the etiology of AV.