Abstract-The causes of transplant-associated coronary artery disease remain obscure, and there is no known treatment.Preservation injury of murine heterotopic vascularized cardiac isografts caused a small, albeit significant, increase in neointimal formation; preservation injury of allografts markedly increased both the incidence and severity of transplant-associated coronary artery disease. As cAMP is an important vascular homeostatic mediator the levels of which decline during organ preservation, buttressing cAMP levels solely during initial preservation both improved acute allograft function and reduced the severity of transplant-associated coronary artery disease in grafts examined 2 months later. Inhibiting the cAMP-dependent protein kinase abrogated these beneficial effects. cAMP treatment was associated with an early reduction in leukocyte infiltration and a reciprocal decrease in superoxide and increase in NO levels. These data indicate that alloantigen-independent injury to the graft, which occurs at the time of cardiac preservation, can set in motion pathological vascular events that are manifest months later. Furthermore, a cAMP pulse during cardiac preservation reduces the incidence and severity of transplant-associated coronary artery disease. (Circ Res. 2000;86:982-988.)Key Words: cAMP Ⅲ protein kinase Ⅲ heart transplantation Ⅲ allograft arteriopathy Ⅲ organ preservation A lthough cardiac transplantation is a life-saving procedure for patients who would otherwise die from intractable heart failure, Ϸ50% of all recipients of heart transplants develop cardiac transplant-associated coronary artery disease (TCAD) by 5 years after transplantation. 1 The progression of TCAD in human heart transplant recipients is inexorable, with no effective therapy short of retransplantation. Identification of the precise etiologic factors leading to TCAD remains elusive. It is believed that TCAD may be related to a donor-specific, cell-mediated alloreactivity to donor vascular endothelium. 2 Although immunologic disparity between donor and recipient undoubtedly exacerbates TCAD, 3 in addition to immune system-activating mechanisms, 4 there remains the possibility that antigen-independent factors can also contribute to or accelerate the progression of TCAD.In clinical studies, pinpointing a causal role for ischemia in TCAD development has been elusive, although there is a significant amount of circumstantial data suggesting a role for ischemic injury in the evolution of human TCAD. In a large study by Opelz and Wujciak, 5 in which Ͼ8000 cardiac transplant recipients were examined, a clear relation was seen between the duration of cold ischemia and graft survival as long as 3 years after cardiac transplantation (TCAD was not specifically examined). In fact, when the duration of cold ischemia was 6 hours, graft survival by 3 years out was nearly 25% less than those grafts preserved under hypothermic conditions for Ͻ2 hours. In this study, intermediate preservation durations were associated with intermediate durations of ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.