cAMP Pulse During Preservation Inhibits the Late Development of Cardiac Isograft and Allograft Vasculopathy

Abstract

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 ...

cAMP/CREB-mediated Transcriptional Regulation of Ectonucleoside Triphosphate Diphosphohydrolase 1 (CD39) Expression

“…Provision of cAMP also enhances lung preservation in an orthotopic rat left lung transplant model. Furthermore, a cAMP pulse during cardiac preservation reduces the incidence and severity of transplant-associated coronary artery disease (57). Given the protective effects of CD39 in cerebral, myocardial, renal, and intestinal ischemia reperfusion models, our data suggest a potential pharmacological means to bolster endogenous CD39 expression, by provision of a cAMP analogue, phosphodiesterase inhibitors that augment endogenous cAMP levels, or perhaps even another agent that activates CRE sites.…”

Suppression of Murine Cardiac Allograft Arteriopathy by Long-Term Blockade of CD40-CD154 Interactions

“…7 Increased FAC correlates with better cardiac function. Echocardiograms were performed on the MR1(c)-treated recipients at days 20 to 25 and on the Ha4/8(c)-treated recipients at days 5 to 7.…”

“…7 In brief, after anesthesia, donor hearts were harvested and transplanted heterotopically into recipient abdomens. The donor aorta and pulmonary artery were anastomosed end-to-side to the recipient's abdominal aorta and inferior vena cava, respectively, with warm ischemic time maintained constant at 30 minutes.…”

“…This technique has been previously described to measure the function of native and transplanted murine hearts. 7,9 …”

“…7 At 60 days after transplantation, grafts from MR1-treated recipients were harvested and fixed in 10% formalin, embedded in paraffin, and sliced into 5-mol/L sections with a microtome. Grafts from Ha4/8-treated recipients were harvested at graft failure (mean, 25 days).…”