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Graft arteriosclerosis (GA) remains the leading obstacle to long-term survival of cardiac allografts. The pathogenesis of this chronic disease, though perceived to be multifactorial, is most likely immune-driven. Based on clinical and experimental observations, the humoral arm of the immune system has long been suspected to play a pivotal role in the disease process. In this article, we shall review the evidence generated from key clinical and experimental studies on the role of alloantibodies in GA. We will argue that although the strong correlation between the presence of anti-donor antibodies in clinical and experimental GA is highly suggestive of a pathogenic role for alloantibodies, a direct causal link between GA and the humoral arm of the alloresponse cannot yet be established based on the currently available evidence, and may in fact be one of a number of pathogenic processes that potentiate this vasculopathy. Finally, in this article, we shall discuss some of the potential mechanisms by which alloantibodies may exert their pathogenic effect in GA.

Background. The development of chronic rejection has emerged as a major cause of long-term graft failure. Previous studies have demonstrated that cytomegalovirus (CMV) infection is associated with an increased incidence of chronic allograft rejection in renal, cardiac, and aortic allografts. This study was designed to investigate the effects of the major histocompatibility complex (MHC) class I or class II mismatches on CMV-enhanced chronic rejection.Methods. Aortic transplantation was performed between different inbred Pat strain combinations; the Lewis to RP combination was class I-mismatched and Wag/Rij to RP class II-mismatched. At 7, 28, and 90 days after transplantation, the intensity of chronic rejection in mismatched grafts with or without CMV infection was evaluated using histological and immunohistological analysis.Results. The results of this study demonstrated that CMV infection led to an increased influx of monocytes/macrophages in class I-mismatched grafts at 1 week after transplantation and enhanced infiltration of T lymphocytes in class II-mismatched grafts at 4 weeks. Although more vascular lesions were observed in the class II-mismatched combinations, an intensified neointima formation by CMV infection was observed only in the MHC class I-mismatched allografts.Conclusions. CMV infection may increase neointima formation of allografts when arm MHC class I disparity between donor and recipient is present. This may be associated with the increased perivascular influx of monocytes/macrophages observed in CMV-infected animals early after transplantation.

0 ver the last 25 years, organ transplantation has developed from an experimental procedure to an established clinical tool. At present, engraftment of kidney, heart, liver, lung, and pancreas has become relatively commonplace and is often the treatment of choice for many patients with end-stage organ failure. The results have improved progressively because of better periand postoperative care, more effective immunosuppression, and greater understanding of particular disease states. As a result, the demand for organs is growing exponentially, with ever increasing numbers of patients seeking help. Part of this demand results from greater access for more candidates to such expensive and highly technical care; part results from the very success of the procedure that has allowed engraftment of individuals who would not have been accepted previously, including persons over 65 years, juvenile diabetics, individuals with a history of hepatitis, alcoholics, and other populations with diminished prognosis and critical comorbid risk factors. As a result, the discrepancy between the supply of cadaver kidneys for transplantation and demand from potential recipients is increasing steadily.’ Organs are now being used from donors who would not have been seriously considered in past years. Despite ever expanding criteria for acceptance of both donors and recipients, functional success of most organs at 1 year has reached 80% or more.’ Despite this progressive improvement, however, the rate of attrition of organ grafts has not changed throughout the entire experience: the half-life of kidney grafts remains between 7 to 10 years; 50% of heart graft recipients develop graft arteriosclerosis

Current interest in permanent mechanical support systems has been renewed as a result of the present shortage of human heart donors, and in view of the satisfactory results obtained with their use as a bridge-to-transplant. As the number of donors is unlikely to increase dramatically in the near future, there is an urgent need to develop mechanical alternatives to transplantation. Preliminary data on the use of the implantable electric LVAD as a bridge-to-transplant indicate that the adverse clinical and mechanical events in outpatients are few and do not preclude use of the device on a permanent basis. Except for infections, transplant issues relating to need for endomyocardial biopsies, rejection, malignancies, and graft arteriosclerosis do not apply to LVAD recipients who face important issues relating to device durability, cost, and potential need for concomitant right heart support. This lack of data on long-term durability contrasts with a yearly mortality rate of about 5% after the first year of transplant. With the initiation of clinical trials on the permanent use of the electric LVAD, several design modifications and upgrading of the currently available devices are expected. Completely sealed systems with steadily improving durability will hopefully appear. Inductive coupling techniques under investigation and development appear to be able to transmit energy without damage across the skin. It is anticipated that with more reliable electronic microprocessors, the future generation of implantable LVADs will be smaller, more reliable and longer lasting.

The purpose of the current study was to evaluate the effects of thalidomide on graft arteriosclerosis.Male Lewis rats received abdominal aorta grafts from male Brown-Norway rats. The animals were divided into 4 groups: no treatment controls, a low-dose group that received thalidomide (50 mg/kg per day), a middle dose group that received thalidomide (100 mg/kg per day), and a high-dose group that received thalidomide (200 mg/kg per day) by daily intragastric administration. Rats were humanely killed at 60 days after surgery. The grafted aortas were analyzed by histology, immunohistochemistry, and Western blot analysis. The serum was analyzed by an enzyme-linked immunosorbent assay (ELISA).The neointimal thickness of the thalidomide treated aortas was significantly thinner compared with that of no treatment aortas (P.05). Vascular endothelial growth factor (VEGF), platelet-derived growth factor, and intracellular adhesian molecule (ICAM-1) protein expression in the treatment group were significantly lower than those in the control group (P.05). Moreover, thalidomide significantly inhibited the production of VEGF and ICAM-1 in serum (P.05).Our data suggested that thalidomide can attenuate graft arteriosclerosis so as to protect aortic grafts.

Echocardiography has gained increasing importance as an imaging modality in the care of the cardiac transplant recipient. Its utility in detecting the complications of transplantation, with special reference to the diagnosis of rejection and graft arteriosclerosis, is discussed. On the basis of a review of the current literature, an outline for serial echocardiographic studies is proposed.

Progressive graft arteriosclerosis is responsible for the majority of late deaths occurring in cardiac transplant recipients. In order to define a model of this disease in the rat, we exchanged heterotopic cardiac allografts between MHC-compatible inbred strains. Lewis rats served as donors and F-344 rats as recipients. Twenty allografts were followed by daily palpation and removed at the time of terminal rejection or on the 120th postoperative day for pathologic study. Sixteen allografts (80%) survived at least three weeks, and five allografts (25%) survived indefinitely. The majority of arteries (greater than 90%) examined demonstrated significant intimal disease; histologic findings in lesions in allografts rejecting at early time points included intense mononuclear cell infiltration of the intima, while lesions in long-term-surviving allografts demonstrated fibrous intimal thickening, which is characteristic of graft arteriosclerosis seen clinically. A limited course of cyclosporine therapy in F-344 recipients increased the incidence of indefinite allograft survival from 25% to 86%, and was associated with a modest reduction in the amount of intimal disease observed. These results suggest that this model should be useful in future studies regarding the pathogenesis and therapy of cardiac graft arteriosclerosis.

BACKGROUND Lumen loss in graft arteriosclerosis is the consequence of the development of a thick neointima and constrictive arterial remodeling. The latter is due to adventitial chronic inflammation and excessive perivascular collagen deposition. We reasoned that blockade of the portal of entry of inflammatory effectors may constitute a strategy to prevent constrictive arterial remodeling. METHODS AND RESULTS We found that an anti-angiogenic therapy (ABT-510 nonapeptide), devoid of direct immunomodulatory properties, dramatically reduced adventitial angiogenesis by 66% (P\textless0.0001) in the rat aortic interposition model of graft arteriosclerosis. The associated decreased entry of inflammatory cells (44%; P\textless0.00001) resulted in drastic reduction of collagen deposition (57%; P\textless0.0001) thereby preventing subsequent adventitial constrictive remodeling and reduction of lumen surface area (5.26+/-0.74 vs. 8.58+/-2.48 microm2; Control vs. ABT-510-treated rats; P\textless0.0001). ABT-510 had no effect on the development of the neointima. CONCLUSION This work supports the idea that targeting angiogenesis may act synergistically with conventional immunosuppressive therapy in preventing graft arteriosclerosis, a crucial feature of chronic graft rejection.

Objective—Chronic vascular rejection, the main cause of allograft failure, is characterized by the destruction of smooth muscle cells (SMCs) in the media concomitantly with the proliferation of SMCs in the adjacent neointima. We hypothesized that alloantibodies might be responsible for these 2 opposite but coordinated events.Methods and Results—We used the rat aortic interposition model of chronic vascular rejection. During the rejection process, a neointima composed of proliferating SMCs from the recipient developed, whereas the SMCs in the media, all of donor origin, underwent apoptosis. Alloantibody deposition was detected only in the media. Using in vitro cultures experiments, we observed that alloantibody binding to donor SMCs exerts (1) a rapid upregulation of the transcription of growth factors genes, followed by (2) the induction of apoptosis after 24 hours. The transient production of growth factors by donor SMCs in response to the binding of alloantibodies induced the proliferation of recipient SMCs in culture supernatant transfer experiments. Additional data suggest that among the repertoire of alloantibodies, those directed against major histocompatibility complex I might carry the remodeling effect.Conclusions—Our data suggest that during chronic vascular rejection, alloantibody binding to donor medial SMCs is a crucial event that links neointimal and medial remodeling.

Graft arteriosclerosis (GA) is the leading cause of mortality in long-term survivors of solid organ transplantation. Although clinical studies have suggested a multifactorial etiology, the precise mechanism of disease remains obscure. Many animal models have been developed that manifest lesions resembling those of human arteriosclerosis. These models have helped us address specific mechanistic and interventional issues but, for reasons that will be discussed, have failed to assign a unitary pathogenic mechanism to clinical GA. In this chapter we describe the commonly available experimental models of GA. We further discuss the merits and limitations of each model and outline their contribution to our understanding of the pathogenesis of the disease.

To date established treatment of transplant arteriosclerosis is basically missing and there is a need for new therapeutic approaches. Angiotensin II (Ang II) and Ang II receptor type 1 (AT) are present in the vascular wall. Blocking of the AT1 receptor by pharmacological agents may inhibit damaging effects of Ang II on endothelial and smooth muscle cells. The purpose of the study was to evaluate the effect of the AT1 receptor blocker Candesartan cilexetil on the development of graft arteriosclerosis in a rat aortic transplant model. Two strain combinations were used for aortic transplantation: DA to PVG; and PVG to PVG. The animals received Candesartan cilexetil treatment (9.5 + 1.4 mg/kg/day) for 8 weeks. Candesartan cilexetil treatment reduced neointimal formation both in allografts (Qint 30.2 +/- 8.8% vs. 22.1 +/- 8.7%, P0.05) and in isografts (Qint 15.5 +/- 4.4% vs. 6.7 +/- 3.3%, P = 0.0001). Blocking of the AT1 receptor signalling by Candesartan cilexetil was also associated with a reduced expression of TGF-beta1. Macrophage infiltration was not affected by the treatment. Candesartan cilexetil treatment leads to reduced neointimal formation in aortic transplant. The positive effect of the drug might be partly explained by a reduction of TGF-beta1 expression in the grafts. Candesartan treatment may provide another possibility for prevention of transplant arteriosclerosis and chronic rejection.

Background. The development of chronic rejection has emerged as a major cause of long-term graft failure. Previous studies have demonstrated that cytomegalovirus (CMV) infection is associated with an increased incidence of chronic allograft rejection in renal, cardiac, and aortic allografts. This study was designed to investigate the effects of the major histocompatibility complex (MHC) class I or class II mismatches on CMV-enhanced chronic rejection. Methods. Aortic transplantation was performed between different inbred Pat strain combinations; the Lewis to RP combination was class I-mismatched and Wag/Rij to RP class II-mismatched. At 7, 28, and 90 days after transplantation, the intensity of chronic rejection in mismatched grafts with or without CMV infection was evaluated using histological and immunohistological analysis. Results. The results of this study demonstrated that CMV infection led to an increased influx of monocytes/macrophages in class I-mismatched grafts at 1 week after transplantation and enhanced infiltration of T lymphocytes in class II-mismatched grafts at 4 weeks. Although more vascular lesions were observed in the class II-mismatched combinations, an intensified neointima formation by CMV infection was observed only in the MHC class I-mismatched allografts. Conclusions. CMV infection may increase neointima formation of allografts when arm MHC class I disparity between donor and recipient is present. This may be associated with the increased perivascular influx of monocytes/macrophages observed in CMV-infected animals early after transplantation.

The development of progressive graft arteriosclerosis causes the majority of late deaths occurring in cardiac transplant recipients. The pathogenesis of this process remains unclear. In order to characterize the cellular composition of lesions progressively, we employed a model of graft arteriosclerosis in the rat involving untreated heterotopic cardiac allografts transplanted across minor histocompatibility barriers. Immunocytochemical studies were performed on arterial lesions in allografts removed at 15, 45, 75, and 120 days posttransplantation, using monoclonal antibodies specific for smooth muscle cells (HHF35, CGA7), monocytes/macrophages (ED1), T cells (W313), and endothelial cells (anti-vWf). We found areas of coronary intimal thickening demonstrated marked cellular heterogeneity. The earliest lesions involved the adherence of monocytes and T cells to the coronary endothelial surface. At later time points, we noted marked subendothelial accumulations of macrophages and occasional T cells in areas of intimal thickening. In contrast, smooth muscle cells were the major cell type identified in intimal lesions in 120-day-old allografts. Intimal macrophages are frequently seen in spontaneous human arteriosclerotic lesions; our findings suggest that macrophages, perhaps interacting with T cells, play an important role in the pathogenesis of graft arteriosclerosis.

The morphologic features of graft arteriosclerosis (GA) and other vascular lesions were semiquantitatively evaluated. Five failed cardiac allografts attributable to GA and five other allografts were obtained from nine autopsies and one surgical explanation. The subjects, aged 4.5 to 67 years, had a mean allograft survival of 735 +/- 184 days. A total of 1,174 arterial and 754 venous cross-sections were reviewed. Intimal fibrosis (nine cases, 254 arteries, and 118 veins), fibrofatty plaques (eight cases and 35 arteries), and cellular intima thickening and concentric foam cell lesions (eight cases, 326 arteries, and 20 veins) were seen. Cellular lesions contained T lymphocytes, monocytes, and cells of smooth muscle cell origin detected by staining using the immunoperoxidase technique. Allografts with severe GA had a greater luminal stenosis in epicardial arteries (P less than .05), greater cellular proliferation in large mural arterial lesions (P less than .004), and more foam cell lesions in both arteries (P less than .06) and veins (P less than .03) than other allografts. Medical fibrosis and thinning were present in six allografts. Severity of acute rejection (P less than .01) was correlated with the presence of GA. The morphology and distribution of GA is heterogeneous, with evidence supporting an immune-mediated pathogenesis.

Chronic rejection and graft arteriosclerosis: 4 years after the Alexis Carrel proposal on diagnostic criteria.

To the Editors: Graft arteriosclerosis following cardiac transplantation is a significant complication and is felt to have an immunologic cause. I describe a case of acute myocardial infarction in ...

Two hundred twenty-seven cardiac transplant procedures have been performed in 206 patients from January, 1968, to April, 1981. Postoperative survival rates, calculated by the actuarial method for program years 1968 to 1973 (66 patients), are 44%, 35%, 27%, 21%, and 18% at 1, 2, 3, 4, and 5 rears after transplantation, respectively. Postoperative survival rates for program years 1974 to 1981 (140 patients) are 63%, 55%, 51%, 44%, and 39% at 1, 2, 3, 4, and 5 years after transplantation, respectively. This increase results primarily from improvement in survival achieved in the first 3 postoperative months (59% ± 7%, 1968 to 1973, versus 80% ±40%, 1974 to 1980), reflecting improved patient management. Infection remains the primary cause of death following transplantation (76/131 patients, 58%), followed by acute rejection (24/181, 18.3%), graft arteriosclerosis (14/131, 10.7%), and malignancy (6/131, 4.6%). The development of graft arteriosclerosis has been examined in 85 one-year survivors studied by annual coronary arteriograms. Coronary lesions of varying severity have developed in 21 patients. HLA-A2 incompatibility was associated with a higher incidence of graft arteriosclerosis than was apparent for all other A locus incompatibilities (p

Seven patients with heterotopic heart transplants have undergone further heart transplant procedures. In 5, the first heterotopically placed donor heart was excised and replaced with the second donor heart. In 2, the first heterotopic donor heart was left in situ and the patient's own heart (then nonfunctioning) was excised and replaced by the second donor heart; thus, these patients underwent orthotopic transplantation and were left with two donor hearts. The decision to perform retransplantation in a patient undergoing irreversible acute rejection is usually straightforward, but the timing of a further transplant procedure in a patient with advanced graft arteriosclerosis may present a difficult problem. Two of the 7 patients in this series died of infectious complications within the first 3 months after retransplantation. A third patient acutely rejected the second donor heart within 5 days, but survived an additional 17 months with the support of his own cardiomyopathic heart. Four patients remain alive and well between 5 and 36 months following the second transplant and between 17 and 54 months following the first transplant procedure.

Accelerated graft arteriosclerosis is a major cause of death in human heart transplantation. Despite many investigations, the pathogenesis of this disease remains undetermined and its control inadequate. In this study using a rat heart transplant model and cyclosporin A, a new immunosuppressant, acute rejection was prevented but arteriosclerotic-like vessel disease still developed consistently as early as 20 days postoperatively. The combination of cyclosporin A and dipyridamole prevented the development of this vessel disease in transplanted hearts at 20 and 50 days postoperatively. Sulfinpyrazone and cyclosporin A reduced but did not prevent the disease. These findings suggest that immunologically induced graft arteriosclerosis can be prevented in transplanted rat hearts by the combination of cyclosporin A and dipyridamole.