“Cardiac allograft vasculopathy (CAV) is characterized by the proliferation of vascular smooth muscle cells in the allograft and concentric intimal thickening. The etiology of CAV is both immune and non-immune and may be related to ischemia at the time of transplant, humoral rejection, multiple episodes of cellular rejection, and cardiovascular risk factors. CAV leads to significant morbidity and mortality after transplant leading to the possibility of arrhythmogenic sudden death. CAV is diagnosed by the presence of coronary angiographic findings, intravascular ultrasound (though limited in younger donors), and the presence of wall motion abnormalities during dobutamine stress echocardiogram.”

“For thoracic organ transplantation (heart, lung, or heart and lung transplantation), transplant graft failure will be defined as the need for mechanical circulatory support or mechanical cardiopulmonary support and/or relisting for transplant”

“Transplant rejection is defined as evidence of rejection after transplantation. Heart transplant rejection is defined as intensification of immunosuppression associated with an abnormal biopsy (equal to or greater than grade 2R by the International Society of Heart and Lung Transplantation [ISHLT]) and/or new-onset hemodynamic abnormalities confirmed by echocardiography. Rejection in a heart-lung transplant recipient is defined as intensification of immunosuppression associated with an abnormal biopsy (equal to or greater than grade 2R by the International Society of Heart and Lung Transplantation [ISHLT]) and/or new-onset hemodynamic abnormalities confirmed by echocardiography. Lung transplant rejection is defined as intensification of immunosuppression associated with clinical characteristics of rejection and/or an abnormal biopsy with histologic classification of Grade A by the International Society of Heart and Lung Transplantation [ISHLT] in the acute setting, and by the development of bronchiolitis obliterans in the chronic setting.”

“Antibody-mediated rejection (AMR) is defined as rejection where donor specific antibodies are involved in the rejection process. AMR can happen early post-transplant from pre-formed antibodies, or from the persistence of these antibodies later on after transplant, or from the de novo development of donor specific antibodies. AMR results in the pathohistological findings of C4d deposition, endothelial cell activation, and interstitial edema with cell injury. Antibody induces rejection acutely through the fixation of complement, resulting in tissue injury and coagulation. In addition, complement activation recruits macrophages and neutrophils, causing additional endothelial injury. Antibody and complement also induce gene expression by endothelial cells, which is thought to remodel arteries and basement membranes, leading to fixed and irreversible anatomical lesions that permanently compromise graft function.”

“Cellular rejection is defined as rejection where graft antigens are recognized by T cells which mediate this rejection. This recognition of antigen by T cells results in activation of these cells. Activated T cells cause the graft cells to lyse or produce cytokines that recruit other inflammatory cells, eventually causing necrosis of allograft tissue.”

“In acute rejection, graft antigens are recognized by T cells; the resulting cytokine release eventually leads to tissue distortion, vascular insufficiency, and cell destruction. Histologically, leukocytes are present, dominated by equivalent numbers of macrophages and T cells within the interstitium. These processes can occur within 24 hours of transplantation and occur over a period of days to weeks. ([http://www.emedicine.com/ped/topic2841.htm], accessed July 20, 2006). Acute rejection usually begins after the first week of transplantation, and most likely occurs to some degree in all transplants (except between identical twins). It is caused by mismatched HLA antigens that are present on all cells. HLA antigens are polymorphic; therefore, the chance of a perfect match is extremely rare. The reason that acute rejection occurs a week after transplantation is because the T-cells involved in rejection must differentiate and the antibodies in response to the allograft must be produced before rejection is initiated. These T-cells cause the graft cells to lyse or produce cytokines that recruit other inflammatory cells, eventually causing necrosis of allograft tissue. Endothelial cells in vascularized grafts are some of the earliest victims of acute rejection. The risk of acute rejection is highest in the first 3 months after transplantation, and is lowered by immunosuppressive agents in maintenance therapy. However, acute rejection can occur at any time after transplantation. The onset of acute rejection is combated by intensification of immunosuppression with episodic treatment. ([http://biomed.brown.edu/Courses/BI108/BI108_2004_Groups/Group04/Rejection_overview.htm], accessed July, 20, 2006). Acute cardiac rejection is diagnosed in the situation of new cardiac failure symptoms with associated hemodynamic compromise, or new echocardiographic findings of cardiac dysfunction, with or without histologic evidence of rejection. Acute rejection requires rescue therapy with pulse dose steroids, anti-thymocyte globulin, and antibody directed therapy including plasmapheresis. Acute lung rejection is defined by the International Society of Heart and Lung Transplantation (ISHLT) as Grade A rejection according to a revised clinical update of the 1996 lung allograft rejection working formula. This formulation utilized Grades A through D to define rejection, with grade A being the “gold standard” for the assessment of acute allograft rejection, though it must be interpreted in the setting of the clinical findings. In the 2007 update to the above working formulation, Grade A rejection is stated as being “robust and reproducible”, though the other grades have fallen short of this measure and their clinical correlations have been minimal.”

“Chronic rejection occurs months to years after transplantation. In chronic rejection, pathologic tissue remodeling results from peritransplant and posttransplant trauma. ([http://www.emedicine.com/ped/topic2841.htm], accessed July 20, 2006). It is characterized by graft arterial occlusions, which results from the proliferation of smooth muscle cells and production of collagen by fibroblasts. This process, termed accelerated or graft arteriosclerosis, results in fibrosis that can cause ischemia and cell death. ([http://biomed.brown.edu/Courses/BI108/BI108_2004_Groups/Group04/Rejection_overview.htm], accessed July, 20, 2006). This process of chronic rejection is not an acute postoperative entity. Chronic rejection is dominated by the response of the transplanted organ tissue itself. Chronic rejection typically occurs after hospital discharge from the transplantation. Therapy for chronic rejection involves intensification of baseline immunosuppressive regimen, followed by the addition of steroids, anti-thymocyte globulin and total lymphocyte irradiation in refractory cases. Chronic cardiac transplant rejection is the presence of graft dysfunction and/or cardiac allograft vasculopathy and may occur months to years after transplantation. For cardiac transplantation, this disease is often manifest as coronary artery disease (CAD) and is known as “transplant graft vasculopathy” or “cardiac allograft vasculopathy (CAV)” ([http://www.clinicaltrials.gov/ct/show/NCT00042614], accessed July 20, 2006). Chronic rejection after cardiac transplantation involves new electrocardiographic (ECG), lab, or other clinical findings consistent with myocardial infarction and/or coronary arterial changes on catheterization lab angiography, CT angiography, or intravascular ultrasound, in addition to persistent findings of histologic rejection on biopsy. Chronic rejection of the lung allograft is defined as a fibrosing process affecting the lung, which primarily affects the conducting airways and the pulmonary vasculature. The process affecting the conducting airways has been labeled bronchiolitis obliterans, while that affecting the pulmonary arteries and veins has been named graft atherosclerosis/graft phlebosclerosis. ([http://path.upmc.edu/divisions/pulmpath/bron02.htm], accessed July 22, 2006). Chronic rejection after lung transplantation is defined as an acute drop in FEV1 of 20% from baseline pulmonary function tests recorded in the first 6 months after transplant. In addition chronic rejection after lung transplantation is characterized by the development of bronchiolitis obliterans.”

“Hyperacute rejection occurs usually within the first 24 hours after transplantation and is caused by pre-existing host antibodies to the transplanted organ. Recipients are more prone to have pre-formed reactive antibodies to the Human Leukocyte Antigens (HLA) of other individuals after previous blood transfusions, pregnancies, transplantations, or even exposure to allograft material such as cryopreserved aortic and pulmonary homografts. These preformed anti-graft antibodies bind to antigens present in the graft endothelium. Antigen recognition activates the complement system and is associated with an influx of neutrophils. Endothelial cells and platelets are also induced to shed lipid particles from their membrane that promote coagulation. The resulting inflammation prevents vascularization of the graft. The graft then suffers irreversible damage from ischemia. ([http://biomed.brown.edu/Courses/BI108/BI108_2004_Groups/Group04/Rejection_overview.htm], accessed July, 20, 2006) Hyperacute rejection is usually immediate, and complete graft failure is usually recognized at or near the time of organ reperfusion. For cardiac transplantation, this process occurs at or near the time of initial aortic cross clamp removal and is followed by 1) initiation of mechanical circulatory support and relisting for transplant and/or 2) death.”