Pathology and etiology of chronic rejection of the heart

As there are other lesions in the cardiac allografts of long‐term survivors, it is best to refer to the vascular lesion as “graft vascular disease”. Graft vascular disease may be evident as early as 3 months after cardiac transplantation and may cause death in the recipient as late as 22 years post‐transplant. The disease affects infants, children, and adults as well as the recipients of combined heart‐lung transplants. It is one of the most discouraging aspects of long‐term survival in combined heart‐lung and heart transplantation, accounting for 18% of the deaths among the 201 cardiac transplants performed at Stanford during the cyclosporine era. The pathology of graft vascular disease is that of a concentric intimai proliferation with minimal damage to the elastic lamina and minimal or no change in the media of the coronary vessel wall. The lesion may affect the entire length of the vessel wall as well as the branches and small branches that penetrate into the myocardium of the coronary system. These changes differ from that of naturally occurring atherosclerosis in that, instead of focal lesions developing, the whole length of the vessel is affected, including the small branches. This precludes optimal treatment with angioplasty and other therapies. Because small vessels are involved, the resulting myocardial infarcts may be patchy and small. Presently, no strong correlation has been made with usual risk factors or transplantation for end‐stage coronary atherosclerosis, cardiomyopathy or congenital heart disease. The etiology of graft coronary disease remains unclear. Studies have suggested vascular cell activation of various kinds, including cytokines. Some of these processes, however, have been found in nontransplant coronary disease as well. A correlation with acute rejection, although suspected, has not been definitively proved; in combined heart‐ lung transplantation, the cardiac graft rarely rejects and yet graft vascular disease develops. The only correlation thus far has been with cytomegalovirus (CVM) infection, in which death from graft vascular disease is higher in infected recipients. More recently, a correlation has been made with the so‐called “Quilty lesion”. Early animal studies with in vivo blockade of tumor necrosis factor (TNF) indicated that it inhibits the development of graft arteriopathy. Such studies are being conducted extensively in America and elsewhere.