Coronary artery disease after heart transplantation and its relation to cytomegalovirus

The most common cause of death and retransplantation after heart transplantation is a rapidly progressive, obliterative vascular disease involving the coronary arteries, termed cardiac allograft vasculopathy (CAV). Most believe that this is a form of chronic rejection. Several clinical series have suggested an association between cytomegalovirus and CAV. Rat cytomegalovirus enhances the development of CAV in rat heterotopic heart or aortic transplantation models. The mechanism(s) by which cytomegalovirus might have an impact on the severity of chronic rejection include the augmentation of vascular growth factors, the alteration in the alloimmune response directly or the alteration of cytokines and cell adhesion molecules, enhancing cellular and humoral interactions. We previously reported that the infection of smooth muscle cells by cytomegalovirus resulted in the alteration of major histocompatibility complex class I molecules on the smooth muscle cell surface. In a subsequent report we demonstrated that a sublethal inoculum of cytomegalovirus produced no cytopathology in smooth muscle cells yet had the same viral burden as fibroblasts, which demonstrated cytopathology. The identical effects on major histocompatibility complex class I were observed in smooth muscle cells, and cytokine gene transcription was altered, favoring a proinflammatory milieu. These and most in vitro studies are carried out with the use of traditional laboratory strains of cytomegalovirus. We have subsequently demonstrated major genotypic differences between laboratory and clinical strains of cytomegalovirus that are associated in differences in biological activity in vitro. These include differences in tropism for vascular cells, differences in cell surface antigen expression, and differences in mesenchymal growth factor gene expression. All of these may have important implications with regard to associating cytomegalovirus with CAV.