CYTOMEGALOVIRUS ANTIGEN EXPRESSION, ENDOTHELIAL-CELL PROLIFERATION, AND INTIMAL THICKENING IN RAT CARDIAC ALLOGRAFTS AFTER CYTOMEGALOVIRUS-INFECTION

Background Cardiac allograft arteriosclerosis is the primary cause of late death in heart transplant recipients. Clinical studies have sugge sted that humoral and cellular immune response, hyperlipidemia, and cy tomegalovirus (CMV) infection may amplify the disease. In this study, the role of CMV infection in the development of rat cardiac allograft arteriosclerosis is investigated. Methods and Results Heterotopic rat cardiac allografts were performed from the DA to the WF rat strains. T o prevent rejection, the recipients received triple-drug (cyclosporine A 20 mg . kg(-1). d(-1), azathioprine 2 mg . kg(-1). d(-1), and methy lprednisolone 0.5 mg . kg(-1). d(-1)) immunosuppression postoperativel y. Recipient rats were infected intraperitoneally (n=21) with 10(5) pl aque-forming units of rat CMV (RCMV) 1 day after transplantation or we re left uninfected and used as controls (n=18). The grafts were remove d 7 and 14 days and 1 and 3 months after transplantation. In 42% (9 of 21) of cardiac allografts in RCMV-infected rats, an intramural, monon uclear cell inflammation of small intramyocardial arterioles was obser ved compared with none in uninfected rats (P=.005). Acute RCMV infecti on was associated with an early perivascular inflammatory cell respons e of helper T (W3/25), cytotoxic T (OX8), and NK (3.2.3) cells, macrop hages (OX42), and major histocompatibility complex class II expression around small intramyocardial arterioles and capillaries. No upregulat ion of interleukin-2 receptor expression was seen. In arteries and sma ll intramyocardial arterioles, RCMV infection was associated with a si gnificant endothelial cell proliferation and a clear increase in intim a! thickening. Significant endothelial cell proliferation was also obs erved in the capillaries after RCMV infection. Immunohistochemistry re vealed specific focal RCMV early and late antigen expression in epicar dial and interstitial ED1-immunoreactive mononuclear cell infiltrates and around small arterioles of RCMV-infected cardiac allografts. Occas ionally, media cells of stenosed small intramyocardial arterioles also showed strong focal RCMV antigen expression. In addition, infectious RCMV could be recovered by plaque assay in cardiac allografts expressi ng RCMV antigens. Conclusions These results demonstrate a productive R CMV infection in cardiac allograft structures and suggest that RCMV in fection accelerates cardiac allograft arteriosclerosis, particularly i n small intramyocardial arterioles mediated by inflammatory responses in the vascular wall and perivascular space.