Author(s): Lemstrm K, Koskinen P, Krogerus L, Daemen M, Bruggeman C
BACKGROUND: Cardiac allograft arteriosclerosis is the primary cause of late death in heart transplant recipients. Clinical studies have suggested that humoral and cellular immune response, hyperlipidemia, and cytomegalovirus (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. To prevent rejection, the recipients received triple-drug (cyclosporine A 20 mg.kg-1.d-1, azathioprine 2 mg.kg-1.d-1, and methylprednisolone 0.5 mg.kg-1.d-1) immunosuppression postoperatively. Recipient rats were infected intraperitoneally (n = 21) with 10(5) plaque-forming units of rat CMV (RCMV) 1 day after transplantation or were left uninfected and used as controls (n = 18). The grafts were removed 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, mononuclear cell inflammation of small intramyocardial arterioles was observed compared with none in uninfected rats (P = .005). Acute RCMV infection was associated with an early perivascular inflammatory cell response of helper T (W3/25), cytotoxic T (OX8), and NK (3.2.3) cells, macrophages (OX42), and major histocompatibility complex class II expression around small intramyocardial arterioles and capillaries. No upregulation of interleukin-2 receptor expression was seen. In arteries and small intramyocardial arterioles, RCMV infection was associated with a significant endothelial cell proliferation and a clear increase in intimal thickening. Significant endothelial cell proliferation was also observed in the capillaries after RCMV infection. Immunohistochemistry revealed specific focal RCMV early and late antigen expression in epicardial and interstitial ED1-immunoreactive mononuclear cell infiltrates and around small arterioles of RCMV-infected cardiac allografts. Occasionally, 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 expressing RCMV antigens.
CONCLUSIONS: These results demonstrate a productive RCMV infection in cardiac allograft structures and suggest that RCMV infection accelerates cardiac allograft arteriosclerosis, particularly in small intramyocardial arterioles mediated by inflammatory responses in the vascular wall and perivascular space.