Coronary artery disease after heart transplantation and its relation to cytomegalovirus

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Abstract

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. (Am Heart J 1999;138:S469-S472.)

Section snippets

Clinical studies

The first suggestion that there was an association between cytomegalovirus and CAV was from the Stanford group, who reported their experience with 301 patients. In 28% of cytomegalovirus-infected patients “severe” coronary obstructive lesions developed, whereas in only 10% of patients not infected with cytomegalovirus, the same degree of CAV developed.9A similar association between cytomegalovirus and CAV has been reported by others.10, 11 In contrast, Balk et el12 failed to find a relation

In vitro/animal studies

Several reports of cytomegalovirus accelerating chronic rejection in the animal model have been reported. Lemstrom et al16 have demonstrated cytomegalovirus to be a chronic rejection–accelerating factor in the aortic allograft model and its inhibition with intensive immunosuppression17 or treatment with gancyclovir.18 In these experiments, cytomegalovirus infection was introduced at the time of transplantation or later after transplantation. Whether pretreatment of the donor or recipient with

Summary

The development of transplantation coronary artery disease clearly requires the allogeneic response, given its limitation to the allograft. Therefore effects of cytomegalovirus on the development of this obliterative vasculopathy cannot be direct but must somehow alter (augment) the primary allogeneic response. Although the endothelial cell does not appear to allow cytomegalovirus viral replication, infection does result in widespread alterations in endothelial cell biology. Alternatively, if

References (35)

  • JD Smith et al.

    Specificity of lymphocytotoxic antibodies formed after cardiac transplantation and correlation with rejection episodes

    Transplantation

    (1992)
  • MT Grattan et al.

    Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis

    JAMA

    (1989)
  • M Loebe et al.

    Role of cytomegalovirus infection in the development of coronary artery disease in the transplanted heart

    J Heart Transplant

    (1990)
  • A Balk et al.

    Is there a relation between transplant coronary artery disease and the occurrence of CMV infection [abstract]?

    J Heart Lung Transplant

    (1991)
  • PK Koskinen et al.

    Cytomegalovirus infection and accelerated cardiac allograft vasculopathy in human cardiac allografts

    J Heart Lung Transplant

    (1993)
  • JP Everett et al.

    Prolonged cytomegalovirus infection with viremia is associated with development of cardiac allograft vasculopathy

    J Heart Lung Transplant

    (1992)
  • T-C Wu et al.

    Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts

    Am J Pathol

    (1992)
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