Relevance of Cytomegalovirus Infection and Coronary-Artery Remodeling in the First Year after Heart Transplantation: A Prospective Three-Dimensional Intravascular Ultrasound Study.

Relevance of Cytomegalovirus Infection and Coronary-Artery Remodeling in the First Year after Heart Transplantation: A Prospective Three-Dimensional Intravascular Ultrasound Study. Transplantation 2003;75:839. L. Potena, F. Grigioni, P. Ortolani, G. Magnani, C. Marrozzini, E. Falchetti, A. Barbieri, L. Bacchi-Reggiani, T. Lazzarotto, A. Marzocchi, C. Magelli, M. P. Landini, A. Branzi CYTOMEGALOVIRUS AND TRANSPLANT ARTERIOPATHY: EVIDENCE FOR A LINK IS MOUNTING, BUT THE JURY IS STILL OUT As with many other members of the Herpesviridae family, cytomegalovirus (CMV) infection in humans is both common and chronic, although it only assumes clinical importance in the immunocompromised host. CMV infection in allograft recipients has been “under the microscope” since the late 1960s, when it was linked to rapid graft demise (1). Transplant arteriopathy, first described in 1970 (2), currently ranks as the leading cause of late cardiac graft failure. A putative link between the two first emerged 13 years ago from a study by the Stanford group (3). In this frequently cited paper, long-term outcome in 210 CMV-free cardiac-graft recipients was compared with that of 91 patients that had experienced at least one episode of active CMV infection during follow-up. Both graft loss and patient death caused by transplant arteriopathy were found to be more common in CMV-positive patients; furthermore, the degree of coronary stenosis, as judged by angiography or at autopsy, was higher in the grafts of CMV-positive patients. It seemed like an open and shut case at the time. . . or was it? Ever since CMV was labeled as a usual suspect for transplant arteriopathy, much effort has gone towards identifying the “murder weapon,” that is, the cellular and molecular basis of this clinical association (4). This quest has been fruitful, showing that CMV can infect native vascular cells (endothelial and smooth muscle) as well as host-derived components of neointimal lesions (leukocytes), and that it can scramble major histocompatibility complex (MHC), adhesion molecule, cytokine, chemokine, and growth factor pathways in its bid to evade the immune system. However, its status as a nanoscale hell raiser only shows that CMV has the potential to accelerate vascular obliteration; this does not constitute irrefutable evidence that it actually does, nor does it reveal any clues as to exactly how it might. These unresolved issues assume particular significance in light of recent failed attempts to localize the virus in the vasculature of cardiac allografts, even in recipients that had experienced posttransplant active infection (5,6). In forensic terms, the current status of our knowledge on the putative link between CMV and transplant arteriopathy can be summarized as follows: one dead body, several potential smoking guns, and a suspect that cannot be conclusively placed at the scene of the crime. Nevertheless, clinical diligence demands that CMV be treated as guilty until proven innocent. In this issue of Transplantation, Potena and colleagues revisit the CMV enigma, focusing on a little-studied aspect of the current controversy. It has been known for some time that the vascular wall is capable of spontaneously expanding to offset lumen loss, for example, because of neointimal hyperplasia. Indeed, we now know that this normal compensatory mechanism operates in transplanted hearts during the early stages of coronary arteriopathy; progressively, however, this mechanism fails, and pronounced vasoconstriction sets in, exacerbating lumen loss (7–10). The significant association between active CMV infection and impaired coronary remodeling shown in the present study highlights a previously unrecognized functional consequence of viral activity. In essence, the findings reported here by Potena et al. suggest that CMV infection exacerbates transplant arteriopathy both by promoting neointimal hyperplasia and by impairing compensatory vasodilatation in response to the ensuing increase in vascular resistance. Although the former finding is akin to our current understanding of the deleterious molecular events triggered by CMV, the latter finding calls for some fresh thinking. The late vasoconstriction compounding transplant arteriopathy is thought to develop because of endothelial dysfunction, a poorly understood state characterized by reduced bioavailability of nitric oxide (NO) and increased activity of vasopressor molecules, such as endothelin (ET)-1. Importantly, inhibition of ET-1 synthesis was recently shown to attenuate transplant arteriopathy in rat cardiac allografts (11); thus, therapeutic means of correcting endothelial dysfunction will soon exist. The findings reported here implicate CMV in the pathogenesis of endothelial dysfunction and, if corroborated, may influence clinical practice. For the clinician and scientist alike, however, the daunting question remains: does CMV infection constitute a special risk factor for transplant arteriopathy, one that needs to be monitored and managed aggressively? In view of the apparent paucity of CMV in vascular lesions, it has been proposed that systemic, rather than local, effects of infection might compromise vascular function. Interestingly, the presence of other viruses, particularly adenovirus, has also been linked to arteriopathy in pediatric cardiac graft recipients (12), whereas bacterial lipopolysaccharide (LPS) has been shown to accelerate this process in animal models (13,14). The take-home message from these studies is that potentially any infection is bad news for the graft vasculature. Could it be the peculiar features of CMV infection, high incidence and persistence, that have drawn research attention, resulting in the bad name that comes with bad press? Although clinical surveillance of this virus is, at present, clearly warranted, it may well be that a future commentary on the subject will bear the title: “CMV Gets a Break.”