The contribution of cytomegalovirus to atherosclerotic events after kidney transplantation.

With improvements in management of acute rejection and allograft function over the past decades, short-term survival after solid-organ transplantation is excellent, and death with a functioning graft has become the outcome for the majority of solid-organ transplant recipients. Thus, there is a necessity to focus not only on interventions to maintain graft function, but also to address other posttransplantation complications contributing to death among transplant recipients. Chief among these concerns is posttransplantation atherosclerosis. Atherosclerosis resulting in cardiovascular events is now the major cause of death in long-term survivors of renal, cardiac, and hematopoietic stem cell transplantations [1–3]. In a cohort of 2202 adult kidney transplant recipients with >10year graft survival, cardiovascular disease (CVD) was the major cause of mortality, followed by malignancy and infection [4]. The cause of posttransplantation atherosclerosis is multifactorial. Risk factors resembling those for atherosclerosis in the general population include pretransplantation CVD, diabetes, hypertension, hyperlipidemia, tobacco use, obesity, and renal disease [1]. For transplant recipients, additional contributors include transplant-related medications such as steroids, transplant nephropathy, posttransplantation diabetes, and posttransplantation dyslipidemia. Thus, identifying comorbidities that influence the progression of CVD in transplant recipients might provide interventions to prolong survival and quality of life. Cytomegalovirus (CMV) has been associated with atherosclerosis in large seroepidemiologic studies of nontransplant recipients [5–7]. In one longitudinal prospective study (the Atherosclerosis Risk in Communities [ARIC] study), patients who developed elevated carotid intimalmedial thickening had higher CMV antibody titers measured 13–18 years prior to onset of the carotid lesions, compared with matched control patients who did not develop carotid intimal-medial thickening [5]. In the ARIC study, high CMV antibody titers also correlated to later onset of coronary heart disease [6]. In the Heart Outcomes Prevention Evaluation study, CMV-positive serostatus was associated with increased risk of myocardial infarction, stroke, or cardiovascular death [7]. In an elderly Latino population (the Sacramento Area Latino Study on Aging), high CMV antibody titers were related to increased risk for both all-cause mortality and mortality from CVD [8]. Among these patients, serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) quantities were covariates with CMV titers, suggesting a relationship between ongoing inflammation, high CMV titers, and observed mortality. These studies suggest that the magnitude of the antibody response, and not CMV seropositivity itself, is associated with the observed risk. However, as for all seroepidemiologic studies, a mechanistic etiology cannot be assigned directly to CMV. To address pathogenesis, animal models have been developed to analyze the contribution of CMV to cardiovascular events. In murine models, murine CMV infection exacerbates atherogenesis in apoE-knockout mice [9, 10] and increases arterial blood pressure in mice fed a high-fat diet [11]. In the latter study, murine CMV–infected mice also had elevated serum levels of the proinflammatory cytokines TNF-α, IL-6, and monocyte chemoattractant protein 1 (MCP-1). In vitro human CMV–infected endothelial cells can secrete a number of proinflammatory cytokines and chemokines, including IL-6, interleukin 8, TNF-α, regulated and normal T-cell expressed and secreted chemokine, MCP-2, CXC ligand 6, and interferon γ–induced protein 10, among others [12]. These studies provide potential mechanistic pathways by which CMV might contribute to atherogenesis in human populations. Received 15 January 2013; accepted 16 January 2013; electronically published 14 February 2013. Correspondence: Masako Shimamura, MD, Division of Pediatric Infectious Diseases, University of Alabama at Birmingham, 1600-6th Avenue South, CHB 114, Birmingham, AL 35233 ([email protected]). The Journal of Infectious Diseases 2013;207:1487–90 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit065