Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis

Valantine, Hannah A.; Gao, Shao-Zhou; Menon, Santosh; Renlund, Dale G.; Hunt, Sharon A.; Oyer, Philip E.; Stinson, Edward B.; Brown, Byron W.; Merigan, Thomas C.; Schroeder, John S.

doi:10.1161/01.cir.100.1.61

Cited by 274 publications

(142 citation statements)

References 15 publications

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“…For example, Lemstrom et al demonstrated that prophylactic administration of ganciclovir, a drug that inhibits viral replication, entirely abolishes the accelerating effect of rat CMV infection on CAV in immunosuppressed and nonimmunosuppressed rat recipients (49). We have reported similar findings in heart transplant recipients, showing patients who received prophylactic treatment with ganciclovir during the initial 28 days after transplantation, had a significantly lower prevalence rate of CAV diagnosed by coronary angiography, compared with placebo (50). It should be emphasized that this cohort of patients received antilymphocyte antibody therapy as part of their routine immunosuppressive regimen early after transplant, a practice that has been shown to increase the rate of CMV activation and disease.…”

Section: Evidence From Therapeutic Trialssupporting

confidence: 67%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

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Section: Evidence From Therapeutic Trialssupporting

confidence: 67%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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“…In recipients of heart transplants, treatment with ganciclovir, a potent inhibitor of viral replication and CMV disease, delayed the time to allograft rejection (Merigan et al 1992). A subsequent post-hoc analysis of these data confirmed that prophylactic ganciclovir treatment delayed graft rejection compared to controls (Valantine et al 1999). Moreover, the early control of sub-clinical HCMV replication after cardiac transplantation by T-cell immunity reduces allograft TVS and CR (Tu et al 2006).…”

mentioning

confidence: 80%

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

Streblow

Dumortier

Moses

et al. 2008

Current Topics in Microbiology and Immunology

108

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Human cytomegalovirus (HCMV) is associated with the acceleration of a number of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune-mediated injury followed by inflammation and subsequent smooth muscle cell (SMC) migration from the vessel media to the intima and proliferation that culminates in vessel narrowing. A number of epidemiological and animal studies have demonstrated that CMV significantly accelerates TVS and chronic rejection (CR) in solid organ allografts. In addition, treatment of human recipients and animals alike with the antiviral drug ganciclovir results in prolonged survival of the allograft indicating that CMV replication is a requirement for acceleration of disease. However, although virus persists in the allograft throughout the course of disease, the number of directly infected cells does not account for the global effects that the virus has on the acceleration of TVS and CR. Recent investigations of up-and down-regulated cellular genes in infected allografts in comparison to native heart has demonstrated that Rat-CMV (RCMV) up-regulates genes involved in wound healing (WH) and angiogenesis (AG). Consistent with this result, we have found that supernatants from HCMV infected cells (HCMV secretome) induce WH and AG using in vitro models. Taken together these findings suggest that one mechanism for HCMV acceleration of TVS is mediated through induction of secreted cytokines and growth factors from virus-infected cells that promote WH and AG in the allograft, resulting in the acceleration of TVS. We review here the ability of CMV infection to alter the local environment by producing cellular factors that act in a paracrine fashion to enhance WH and AG processes associated with the development of vascular disease, which accelerates chronic allograft rejection.

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“…In contrast, another study failed to obtain a difference between renal transplant recipients with and without diabetes in terms of graft loss [19]. It could be likely, that either a follow-up period of 10 years is too short or our immunosuppressive protocol per se delays to a certain extent the development of atherosclerosis in coronary arteries [15,20,21,22].…”

Section: Discussionmentioning

confidence: 98%

The impact of diabetes mellitus at the time of heart transplantation on long-term survival

Czerny

Şahin

Fasching³

et al. 2002

Diabetologia

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Aims/hypothesis. To analyse the impact of diabetes mellitus (DM) at the time of heart transplantation on long-term survival and incidence of transplant coronary artery disease (TxCAD). Methods. We analysed 773 consecutive adult heart transplant recipients who underwent primary heart transplantation from May 1986 until December 2000. The cohort consisted of 140 patients with diabetes mellitus (with DM, men 82%) and 633 patients without (wo DM, men 84%) diabetes mellitus at the time of transplantation. The patients were documented as to survival and incidence of TxCAD. Results. Patients with diabetes mellitus were older compared to those without diabetes mellitus (with DM 54.9±6.8a vs wo DM 49.7±10.8a; p=0.0001), they had a higher incidence of ischaemic cardiomyopathy prior to transplantation (with DM 52% vs wo DM 30%; p=0.0001), but reduced long-term survival (10 year survival: with DM 40% vs wo DM 58%; logrank=0.025). Surprisingly, the incidence of transplant coronary artery disease (TxCAD) was comparable at 10 years (with DM 28% vs wo DM 22%; logrank=0.625). In multivariate Cox proportional hazard analysis, diabetes mellitus present at the time of heart transplantation (HR 1.594; 95%CI 1.009-2.518; p=0.045), but not age (HR 0.990; 95%CI 0.965-1.014; p=0.404) was an independent predictor affecting long-term survival. Conclusion/interpretation. The presence of diabetes mellitus at the time of heart transplantation adversely affects long-term patient survival, but does not predict the occurrence of transplant coronary artery disease. The definite mechanisms of adverse survival primarily seem to relate to generally impaired global organ function. Despite a less favourable long-term outcome, our data still justify heart transplantation in end-stage heart failure patients with diabetes mellitus.

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Impact of Prophylactic Immediate Posttransplant Ganciclovir on Development of Transplant Atherosclerosis

Abstract: TxCAD incidence appears to be lower in patients treated with ganciclovir who are not treated with calcium blockers. Given the limitations imposed by post hoc analysis, a randomized clinical trial is required to address this issue.

Cited by 274 publications

References 15 publications

The Role of Viruses in Cardiac Allograft Vasculopathy

The Role of Viruses in Cardiac Allograft Vasculopathy

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

The impact of diabetes mellitus at the time of heart transplantation on long-term survival

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