The Role of Viruses in Cardiac Allograft Vasculopathy

Abstract

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.

Frequent Occult Infection with Cytomegalovirus in Cardiac Transplant Recipients despite Antiviral Prophylaxis

“…Complementary strategies that monitor for active viral replication above a threshold level and then employ preemptive antiviral therapy are also effective in reducing acute CMV disease (13). The long-term consequence of subclinical CMV infection in either setting has remained a concern (13) because of the association of this virus with allograft rejection and cardiac allograft vasculopathy (CAV; also known as transplant arteriopathy or transplant vascular disease) (14,17,22,23). Recent concern about CMV as well as other chronic virus infections has been focused on chronic or indirect viral damage to the graft, leading to acute rejection and CAV (17,23).…”

“…The long-term consequence of subclinical CMV infection in either setting has remained a concern (13) because of the association of this virus with allograft rejection and cardiac allograft vasculopathy (CAV; also known as transplant arteriopathy or transplant vascular disease) (14,17,22,23). Recent concern about CMV as well as other chronic virus infections has been focused on chronic or indirect viral damage to the graft, leading to acute rejection and CAV (17,23). Consistent with this, the frequency of CAV appeared to be greater in the pre-ganciclovir era, suggesting a benefit of antiviral prophylaxis in reducing the incidence of CAV (24).…”

“…Pathogenesis of chronic vascular disease generally assumes persistent viral infection within the transplanted organ that causes damage and promotes disease (8,23). Current prophylaxis regimens suppress acute disease and CMV replication levels, although subclinical infection has consistently been detected despite prophylaxis (4,7,11,16,17).…”

Untitled

“…19 It has been shown that CMV infection is an independent risk factor for CAV after transplant, likely due to alteration of endothelial nitric oxide synthase pathway. 20 The ISHLT guidelines recom mend a strict control of cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, smoking, and obesity), prophylaxis of CMV infection, and the use of statins for the prevention of CAV. 21 In our study, patients with CAV progression tended to have more CMV infections than patients without CAV progression, although there was no difference between the groups in terms of other atherosclerotic risk factors and the use of statins or immunosuppressive drugs.…”

Characteristics of Chronic Rejection in Heart Transplantation: Important Elements of Pathogenesis and Future Treatments

“…16,17 Cytomegalovirus is known to be associated with an increased incidence of CAV, which in turn is associated with enhancement of multiple genes associated with wound repair and angiogenesis. 18,19 Costimulatory Signals Costimulatory signals are important for stimulation of T cells and inflammatory cell recruitment into the allograft. 20 It has been reported that CAV correlates with expression of adhesion molecules, including intracellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1, and the E-and P-selectins.…”