Cytomegalovirus Infection in Heart Transplant Recipients Is Associated With Impaired Endothelial Function

Abstract

Background-Cardiac allograft vasculopathy (CAV) is initiated by allograft endothelial injury. We hypothesized that a major mechanism by which cytomegalovirus (CMV) could contribute to CAV is by dysregulation of the endothelial vasomotor response. Methods-Coronary endothelial vasomotor function was determined in 183 consecutive patients (24Ϯ33 months after transplantation), and was correlated with recipient and donor CMV serological status before transplantation and with documented CMV infection episodes (CMVpp65Agϩ). Serial endothelial function measurements were performed in a subgroup of 53 transplant recipients (1 month and 12 months after transplantation). The composite endpoint of cardiovascular related events and death during a follow-up of 66Ϯ41 months was analyzed based on the CMV serological status before transplantation. Results-The medium event-free time for CMV-negative recipients of CMV-positive hearts was 8.1 years compared with 13.3 years for the other groups (PϽ0.05). Distal epicardial but not microvascular endothelial function was significantly impaired in CMV seronegative recipients of seropositive donor hearts (nϭ48) compared with all other groups (PϽ0.01 versus seronegative recipient/seronegative donor; PϽ0.05 versus seropositive recipient/seronegative donor; PϽ0.05 versus seropositive recipient/seropositive donor). Distal epicardial endothelial dysfunction was more pronounced in heart transplant recipients with a history of documented CMV infection compared with patients without any documented CMV infection (PϽ0.01). In a longitudinal subgroup analysis, distal epicardial and microcirculatory endothelial vasomotor response deteriorated significantly in recipients with documented CMV infection (PϽ0.05 versus baseline) but not in patients without previous CMV infection. Conclusion-Documented CMV infection episodes in heart transplant recipients are associated with impaired coronary endothelial function. CMV-negative recipients of CMV-positive donor hearts have an impaired distal epicardial endothelial function and an increased incidence of cardiovascular-related events and death during follow-up. CMV infection may contribute to allograft failure by accelerating coronary endothelial dysfunction.

Signature microRNA Expression Profile of Essential Hypertension and Its Novel Link to Human Cytomegalovirus Infection

“…Human cytomegalovirus infection exerts an inhibitory effect on endothelial nitric oxide synthase activation, thereby reducing nitric oxide production, activating the stress-response signal P38-MAPK pathway, and upregulating phosphatase and tensin homolog, 21,22 leading to endothelial dysfunction. 23,24 Human cytomegalovirus infection stimulates renin and angiotensin II expression in human vascular endothelial cells, 39 enhancing NAD(P)H oxidase activity, and elicits the production of reactive oxygen species. Reactive oxygen species directly cause vasoconstriction through modulation of calcium levels and/or arachidonic acid metabolism.…”

“…17 It has been implicated in several cardiovascular disorders, including atherosclerosis, coronary heart disease, and cardiac transplant arteriopathy. 18 -20 Some studies suggest an association between HCMV and cardiovascular disorders through impaired endothelial nitric oxide synthase function 21,22 and subsequent endothelial dysfunction, 23,24 resulting in reduced vascular dilation in vivo. However, direct links between HCMV infection, endothelial dysfunction, and essential hypertension remain undefined.…”

Significant Increase in 1-Year Posttransplant Renal Arterial Index Predicts Graft Loss

“…CMV is implicated in vascular complications through endothelial dysfunction. In heart transplant patients, CMV infection episodes are associated with impaired coronary endothelial function (13). Moreover, Fearon et al (14) reported that CMV seropositivity and the lack of prophylaxis against CMV correlate with negative remodeling of coronary arteries.…”

Cardiac Allograft Vasculopathy

“…43 Epicardial and microvascular endothelium-dependent and -independent vasomotor dysfunction are frequently observed after HTx. 44 Coronary allograft endothelial dysfunction is associated with circulating endothelin levels, 45 enhanced graft cytokine activation, 46 and CMV infection, 47 whereas statin treatment reduces the progression of epicardial and microvascular dysfunction. 48 Coronary endothelial dysfunction predicts the development of intimal thickening 49 and predicts cardiovascular end points after HTx.…”