A high burden of cytomegalovirus marks poor vascular health in transplant recipients more clearly than in the general population

Lee, Silvia; Brook, Emily; Affandi, Jacquita S.; Howson, Prue; Tanudjaja, Selita Agnes; Dhaliwal, Satvinder S.; Irish, Ashley; Price, Patricia

doi:10.1002/cti2.1043

Cited by 16 publications

(17 citation statements)

References 31 publications

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“…HCMV has long been associated with cardiovascular complications (17). HCMVassociated cardiovascular dysfunction includes increased morbidity during atherosclerosis, myocarditis, and transplant vasculopathy (20,32,34,41). Myocarditis is defined as inflammation of the heart muscle caused by infiltrating immune cells, which results in dysfunction of the heart.…”

Section: Introductionmentioning

confidence: 99%

Heart Dysfunction Following Long-Term Murine Cytomegalovirus Infection: Fibrosis, Hypertrophy, and Tachycardia

et al. 2020

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Human cytomegalovirus (HCMV) is associated with increased risk of chronic diseases of the heart and vasculature, including myocarditis, atherosclerosis, and transplant vasculopathy. To investigate CMV infection of the heart, murine cytomegalovirus (MCMV) was used to evaluate both acute and latent infection and the subsequent phenotypic and functional consequences of infection. Female BALB/c mice were intraperitoneally (i.p.) inoculated with 1 • 10 6 pfu of MCMV and evaluated at 14 and 50 days postinfection (dpi). At each time point, echocardiography was used to evaluate cardiac function and histology was conducted for phenotypic evaluation. MCMV replication in the heart was detected as early as 3 dpi and was no longer detectable at 14 dpi. Infected animals had significant cardiac pathology at 14 and 50 dpi when compared to uninfected controls. Histology revealed fibrosis of the heart as early as 14 dpi and the presence of white fibrous deposits on the surface of the heart. Functional evaluation showed significantly increased heart rate and muscle thickening in the latently infected animals when compared to the control animals. At 50 dpi, latent virus was measured by explant reactivation assay, demonstrating that MCMV establishes latency and is capable of reactivation from the heart, similar to other tissues such as spleen and salivary glands. Collectively, these studies illustrate that MCMV infection results in phenotypic alterations within the heart as early as 14 dpi, which progress to functional abnormalities during latency. These findings are similar to sinus tachycardia and hypertrophy of the heart muscle observed in cases of HCMV-induced acute myocarditis.

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Section: Introductionmentioning

confidence: 99%

Heart Dysfunction Following Long-Term Murine Cytomegalovirus Infection: Fibrosis, Hypertrophy, and Tachycardia

et al. 2020

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“…In this cohort, levels of CMV antibody were an independent marker of reduced FMD [27] and CMV DNA in both saliva and plasma aligned weakly with impaired FMD. FMD is an assessment of endothelial function based on the ability of the artery to respond to shear stress [28].…”

Section: Discussionmentioning

confidence: 99%

The Detection of CMV in Saliva Can Mark a Systemic Infection with CMV in Renal Transplant Recipients

Waters

Lee

Lloyd

et al. 2019

IJMS

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Human cytomegalovirus (CMV) is often transmitted through saliva. The salivary gland is a site of CMV replication and saliva can be used to diagnose congenital CMV infections. CMV replication is monitored in whole blood or plasma in renal transplant recipients (RTR) and associates with clinical disease. However, these assays may not detect replication in the salivary gland and there is little data linking detection in saliva with systemic infection and clinical sequelae. RTR (n = 82) were recruited > 2 years after transplantation. An in-house quantitative PCR assay was used to detect CMV UL54 in saliva samples. CMV DNA was sought in plasma using a commercial assay. Vascular health was predicted using flow mediated dilatation (FMD) and plasma biomarkers. CMV-reactive antibodies were quantified by ELISA and circulating CMV-specific T-cells by an interferon-γ ELISpot assay. Vδ2− γδ T-cells were detected using multicolor flow cytometry reflecting population expansion after CMV infection. The presence of CMV DNA in saliva and plasma associated with plasma levels of antibodies reactive with CMV gB and with populations of circulating Vδ2− γδ T -cells (p < 0.01). T-cells reactive to CMV immediate early (IE)-1 protein were generally lower in patients with CMV DNA in saliva or plasma, but the level of significance varied (p = 0.02–0.16). Additionally, CMV DNA in saliva or plasma associated weakly with impaired FMD (p = 0.06–0.09). The data suggest that CMV detected in saliva reflects systemic infections in adult RTR.

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“…As described previously, 14 RTR ( n = 81) were recruited from the renal clinics at Royal Perth Hospital, Western Australia in 2014. This is defined as the baseline.…”

Section: Methodsmentioning

confidence: 99%

“…Coefficients of variance were 6.1% (CMV lysate), 2.9% (gB), and 4.8% (IE‐1). Results are presented as arbitrary units (AU)/mL based on a standard plasma pool 14 . This strategy permits comparisons between volunteers but not between antigens.…”

Section: Methodsmentioning

confidence: 99%

Cytomegalovirus burden improves a predictive model identifying measures of vascular risk in renal transplant recipients and healthy adults

Affandi

Lee

Chih

et al. 2020

Journal of Medical Virology

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Cytomegalovirus (CMV) has been implicated in vascular pathologies and may warrant inclusion in cardiovascular predictive algorithms. We addressed this in healthy older adults and renal transplant recipients (RTR) as they retain a high burden of CMV. RTR (n = 45) stable more than 2 years after transplantation and 58 age‐matched healthy adults were assessed. Plasma inflammatory biomarkers (soluble isoform of the interferon‐β receptor [sIFNAR2], soluble tumour necrosis factorreceptor‐1 [sTNFR1], soluble cluster of differentiation 14 [sCD14], C reactive protein, P‐selectin, intracellular cell adhesion molecule‐1, vascular cell adhesion molecule‐1), and measures of CMV burden (antibodies, saliva CMV DNA, and interferon γ responses to CMV) were assessed in 2014 and evaluated in 2017 as predictors of vascular health—defined using flow‐mediated dilatation (FMD), pulse wave velocity (PWV), and augmentation indices (Aix@ 75). Linear regression models adjusted for age, sex, and body mass index (BMI) were optimized to identify risk factors. In 2017, RTR had inferior vascular health marked by impaired FMD and PWV. Detectable CMV DNA (P = .02) was associated with impaired FMD, whilst CMV glycoprotein B (gB) antibody attenuated this effect (P = .03) (adjusted R2 = .42). In healthy adults, the optimal model for predicting FMD (R2 =.22) incorporated high P‐selectin (P = .03) and low ICAM‐1 (P = .03) levels with no significant impact of CMV. Elevated sIFNAR2 (P = .04) and gB antibody (P = .06) levels predicted increasing Aix@ 75 (poor vascular health) in healthy adults (R2 = .4), whilst optimal models for RTR (R2 = .37) linked low sIFNAR2 and CMV IE‐1 antibody levels with lower Aix@ 75 (better vascular health). CMV IE‐1 antibody was also protective in relation to PWV in healthy adults (R2 = .55). Overall, measures of active CMV replication were more predictive of impaired FMD in RTR than standard biomarkers, but increased CMV gB antibodies may be protective.

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A high burden of cytomegalovirus marks poor vascular health in transplant recipients more clearly than in the general population

Cited by 16 publications

References 31 publications

Heart Dysfunction Following Long-Term Murine Cytomegalovirus Infection: Fibrosis, Hypertrophy, and Tachycardia

Heart Dysfunction Following Long-Term Murine Cytomegalovirus Infection: Fibrosis, Hypertrophy, and Tachycardia

The Detection of CMV in Saliva Can Mark a Systemic Infection with CMV in Renal Transplant Recipients

Cytomegalovirus burden improves a predictive model identifying measures of vascular risk in renal transplant recipients and healthy adults

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