title: CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study.
abstract: Although chronic infection with cytomegalovirus (CMV) is known to drive T lymphocytes toward a senescent phenotype, it remains controversial whether and how CMV can cause coronary heart disease (CHD). To explore whether CMV seropositivity or T-cell populations associated with immunosenescence were informative for adverse cardiovascular outcome in the very old, we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65-month follow-up (47.3% survival rate). CMV-seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%, P = 0.030) compared to CMV-seronegative participants together with lower CD4/CD8 ratio (1.7 vs. 4.1, P < 0.0001) and higher frequencies of senescence-like CD4 memory cells (41.1% vs. 4.5%, P < 0.001) and senescence-like CD8 memory cells (TEMRA, 28.1% vs. 6.7%, P < 0.001). CMV seropositivity was also associated with increased six-year cardiovascular mortality (HR 1.75 [1.09-2.82], P = 0.021) or death from myocardial infarction and stroke (HR 1.89 [107-3.36], P = 0.029). Gender-adjusted multivariate Cox regression analysis revealed that low percentages of senescence-like CD4 T cells (HR 0.48 [0.32-0.72], P < 0.001) and near-senescent (CD27 negative) CD8 T cells (HR 0.60 [0.41-0.88], P = 0.029) reduced the risk of cardiovascular death. For senescence-like CD4, but not near-senescent CD8 T cells, these associations remained robust after additional adjustment for CMV status, comorbidities, and inflammation markers. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T-cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Ioakim
authors.initials: I
authors.lastname: Spyridopoulos
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martin-Ruiz
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Catharien
authors.initials: C
authors.lastname: Hilkens
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute of Health and Society, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Mohammad E
authors.initials: ME
authors.lastname: Yadegarfar
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: John
authors.initials: J
authors.lastname: Isaacs
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute of Health and Society, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Carol
authors.initials: C
authors.lastname: Jagger
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Kirkwood
authors.affiliation: Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.|Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000097:blood / Q000276:immunology* / Q000382:microbiology / Q000401:mortality*; D002908:Chronic Disease / Q000401:mortality; D003586:Cytomegalovirus Infections / Q000097:blood / Q000276:immunology* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006113:United Kingdom / Q000453:epidemiology
keywords: CD4; CD8; T lymphocytes; aging; coronary heart disease; cytomegalovirus; immunosenescence; octogenarians; survival