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.
Highlights
Human cytomegalovirus (CMV) is a ubiquitous herpes virus and shares a high prevalence in developed countries (Crough & Khanna, 2009)
While the immune risk profile (IRP) was present in only 20% of the 85year-olds in the Swedish OCTO/NONA series, CMV seropositivity is present in approx. 80–90% of octogenarians (Olsson et al, 2000; Wikby et al, 2002; Nilsson et al, 2003)
Phenotypical changes in the immune system attributable to CMV are most visible in the T-cell compartment, coinciding with clonal expansion and preferential expansion of CD8+CD45RA+CD27À cytolytic T cells (Khan et al, 2002; Kuijpers et al, 2003)
Summary
Human cytomegalovirus (CMV) is a ubiquitous herpes virus and shares a high prevalence in developed countries (Crough & Khanna, 2009). Seropositivity for CMV is one of the parameters in the immune risk profile (IRP), associated with increased mortality in longitudinal studies in octo- and nonagenarians (Nilsson et al, 2003). CMV has been linked to an increased incidence of coronary heart disease (CHD) in a number of studies (Ridker et al, 1998; Muhlestein et al, 2000; Sorlie et al, 2000; Blankenberg et al, 2001; Simanek et al, 2009). We have shown previously that in CMV-seropositive patients with CHD, the degree of telomere erosion in CD8 cells correlates with deterioration of left ventricular function, linking immunosenescence and cardiovascular disease (Spyridopoulos et al, 2009; Hoffmann et al, 2015). The goal of our study was to evaluate whether in octogenarians CMV seropositivity and T-cell senescence are independent predictors of all-cause and especially cardiovascular and CHD-mediated mortality
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