CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

Abstract

SummaryAlthough 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.

Cytomegalovirus Infection and Relative Risk of Cardiovascular Disease (Ischemic Heart Disease, Stroke, and Cardiovascular Death): A Meta‐Analysis of Prospective Studies Up to 2016

“…Population characteristics are shown in Table . The studies were conducted in the United States, United Kingdom, Canada, Sweden, and Italy . Nine studies included men and women, and the other 1 study included only men …”

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

“…The association between CMV infection and atherosclerotic cardiovascular disease (CVD) is well-known from the literature (Blankenberg et al 2001;Gkrania-Klotsas et al 2012;Muhlestein et al 2000;Roberts et al 2010;Simanek et al 2009Simanek et al , 2011Spyridopoulos et al 2016). Since immunological processes are key features of atherosclerosis, it has been postulated that CMV infection increases cardiovascular mortality via immunological mechanisms.…”

Exploring the Relevance of Senotherapeutics for the Current SARS-CoV-2 Emergency and Similar Future Global Health Threats

“…This hypothesis was also confirmed by the observation that the replication of vesicular stomatitis virus is impaired both in primary and tumor senescent cells in comparison to non-senescent cells [54]. Many studies have described a higher prevalence or increased circulating viral load of some viruses, such as cytomegalovirus (CMV) [55] and Torquetenovirus (TTV) [56,57], with aging. The increased grade of inflammation associated with this phenomenon and the association with mortality of TTV and CMV in the elderly highlights the possible involvement of cellular senescence.…”