Abstract
BackgroundStudies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships.Methodology/Principal FindingsData come from subjects ≥25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31st, 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988–1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels.Conclusions/SignificanceCMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality.
Highlights
Cytomegalovirus (CMV) is a highly transmissible and prevalent beta herpesvirus [1,2]
After adjusting for age, gender, race/ethnicity, country of origin, education level, body mass index (BMI), smoking status and diabetes status, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% confidence intervals (CI): 1.01, 1.41) and follow-up time from exam to death from all causes was significantly different between CMV seronegative and CMV seropositive subjects (Adjusted Wald F = 4.66, p-value = 0.0358) in model 2
The results of our study suggest that CMV seropositivity is independently associated with all-cause mortality, after controlling for age, gender, race/ethnicity, country of origin, education level, BMI, smoking status and diabetes status
Summary
Cytomegalovirus (CMV) is a highly transmissible and prevalent beta herpesvirus [1,2] This pathogen is never cleared from the body, persisting in a number of tissues via hypothesized mechanisms including chronic productive infection and/or latent infection with periodic subclinical reactivation [2,3]. Several mechanisms have been hypothesized to link CMV infection and CVD in both human and animal studies [15,16,17,18,19,20]. CMV antigen and DNA have been identified in atherosclerotic vessels of the human cardiovascular system [21,22,23] and murine models suggest an inflammatory link with CVD progression [19,20]. We assessed whether CRP level mediated or modified these relationships
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