Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States

Abstract

Background: Studies 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 findings: Data come from subjects ≥ 25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31(st), 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/significance: CMV 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.

Figure 1. Kaplan-Meier survival curve for all-cause mortality by cytomegalovirus serostatus.

Unadjusted Kaplan-Meier survival curves for all-cause mortality by cytomegalovirus (CMV) serostatus for 14153 subjects, ≥25 years of age, in the National Health and Nutrition Examination Survey (NHANES) III from 1988–2006. After adjusting for age, gender, race/ethnicity, country of origin, education level, BMI (kg/m²), smoking status and diabetes status, 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). CMV = cytomegalovirus and MEC = mobile examination center.

Figure 2. Kaplan Meier survival curve for cardiovascular disease-related mortality by cytomegalovirus serostatus.

Unadjusted Kaplan-Meier survival curves for cardiovascular disease (CVD)-related mortality by cytomegalovirus (CMV) serostatus for 14105 subjects, ≥25 years of age, in the National Health and Nutrition Examination Survey (NHANES) III from 1988–2006. After adjusting for age, gender, race/ethnicity, country of origin, education level, BMI (kg/m²), smoking status and diabetes status, follow-up time from exam to death from CVD was not significantly different between CMV seronegative and CMV seropositive subjects (Adjusted Wald F  = 2.66, p-value  = 0.1092. CMV = cytomegalovirus and MEC = mobile examination center.

Figure 3. Kaplan-Meier survival curve for all-cause mortality by combined cytomegalovirus serostatus and c-reactive protein level.

Unadjusted Kaplan-Meier survival curves for all-cause mortality by combined cytomegalovirus (CMV) serostatus and C-reactive Protein (CRP) level for 14011 subjects, ≥25 years of age, in the National Health and Nutrition Examination Survey (NHANES) III from 1988–2006. After adjusting for age, gender, race/ethnicity, country of origin, education level, BMI (kg/m²), smoking status, diabetes status and non-steroidal anti-inflammatory drug use, follow-up time from exam to death from all-causes for CMV seropositive individuals with high CRP level was significantly different from CMV seropositive individuals with low CRP level (Adjusted Wald F  = 36.19, p<0.0001). CMV = cytomegalovirus, CRP = C-reactive Protein and MEC = mobile examination center. High CRP level: ≥0.3 mg/dL.

Figure 4. Kaplan-Meier survival curve for cardiovascular disease-related mortality by combined cytomegalovirus serostatus and c-reactive protein level.

Unadjusted Kaplan-Meier survival curves for cardiovascular disease (CVD)-related mortality by combined cytomegalovirus (CMV) serostatus and C-reactive Protein (CRP) level for 13963 subjects, ≥25 years of age, in the National Health and Nutrition Examination Survey (NHANES) III from 1988–2006. After adjusting for age, gender, race/ethnicity, country of origin, education level, BMI (kg/m²), smoking status, diabetes status and non-steroidal anti-inflammatory drug use, follow-up time from exam to CVD-related death for CMV seropositive individuals with high CRP level was significantly different from CMV seropositive individuals with low CRP level (Adjusted Wald F  = 9.10, p = 0.0040). CMV = cytomegalovirus, CRP = C-reactive Protein and MEC = mobile examination center. High CRP level: ≥0.3 mg/dL.