Association Between TTV Viremia, Chronic Inflammation, and Ischemic Heart Disease Risk: Insights From MARK-AGE and Report-Age Projects

Abstract

The implication of Torquetenovirus (TTV) in ischemic heart disease (IHD) has not been thoroughly explored. This study investigated the association between TTV viremia, pro-inflammatory cytokines, and IHD risk in an aging population. This cross-sectional study included 900 non-IHD subjects and 86 individuals with IHD (aged 55-75 years) selected from the MARK-AGE project. Results were verified in another independent Report-Age cohort, including 94 inpatients with chronic IHD and 111 inpatients with non-IHD (aged 65-96 years). Multivariable logistic regression in the MARK-AGE cohort revealed that male sex, TTV viremia ≥4log, Cu/Zn ratio, diabetes, hypertension, and smoking were significant IHD predictors. Notably, TTV viremia ≥4log independently increased the IHD risk (odds ratio [OR]: 2.51, 95% confidence interval [CI]: 1.42-4.43), confirmed in the Report-Age cohort (OR: 4.90, 95% CI: 2.32-10.39). In a RASIG subgroup, individuals with TTV viremia ≥4 log, both with and without IHD, exhibited increased plasma pro-inflammatory cytokine levels (IFN-γ, IL-1β, IL-6, IL-10, IL-12p70, TNF-α) compared to those with TTV viremia <4 log. No significant difference in cytokine production was observed between IHD patients and non-IHD with TTV viremia ≥4 log. A positive correlation between TTV viremia and DNA methylation estimator of leukocyte telomere length was observed in Report-Age patients. Additionally, IHD Report-Age patients with TTV viremia ≥4 log displayed higher NLR and SIRI index than those with TTV viremia <4 log. In conclusion, a high TTV viremia is associated with an elevated IHD risk in the older population, potentially arising from an augmented pro-inflammatory response and immunosenescence.

Keywords: Aging; Inflammation; Ischemic heart disease; Torquetenovirus.

Figure 1.

Plasma cytokine concentrations in ischemic heart disease (IHD) patients and non-ischemic heart disease (NIHD) subjects according to TTV viremia in the MARK-AGE study. IFN-γ, IL-1β, IL-6, IL-10, IL-12p70, and TNF-α increased in IHD patients and NIHD with TTV viremia ≥4 log compared to those with TTV viremia <4 log. IHD with TTV viremia ≥4 log exhibited heightened cytokine production compared to NIHD with TTV viremia <4 log, but this effect was not observed in comparison to NIHD with TTV viremia >4 log. ANCOVA analysis correcting for age, sex and country. HC = healthy controls; TTV = Torquetenovirus. *p < .05. **p < .01.

Figure 2.

NLR and SIRI index in the Report-Age and MARK-AGE cohorts according to TTV viremia and correlation between DNAm-LTL, age and TTV DNA loads in Report-Age participants. IHD Report-Age patients with TTV viremia ≥4 log showed significantly higher NLR and SIRI index compared to those with TTV viremia <4 log in (A, B). No significant differences were found in the NLR and SIRI index among subjects from the MARK-AGE non-ischemic heart disease (NIHD) group or those with ischemic heart disease (IHD), based on TTV viremia (C, D). ANCOVA analysis correcting for age and sex (A, B) or age, sex and countries (C, D) was applied; data are reported mean ± Standard Error of the Mean (SEM) *p < .05 compared to IHD patients with TTV viremia ≥4 log. (E, F) Scatter plots and Sperman correlation between DNAm-LTL, age and TTV DNA loads in Report-Age cohort. A negative correlation between DNAm-LTL and age was observed (r = −0.366, p < .001) in Report-Age cohort (E). TTV DNA loads (log-transformed data) were negatively correlated with DNAm-LTL in both NIHD (r = −0.172, p < .05) and IHD subjects (r = −0.228, p < .05) (F). DNAmTL values were expressed in kilobases (Kb) and viral loads were reported as number of viral genomic copies per mL of whole blood. NLR = neutrophil-to-lymphocyte ratio; SIRI = standardized inflammatory response index; TTV = Torquetenovirus.