Systemic Oxidative Stress, Aging and the Risk of Cardiovascular Events in the General Female Population

Abstract

Introduction: Menopause is associated with increased cardiovascular risk, in which oxidative stress plays a pivotal role. Systemic oxidative stress is reflected by decreased levels of free thiols (R-SH, sulfhydryl groups), which are key components of the extracellular antioxidant machinery. In this study, we investigated the relation between serum free thiols as marker of oxidative stress and the female cardiovascular phenotype, as well as potential associations with the risk of cardiovascular (CV) events in pre- and postmenopausal women from the general population. Methods: Female participants (n = 2,980) of the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort study were included. Serum free thiol concentrations were analyzed for associations with demographic, clinical, biochemical, and gynecological parameters, as well as with menopausal status and, prospectively, with the risk of CV events. Results: Postmenopausal women had significantly reduced levels of serum free thiols (4.8 ± 1.0 vs. 5.2 ± 1.0 μmol/g, P < 0.001) compared to reproductive women. In multivariable analyses, serum free thiols were significantly associated with menopausal status (OR 0.70 [0.49-0.98], P = 0.039), even when adjusted for potential confounding factors, except for age (P = 0.550). Prospectively, serum free thiols were significantly associated with the risk of CV events (HR 0.52 [0.27-0.97], P = 0.040), even with covariate adjustment, although this disappeared when correcting for age. Conclusion: In this study, we revealed serum free thiols to be strongly associated with the female cardiovascular phenotype as well as with female risk of CV events, where the influence of age itself seemed to outweigh that of female menopause. Future studies are warranted to further unravel the clinical utility of serum free thiol levels in the context of female cardiovascular risk management.

Keywords: cardiovascular events; free thiols; menopause; oxidative stress; population study.

Figure 1

Directed Acyclic Graph (DAG) demonstrating the causal paths hypothesized to be underlying the relationship between serum free thiols, representing systemic oxidative stress, and the risk of cardiovascular (CV) events. Following from this graph, several confounders were accounted for in the Cox proportional hazards regression analysis.

Figure 2

(A–C) Tertile distributions of serum free thiols stratified according to the occurrence of CV events (CV-e) during study follow-up among (A) the total cohort, (B) premenopausal women, and (C) postmenopausal women.

Figure 3

Kaplan-Meier survival distributions demonstrating CV-disease free survival among tertiles of serum free thiols. Highest rate of CV-events occurred in the lowest tertile of serum free thiols (log-rank test, P = 0.002).

Figure 4

Restricted cubic splines (RCS) showing no deviance from linear associations of serum free thiols with the risk of CV events in females from the general population. (A) Cox proportional hazards regression analysis of serum free thiols with estimated associations with the risk of cardiovascular events based on restricted cubic splines with three knots (Model 1). (B) Cox proportional hazards regression analysis of serum free thiols with estimated associations derived from the fully adjusted model (Model 4). Median of serum free thiols was taken as reference standard (5.02 μmol/g). Likelihood ratio test for non-linearity was not statistically significant (χ² = 0.14; P = 0.708). Light-blue shaded areas represent 95% confidence intervals.