IL-6 Response to Psychosocial Stress Predicts 12-month Changes in Cardiometabolic Biomarkers in Perimenopausal Women

Abstract

Objective: Cardiometabolic diseases are the number one cause of mortality, accounting for over one third of all deaths in the United States. Cardiometabolic risk further increases with psychosocial stress exposure and during menopausal transition in women. Because disease risk and stress burden are associated with aberrant immune signaling, we hypothesized that responses of interleukin-6 (IL-6) to psychosocial stress may predict longitudinal cardiometabolic outcomes in perimenopausal women.

Methods: We conducted post hoc analyses in 151 perimenopausal or early postmenopausal women participants in a previously completed study. At study onset, participants underwent the Trier Social Stress Test (TSST), and plasma IL-6 was measured repeatedly before and during the 1 hour post-TSST. Subsequently, participants were randomly assigned to either hormonal treatment (HT) or placebo and followed for 12 months to determine longitudinal changes in cardiometabolic biomarkers.

Results: Greater IL-6 reactivity to stress, measured with baseline-adjusted area under the curve, predicted 12-month decrease in flow-mediated dilatation of the brachial artery (P = 0.0005), a measure of endothelial-dependent vascular function, but not in endothelial-independent function measured with nitroglycerin-mediated dilatation (P = 0.17). Greater baseline IL-6 levels predicted 12-month increase in insulin resistance based on the homeostatic model assessment of insulin resistance score (P = 0.0045) and in the number of criteria met for metabolic syndrome (P = 0.0008). These predictions were not moderated by HT.

Conclusions: Greater baseline IL-6 levels as well as its reactivity to stress may predict worsening in distinct cardiometabolic biomarkers as women transition to menopause. Interleukin-6 reactivity predicts decline in endothelial-dependent vascular function, whereas baseline IL-6 presages accumulation of metabolic risk.

Trial registration: ClinicalTrials.gov NCT01308814.

Keywords: IL-6; cardiometabolic diseases; inflammation; menopause; psychosocial stress.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Scheme depicting the experimental design, timing of plasma collection at baseline rest (Sample1) and during the post-TSST period (Sample2–Sample6), and predictive IL-6 measures at study onset. As shown, AUC (highlighted in gray) represents the total surface area demarcated by integrated IL-6 levels measured at all timepoints, whereas AUCadj (highlighted in darker gray) represents the IL-6 reactivity after subtracting its baseline rest levels. Additional details are provided in the “Methods” section. Abbreviations: AUC, total area under the curve; AUCadj, baseline adjusted area under the curve; IL-6, interleukin-6; IV, intravenous; TSST, Trier Social Stress Test.

Figure 2.

Interleukin-6 levels in response to acute psychosocial stress predict 12-month changes in cardiometabolic biomarkers. A: Greater IL-6 AUCadj predicts worsening of FMD, a measure of endothelial-dependent vascular function. B: Greater IL-6 total AUC predicts 12-month increase in insulin resistance (HOMA-IR). For both continuous cardiometabolic measures depicted, positive (higher) values indicate increases, whereas negative (lower) values indicate decreases over time. For further details see also the “Methods” section and Fig. 1. Abbreviations: AUC, total area under the curve; FMD, flow-mediated dilatation; HOMA-IR, homeostatic model assessment of insulin resistance; IL-6, interleukin-6.