Circulating GDF15 attenuates hemodynamic reactivity to acute mental stress in individuals with metabolic syndrome: The SABPA Study

Background: Metabolic disorders have been linked to altered autonomic and hemodynamic reactivity to acute mental stress, contributing to elevated cardiovascular disease risk. Circulating GDF15 is a stress-sensitive metabolic cytokine and marker of energetic strain which is believed to communicate metabolic stress to the central nervous system via signaling in the area postrema and nucleus tractus solitarius of the brainstem. Given the notion that elevated basal metabolic strain reduces the spare energetic capacity to induce a physiological stress response, we hypothesized that higher GDF15 would be associated with attenuated hemodynamic reactivity (Δ systolic and diastolic blood pressure ΔSBP% and ΔDBP%, respectively, heart rate (ΔHR%), Δ cardiac output ΔCO%, Δ total peripheral resistance ΔTPR%, and Δ Windkessel compliance % ΔCwk%) to acute mental stress in individuals with versus without Metabolic Syndrome (MetS vs non-MetS). Methods: We recruited participants with MetS (n=198; age 46±9 y) and non-MetS (n=195; 43±10 y) who completed the Stroop Color-Word test following an overnight fast. Hemodynamic responses were assessed using beat-to-beat blood pressure with Modelflow (Finapres Medical Systems), and GDF15 (Olink, CVDIII panel) was measured in plasma from baseline blood draws. Regression models (adjusted for age, sex, ethnicity, alcohol use, smoking and physical activity) were used to assess the interactive effect of baseline GDF15 and MetS status (i.e., GDF15 x MetS) on the percent change (Δ%) in hemodynamic responses induced by the Stroop Color-Word test in MetS versus non-MetS. Results: Across the whole sample, GDF15 was associated with an increased ΔSBP% (β = 0.55, R2 = 0.71; p< 0.001), ΔDBP% (β = 0.51, R2 = 0.33; p< 0.001), ΔCO% (β = 0.88, R2 = 0.21, p=0.003), and ΔTPR% (β = 0.42, R2 = 0.72, p< 0.001) and a lower ΔHR% (β = -0.45, R2 = 0.35, p=0.004) response, as well as greater stress-induced reductions in ΔCwk% (β = -0.47, R2 = 0.16, p=0.042). In support of our hypothesis, the adjusted regression models indicated that these relations were attenuated in individuals with MetS status for ΔSBP% (interaction term: β = -0.65, R2 = 0.55; p< 0.001), ΔDBP% (β = -0.31, R2 = 0.26; p< 0.001), ΔCO% (β = 0.95, R2 = 0.52, p=0.022), ΔTPR% (β = -0.59, R2 = 0.66, p< 0.001), and ΔCwk% (β = 0.18, R2 = 0.22, p=0.009). Conclusions: Basal circulating GDF15 was associated with greater hemodynamic reactivity to acute mental stress, but this GDF15-related augmentation of hemodynamic reactivity was blunted in individuals with MetS. Thus, these findings support the premise that elevated circulating levels of the centrally-acting metabokine GDF-15 may reflect a reduced capacity to mount a physiological stress response in the context of metabolic dysfunction, thereby linking chronic metabolic stress to increased cardiovascular vulnerability. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.