BACKGROUND: Cardiovascular responses to psychological stressors have been separately associated with preclinical atherosclerosis and hemodynamic brain activity patterns across different studies and cohorts
however, what has not been established is whether cardiovascular stress responses reliably link indicators of stressor-evoked brain activity and preclinical atherosclerosis that have been measured in the same individuals. Accordingly, the present study used cross-validation and predictive modeling to test for the first time whether stressor-evoked systolic blood pressure responses statistically mediated the association between concurrently measured brain activity and a vascular marker of preclinical atherosclerosis in the carotid arteries. METHODS AND RESULTS: Six hundred twenty-four midlife adults (aged 28-56 years, 54.97% women) from 2 different cohorts underwent 2 information-conflict functional magnetic resonance imaging tasks, with concurrent systolic blood pressure measures collected. Carotid artery intima-media thickness was measured by ultrasonography. A mediation framework that included harmonization, cross-validation, and penalized principal component regression was then used. Brain areas where functional magnetic resonance imaging activity exhibited reliable direct and indirect effects were identified through bootstrapping. Sensitivity analysis further tested the robustness of findings after accounting for prevailing levels of cardiovascular disease risk and brain imaging data quality. Task-averaged patterns of functional magnetic resonance imaging activity across distributed brain areas exhibited a generalizable association with carotid artery intima-media thickness, which was reliably mediated by an area under the curve measure of aggregate systolic blood pressure reactivity. Importantly, this effect held in sensitivity analyses. Implicated brain areas in this mediation included the ventromedial prefrontal cortex, anterior cingulate cortex, insula, and amygdala. CONCLUSIONS: These novel findings support a link between stressor-evoked brain activity and preclinical atherosclerosis, which is accounted for by individual differences in corresponding levels of stressor-evoked cardiovascular reactivity.