<h2>Summary</h2><h3>Background</h3> Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events. <h3>Methods</h3> Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent <sup>18</sup>F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses. <h3>Findings</h3> 293 patients (median age 55 years [IQR 45·0–65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7–4·8). Amygdalar activity was associated with increased bone-marrow activity (<i>r</i>=0·47; p<0·0001), arterial inflammation (<i>r</i>=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27–1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (<i>r</i>=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (<i>r</i>=0·56; p=0·0485), arterial inflammation (<i>r</i>=0·59; p=0·0345), and C-reactive protein (<i>r</i>=0·83; p=0·0210). <h3>Interpretation</h3> In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings. <h3>Funding</h3> None.

Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study