A US cohort study suggested that physical activity (PA) appears to reduce cardiovascular disease (CVD) risk in part by acting through the brain’s stress-related activity. The study included a total of 50,359 adults (median age 60 years; 40.1% male). Stress-related neural activity was measured as the ratio of resting amygdalar-to-cortical activity (AmygAC) in a subset of participants. Greater PA was associated with both lower AmygAC (standardized β: −0.245; P = 0.016) and CVD events (HR: 0.802; P < 0.001) in multivariable models. AmygAC reductions partially mediated PA’s CVD benefit (OR: 0.96; P < 0.05). Moreover, PA’s benefit on incident CVD events was greater among those with (vs without) preexisting depression (HR: 0.860; vs HR: 0.929; P interaction = 0.011). Additionally, PA above guideline recommendations further reduced CVD events, but only among those with preexisting depression (P interaction = 0.023). The study provided one of the mechanisms underlying the psychological and CVD benefits of PA and may explain the novel observation that PA reduces CVD risk to a greater extent among individuals with depression. Source: https://www.jacc.org/