Depression and Anxiety Associate With Adverse Cardiovascular Events via Neural, Autonomic, and Inflammatory Pathways

Depression is linked to major adverse cardiac events (MACE), yet the role of stress-related neural activity-previously implicated in stress and anxiety in mediating this association remains unclear. Because anxiety and depression frequently co-occur and share neurobiological pathways, we hypothesized that the relationship between depression, anxiety, and their co-occurrence with MACE is partially mediated by increased stress-related neural activity and related autonomic-immune mechanisms.

Data were obtained from participants enrolled in the Mass General Brigham Biobank (2010-2020). A subset underwent ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography imaging to assess stress-related neural activity, defined as the ratio of amygdala to background prefrontal cortical activity. Heart rate variability and CRP (C-reactive protein) served as indicators of autonomic activity and systemic inflammation. Depression and anxiety were determined at enrollment, and MACE was identified during follow-up using International Classification of Diseases codes. Each exposure (depression, anxiety, or concurrent anxiety plus depression) was modeled separately against study outcomes using linear and Cox regressions.

Of 85 551 study subjects, 3078 (3.6%) participants developed MACE, over a median 3.4 years follow-up (interquartile range, 1.9-4.8). Depression was associated with higher MACE risk (hazard ratio, 1.24 [95% CI, 1.14-1.34]; P<0.001), with stronger associations for concurrent anxiety plus depression (hazard ratio, 1.35 [1.23-1.49]; P<0.001) and remained significant after adjustment for demographics, lifestyle, cardiovascular, and socioeconomic factors. In subsamples with available imaging (N=1123) or biomarkers (heart rate variability, N=7862; CRP, N=12 906), depression was linked to higher amygdala-to-cortex activity ratio (β=0.16; P=0.006), lower heart rate variability (β=-0.20; P<0.001), and higher CRP (β=0.14; P<0.001). Mediation analyses showed indirect effects of amygdala-to-cortex activity ratio, heart rate variability, and CRP on the depression-MACE relationship (log odds ratios, 0.04, 0.04, and 0.02, respectively; all P<0.05). Similar associations were observed for anxiety or concurrent anxiety plus depression.

Depression and anxiety independently associate with increased MACE risk, partly mediated by heightened stress-related neural activity and autonomic-immune dysregulation. The risk is greatest among those with both conditions, underscoring shared stress-related pathophysiology.