Abstract
BACKGROUND: Atrial fibrillation (AF) and major depressive disorder (MDD) frequently co-occur and are each associated with adverse cardiovascular outcomes, yet the biological pathways linking these conditions remain poorly defined. Using the UK Biobank, we evaluated shared neurocardiac, inflammatory, and cardiovascular correlates underlying the AF-MDD association. OBJECTIVES: To assess bidirectional associations between AF and MDD and determine whether shared inflammatory, cardiovascular, autonomic, and neuroimaging correlates characterize their comorbidity. METHODS: We analyzed individuals with AF (N≥1,716), MDD (N≥4,550), comorbid AF-MDD (N≥243), and healthy comparators (HCs; N≥33,041). Bidirectional associations were examined using cross-sectional and Cox proportional hazard models. Mediation analyses evaluated contributions of inflammatory markers and cardiovascular risk. Central autonomic network structure and function was assessed using MRI-derived morphometry and resting-state connectivity. RESULTS: AF and MDD demonstrated bidirectional associations: AF was associated with a 44% higher risk of incident MDD, and MDD with a 26% higher risk of incident AF. Inflammatory biomarkers and cardiovascular risk partially mediated these associations (6.85% and 32.01%, respectively). AF was associated with greater gray matter volume in ventromedial prefrontal and insular cortices and increased central autonomic network connectivity, whereas MDD showed opposite structural and functional patterns. The comorbid AF-MDD group exhibited distinct, non-additive neural profiles. CONCLUSIONS: AF and MDD demonstrate bidirectional associations characterized by shared inflammatory, cardiovascular, and neural correlates, alongside distinct and non-additive alterations within central autonomic network circuits. These findings support a systems-level neurocardiac framework linking cardiac and psychiatric disease and highlight the importance of integrated approaches to risk assessment and multidisciplinary management in patients with AF-MDD comorbidity.