Shared Neurocardiac Pathways Linking Atrial Fibrillation and Depression: A UK Biobank Analysis

O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/26346796v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1303a7aorg.highwire.dtl.DTLVardef@14f223forg.highwire.dtl.DTLVardef@51672eorg.highwire.dtl.DTLVardef@4d273a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOCentral IllustrationC_FLOATNO C_FIG HIGHLIGHTSO_LIAtrial fibrillation and depression are linked via central autonomic network disruption, cardiovascular risk, and inflammation. C_LIO_LIHeightened inflammatory response and cardiovascular risk mediates the bidirectional relationship between atrial fibrillation and depression. C_LIO_LIAtrial fibrillation, depression, and their comorbidity exhibit distinct, non-additive neural and autonomic signatures. C_LI BACKGROUNDAtrial 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. OBJECTIVESTo assess bidirectional associations between AF and MDD and determine whether shared inflammatory, cardiovascular, autonomic, and neuroimaging correlates characterize their comorbidity. METHODSWe 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. RESULTSAF 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. CONCLUSIONSAF 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.