Intereye Retinal Asymmetry, Incident Cardiovascular Disease, and Circulating Proteomic Signatures

BACKGROUND: Retinal imaging provides a noninvasive window into systemic microvascular health. Many optical coherence tomography studies of cardiovascular disease have focused on mean retinal thickness, which may be influenced by demographic and ocular factors. Whether intereye retinal asymmetry provides additional prognostic information beyond mean retinal thickness remains unclear. METHODS: We conducted a prospective cohort study in the UK Biobank including 46 836 participants with bilateral optical coherence tomography imaging. Across the 4 end point-specific analyses, the maximum follow-up was 12.86 years, and median follow-up ranged from 9.22 to 9.38 years. Intereye absolute difference and intereye percentage difference were calculated for multiple retinal layers. Associations with incident coronary heart disease, myocardial infarction, atrial fibrillation, and heart failure were evaluated using multivariable Cox models. Dose-response analyses and predictive performance comparisons were performed. Proteomic data were integrated to explore circulating molecular signatures associated with retinal asymmetry and cardiovascular outcomes. RESULTS: Greater retinal asymmetry was consistently observed in participants who developed cardiovascular disease. Retinal nerve fiber layer asymmetry showed the most consistent associations with incident outcomes, with hazard ratios ranging from ∼1.07 for atrial fibrillation to 1.15 for heart failure per SD increase. Models including retinal nerve fiber layer asymmetry modestly improved cardiovascular risk prediction compared with mean retinal thickness alone. Exploratory proteomic analyses suggested associations between retinal nerve fiber layer asymmetry and circulating signatures related to extracellular matrix remodeling, inflammation, and insulin-like growth factor signaling. CONCLUSIONS: Intereye retinal asymmetry, particularly retinal nerve fiber layer asymmetry, is associated with incident cardiovascular disease and may represent a candidate optical coherence tomography-derived marker for cardiovascular risk stratification.