In a large UK Biobank study, higher levels of the chronic inflammation marker GlycA were associated with smaller heart chambers, thicker heart walls, impaired diastolic function, reduced stroke volume, and a 43% higher risk of major adverse cardiovascular events in the highest versus lowest GlycA group. Genetic susceptibility also modified the associations between environmental exposures, inflammation, and cardiovascular risk, while inflammatory proteins in the IL-1, TNF, and IL-6 pathways statistically mediated several of these associations.