<p>While cardiac abnormalities are well-documented in epilepsy patients, the underlying mechanisms mediating epilepsy-heart interplay remain incompletely understood. This study aimed to investigate epilepsy- related structural and functional cardiac alterations, and to assess the potential mediating role of inflammation from a genetic standpoint. We conducted a two-step Mendelian randomization (MR) analysis in this study, with epilepsy and its two subtypes (generalized epilepsy and focal epilepsy) as exposures, 82 cardiac traits (76 cardiac phenotypes based on cardiac magnetic resonance imaging and 6 electrocardiogram - based characteristics) as outcomes, as well as 91 plasma inflammatory proteins as mediators. The MR results demonstrated causal correlations of epilepsy and generalized epilepsy on cardiac traits. Epilepsy and its two subtypes can causally induce alterations in plasma inflammatory protein levels. Mediation analysis identified C-X-C motif chemokine ligand (CXCL) 1 and CXCL9 as potential mediators of epilepsy’s effect on regional end-diastolic left ventricular wall thickness, accounting for 9.3%~10.0% and 9.1% of the total effects, respectively. In conclusion, epilepsy exhibited significant causal effects on cardiac structure and function, with inflammation potentially serving as a key mediating mechanism. Specifically, CXCL1 and CXCL9 may participate in inflammatory pathways associated with epilepsy-related ventricular remodeling.</p>