Enhancer of Zeste Homolog 2 Inhibition Attenuates Atrial Fibrillation Post-Myocardial Infarction Through Reduced Atrial Fibrosis

Background: Atrial fibrillation (AF) is one of the most prevalent arrhythmias following a myocardial infarction (MI), yet the pathogenesis associated with post-MI AF remains poorly understood. Enhancer of zeste homolog 2 (EZH2), an enzyme that regulates histone modifications, has been implicated in various cardiovascular diseases; however, the role of EZH2 in the development of post-MI AF also remains unclear. Methods: MI was induced in mice by ligation of the left anterior descending coronary artery (LAD), followed by intraperitoneal administration of GSK126 or vehicle control (polyethylene glycol 300 and saline). Results: MI significantly increased the incidence and duration of AF, while electrical mapping revealed decreased conduction velocity. These changes were accompanied by increased atrial fibrosis, which was associated with upregulation of EZH2 and trimethylated histone H3 at lysine 27 (H3K27me3). In GSK126-treated mice, the incidence of AF was reduced, along with a significant decrease in H3K27me3 expression and atrial fibrosis. Conclusion: Upregulation of EZH2 is associated with post-MI AF. Pharmacological inhibition of EZH2 using GSK126 attenuates atrial fibrosis and reduces the incidence of AF. These findings suggest that EZH2 may represent a potential therapeutic candidate for post-MI AF, although further validation is required.