Myocardial infarction (MI) is an important risk factor for the development of atrial fibrillation (AF), and the gut microbial metabolite phenylacetylglutamine (PAGln) is strongly associated with the prognosis of MI patients. However, whether PAGln is involved in the regulation of AF after MI is currently unknown. Therefore, the present study aimed to explore the effect of PAGln on the susceptibility to AF after MI.MI model was constructed by surgically ligating the left anterior descending branch of the coronary artery. PAGln was administered by intraperitoneal injection for 7 consecutive days starting after surgery and then investigated by histopathologic, molecular biological, and electrophysiologic studies.Myocardial ischemia resulted in intestinal barrier dysfunction and significantly increased circulating levels of PAGln. Compared with the myocardial ischemia group, administration of PAGln significantly exacerbated atrial fibrosis and atrial electrical remodeling in mice after myocardial ischemia, as evidenced by shortening of the ERP (at varying pacing cycle lengths of 40, 60, 80, and 100), ion channel remodeling (Nav1.5, Cav1.2, and Kv1.5), and decreased expression of CX40, which led to an increase in the susceptibility to AF (54.5% vs. 90.9%, P < 0.05). In addition, administration of PAGln further exacerbated MI-induced intestinal barrier dysfunction compared with the MI group. Mechanistically, PAGln may affect atrial remodeling and AF susceptibility after MI by modulating ferroptosis and NLRP3 inflammasome.The present study preliminarily reveals that the gut microbial metabolite PAGln exacerbates post-MI AF remodeling and AF susceptibility, possibly through ferroptosis and activation of NLRP3 inflammasome.
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