Exendin-4 inhibits atrial arrhythmogenesis in a model of myocardial infarction-induced heart failure via the GLP-1 receptor signaling pathway

Glucagon-like peptide-1 receptor (GLP-1 receptor) agonists are considered to exert cardioprotective effects in models of acute and chronic heart disease. The present study aimed to investigate the role of exendin-4 (a GLP-1 receptor agonist) in atrial arrhythmogenesis in a model of myocardial infarction (MI)-induced heart failure and to elucidate the mechanisms underlying its effects. For this purpose, male Sprague-Dawley rats underwent sham surgery or left anterior descending artery ligation prior to being treated with saline/exendin-4/exendin-4 plus exendin9-39 (an antagonist of GLP-1 receptor) for 4 weeks. The effects of exendin-4 on atrial electrophysiology, atrial fibrosis and PI3K/AKT signaling were assessed. Rats with MI exhibited depressed left ventricular function, an enlarged left atrium volume, prolonged action potential duration, elevated atrial tachyarrhythmia inducibility, decreased conduction velocity and an increased total activation time, as well as total activation time dispersion and atrial fibrosis. However, these abnormalities were attenuated by treatment with the GLP-1 receptor agonist, exendin-4. Moreover, the expression levels of collagen I, collagen III, transforming growth factor-β1, phosphorylated PI3K and AKT levels in atrial tissues were upregulated in rats with MI. These changes were also attenuated by exendin-4. It was also found that these exedin-4-mediated attenutations were mitigated by the co-administration of exendin9-39 with exendin-4. Overall, the findings of the present study suggested that exendin-4 decreases susceptibility to atrial arrhythmogenesis, improves conduction properties and exerts antifibrotic effects via the GLP-1 receptor signaling pathway. These findings provide evidence for the potential use of GLP-1R in the treatment of atrial fibrillation.