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

Abstract

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.

Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms

“…Indeed, in a canine AF model, liraglutide was found to suppress atrial electrophysiological changes such as AF inducibility and conduction velocity decrease [ 32 ]. Consistently, in a rat model of MI‑induced heart failure, exendin-4 decreased susceptibility to atrial arrhythmogenesis, improved conduction properties, and attenuated atrial fibrosis [ 33 ]. GLP-1RAs might also protect diabetic hearts from AF development through modulating calcium homeostasis.…”

Comparison of Sodium–Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide Receptor Agonists for Atrial Fibrillation in Type 2 Diabetes Mellitus: Systematic Review With Network Meta-analysis of Randomized Controlled Trials

“…The effects on AF/AFL risk reductions of GLP-1RAs have hitherto received scant attention. Chen et al 55 reported that GLP-1RAs decreased susceptibility to atrial arrhythmogenesis by improving conduction properties and exerting antifibrotic effects via the GLP-1 receptor signaling pathway. A previous study indicated that albiglutide may increase the risk of tachyarrhythmia and AF.…”

A meta-analysis evaluating indirectly GLP-1 receptor agonists and arrhythmias in patients with type 2 diabetes and myocardial infarction

“…The clinical study also indicated Liraglutide reduced LV diastolic filling and LV filling pressure and unloaded the LV ( 28 ). The other mechanisms may involve inhibition of the PI3K/AKT signaling pathway and attenuation of atrial fibrosis yet ( 14 ).…”

“…Several previous preclinical studies have been conducted to validate the effects of GLP-1RAs on cardiac arrhythmias under the disease state of MI. Chen et al found that treatment with exendin-4 reduced atrial fibrosis and inhibited atrial arrhythmias in the rat model of MI ( 14 ). Another animal study demonstrated that exendin-4 administered 1 h before ligation of the left anterior descending coronary artery in rats significantly prevented the development of ventricular arrhythmias after ischemia, such as reducing the incidence of ventricular fibrillation (VF) and the duration and number of ventricular tachycardia (VT) and VF episodes ( 15 ).…”