Acute GLP-1 Agonism Induces Arrhythmogenic Electrical Activity in Aged Mice Heart Through Impaired Cellular Na+ and Ca2+ Handlings: The Role of CK2 Hyperphosphorylation.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are known for their benefits in conditions like cardiovascular diseases in type 2 diabetes and obesity. They also show promise for aging-related conditions with minimal side effects. However, their impact on cardiovascular risk is still debated. Notably, some long-acting GLP-1RAs cause a sustained increase in heart rate on the first day of use without a clear mechanism. To understand their short-term effects, we examined acute GLP-1R agonism on the electrical activity of elderly hearts. METHODS: In this study, we utilized in vivo electrocardiography, in vitro cellular electrophysiology experiments, and biochemical measurements on heart preparations from 6-month-old (Adult) and 24-month-old (aged) BALB/c mice. RESULTS: A single liraglutide injection (0.3 mg/kg) induced repetitive, self-sustained arrhythmogenic electrocardiograms in aged mice (24 months old) but had no effect on adults (6 months old) within the first 10 minutes. Acute application of liraglutide to isolated ventricular cardiomyocytes from aged mice significantly prolonged the late phase of action potential repolarization (APR90). This was due to suppressed K+ currents and increased persistent Na+currents (Late-INa), primarily through delayed recovery from inactivation of Na+ currents. Additionally, liraglutide increased Ca2+ spark frequency and wave formation by enhancing Ca2+ release from the sarcoplasmic reticulum, affecting both Na+ and Ca2+ regulation in aging cells. Liraglutide also induced casein kinase 2 (CK2) hyperphosphorylation in aged cardiomyocytes, which a CK2 inhibitor could reverse, normalizing APR90 by reducing Late-INa and enhancing K+ currents. CONCLUSION: These findings reveal that acute GLP-1R agonism can disrupt electrical signaling and induce arrhythmia in aged mice through CK2 hyperphosphorylation, providing new insights into the cardiovascular effects of GLP-1RAs in the elderly.