Long-term glucosamine supplementation aggravates atrial fibrillation susceptibility by impairing AMPK signaling

Aims: Glucosamine, a widely used dietary supplement, has been linked to potential cardiovascular risks, including atrial fibrillation (AF). This study aimed to investigate the effects of long-term glucosamine supplementation on AF susceptibility and the underlying mechanisms. Materials and methods: C57BL/6 J mice were treated with low-dose (15 mg/kg/day) or high-dose (250 mg/kg/day) glucosamine via drinking water for 6 weeks. AF susceptibility was assessed through transesophageal electrical stimulation. Atrial remodeling was characterized through electrophysiological and echocardiography studies, histological analysis, and molecular examination. AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) was used to validation the underlying mechanism in mice and isolated neonatal atrial cardiomyocytes. Key findings: Long-term high-dose glucosamine supplementation increased AF susceptibility in mice, as indicated by an elevated AF incidence and duration. Glucosamine induced notable electrical remodeling, evidenced by intra-atrial conduction slowing (P wave duration, amplitude, and area), likely attributable to reduced conduction velocity, as confirmed by two-dimensional electrical mapping. Structural remodeling including increased left atrial weight, cardiomyocyte hypertrophy and fibrosis was evident in the atria of glucosamine-treated mice, despite unaffected cardiac function. Mechanistically, glucosamine suppressed atrial AMPK signaling, leading to lipid and glycogen accumulation. Intriguingly, despite impaired atrial AMPK signaling, high-dose glucosamine improved systemic insulin sensitivity. Pharmacological activation of AMPK with AICAR mitigated glucosamine-induced AF susceptibility and associated pathological changes both in vivo and in vitro. Significance: Our findings demonstrate that long-term glucosamine supplementation enhances AF susceptibility, potentially by impairing atrial AMPK signaling, underscoring the importance of caution in the utilization of glucosamine.