Background and aims: Although many large-scale clinical studies have confirmed that depression is an independent risk factor for atrial fibrillation (AF), the underlying mechanism remains unclear. This study aimed to investigate the pathogenesis of depression-induced AF.
Methods and results: The chronic unpredictable mild stress model of depression was established. In this model, we observed a significant increase in AF inducibility. In order to explore its potential mechanism, we analyzed the serum metabolomics of humans and rats and the protein metabolomics of atrial tissue in rats. The levels of N-palmitoyl glycine in different tissues were quantified using liquid chromatography-mass spectrometry. Both in vivo and in vitro experiments were performed to validate the proposed mechanisms. Electrophysiological changes in isolated hearts were evaluated using the Langendorff perfusion system and multichannel electrical mapping. Our findings suggest that N-palmitoyl glycine secreted by the white matter acts as a key factor in depression-associated AF. Both in vivo and in vitro experiments revealed that N-palmitoyl glycine reduces autophagy and the synthesis of nebulin-related anchoring protein in atrial myocytes by upregulating α1,2-mannosidase expression. These changes lead to the intercalated disc rupture, a critical event in the pathogenesis of AF.
Conclusion: This study demonstrates that N-palmitoyl glycine plays a crucial role in the development of AF in the context of depression. These findings provide potential therapeutic targets for the prevention and treatment of AF following depression.
Keywords: 2- mannosidase; Atrial fibrillation; Depression; N-palmitoyl glycine; Nebulin-related-anchoring protein; autophagy; α1.
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.