Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate.

Summary

Using endurance training models across species with spatial transcriptomics and in silico validation, this study shows that exercise upregulates automaticity (HCN4/Ca2+ channels), slows conduction (SCN5A/Cx43), and promotes fibrosis/inflammation in pulmonary vein sleeves, leading to enhanced PV firing and peri-antral reentry. The findings mechanistically explain why PV isolation benefits athlete AF and nominate modifiable pathways (e.g., HCN4, TNFα).

Key Findings

• Endurance training increased AF inducibility with PV–LA conduction slowing and rotational activity in vivo.
• PV sleeves showed enhanced β-adrenergic–evoked firing, prolonged bursts, and more pacemaker-like action potentials ex vivo.
• Spatial transcriptomics revealed upregulation of Hcn4/Cacna1d/Cacna1g and downregulation of Scn5a/Gja1, alongside fibroblast expansion and pro-fibrotic/inflammatory signaling (TNFα, IL-6).
• In silico human models reproduced faster spontaneous PV firing and sustained peri-antral reentry from observed molecular and electrophysiologic changes.

Clinical Implications

Supports PV-focused ablation in athlete AF and suggests adjunct strategies targeting automaticity (HCN4/Ca channels) and inflammation/fibrosis (e.g., TNFα pathways) to prevent recurrence.

Limitations

• Preclinical models may not capture all human athletic phenotypes and environmental modifiers
• Causal interventional testing of nominated pathways (e.g., HCN4/TNFα) was not performed in vivo

Future Directions

Interventional studies targeting HCN4/Ca-channel automaticity and TNFα/inflammatory signaling in exercise-induced AF models; prospective biomarker-guided human studies to translate pathway targets to prevention or adjunctive therapy.