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

Background and Aims

The risk of atrial fibrillation (AF) is higher in endurance athletes. Pulmonary vein isolation (PVI) is effective in this group, implicating pulmonary vein (PV) remodelling, but underlying mechanisms are unclear. This study investigated if endurance training remodels PV sleeves and the PV–left atrial (LA) junction to promote PV triggers and a permissive peri-antral substrate for AF.

Methods

In canine and murine endurance-running models, in vivo PV–LA mapping, ex vivo PV electrophysiology, intracellular action potential (AP) profiling with machine learning classification, histology, bulk RNA-seq, and subcellular-resolution spatial transcriptomics of PV–LA tissue were performed. These findings were incorporated into biophysically detailed computer models of human PV cardiomyocytes and a 3D human LA.

Results

Training produced an athlete’s heart phenotype and increased AF inducibility. In vivo, trained animals showed PV–LA conduction slowing and increased rotational activity. Ex vivo, trained PVs showed enhanced β-adrenergically evoked firing, prolonged burst activity, and a higher proportion of pacemaker-like APs. Spatial transcriptomics revealed discrete PV myocyte subpopulations with training upregulated Hcn4, Cacna1d, and Cacna1g (enhancing automaticity), downregulated Scn5a and Gja1 (slowing conduction), and enriched profibrotic/inflammatory signalling (Tnfα, Il6) alongside fibroblast expansion and extracellular matrix deposition. In silico, these changes reproduced faster spontaneous PV firing and sustained re-entry.

Conclusions

Endurance training drives coupled electrical, structural, and inflammatory PV–LA remodelling that provides both trigger and substrate for AF. These data support why PV-targeted strategies can be effective in athletic AF and nominate modifiable pathways including HCN4-linked automaticity and TNFα-associated signalling.