European heart journal · 2026
Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate.
СтатьяНазвание и аннотация: Перевод в очереди
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Soattin Luca, Topal Leila, Tikhomirov Roman, Lagomarsino-Oneto Daniele, Al-Othman Sami, Lee Angela W C, Saluja Sushant, Hornyik Tibor, Husti Zoltán, Pintér Jenő Antal, Mohammed Aiman Saleh A, Smith Matthew, Francis Alice J, McKie Megan, Torre Eleonora, Polyák Alexandra, Farkas Attila, Bentzen Bo Hjorth, Keavney Bernard, Nagy Norbert, Jost Norbert, Casadei Barbara, Mangoni Matteo E, Boyett Mark R, Colman Michael A, Niederer Steven A, Varró András, Morris Gwilym M, Baczkó István, D'Souza Alicia
Аннотация
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.
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.