Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate
Abstract
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.
Related
- Exercise Endurance Effects of Food‐Derived Polysaccharides in Animal Models of Exercise‐Induced Fatigue: A Systematic Review and Meta‐Analysis
- Fueling the Modern Endurance Athlete: The High-Carbohydrate Revolution, Exogenous Ketones, and an Evidence-Based Approach for the Sports Medicine Clinician
- A motor endurance assay for zebrafish larvae: proof of principle in chemical and genetic models of neurological disease
- Research progress on the mechanisms by which gut microbiota dysbiosis remodels the bone marrow neuroimmune microenvironment to drive age-related osteoporosis
- Trichoderma harzianum M2 Induces Systemic Resistance to Fusarium Crown Rot and Remodels Root Architecture to Promote Phosphorus Uptake in Wheat
BibTeX
@article{soattin2026endurance,
title = {{Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate}},
author = {Luca Soattin and Leila Topal and Roman Tikhomirov and Daniele Lagomarsino-Oneto and Sami Al-Othman and Angela Lee and Sushant Saluja and Tibor Hornyik and Zoltán Husti and Jenő Antal Pintér and Aiman Saleh A Mohammed and Matthew Smith and Alice Francis and Megan Mckie and Eleonora Torre and Alexandra Polyák and Attila Farkas and Bo Hjorth Bentzen and Bernard Keavney and Norbert Nagy and Norbert Jost and Barbara Casadei and Matteo Mangoni and Mark Boyett and Michael Colman and Steven Niederer and András Varró and Gwilym Morris and István Baczkó and Alicia D’souza},
journal = {European Heart Journal},
year = {2026},
month = may,
doi = {10.1093/eurheartj/ehag358},
url = {https://hal.science/hal-05845239v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate
AU - Luca Soattin
AU - Leila Topal
AU - Roman Tikhomirov
AU - Daniele Lagomarsino-Oneto
AU - Sami Al-Othman
AU - Angela Lee
AU - Sushant Saluja
AU - Tibor Hornyik
AU - Zoltán Husti
AU - Jenő Antal Pintér
AU - Aiman Saleh A Mohammed
AU - Matthew Smith
AU - Alice Francis
AU - Megan Mckie
AU - Eleonora Torre
AU - Alexandra Polyák
AU - Attila Farkas
AU - Bo Hjorth Bentzen
AU - Bernard Keavney
AU - Norbert Nagy
AU - Norbert Jost
AU - Barbara Casadei
AU - Matteo Mangoni
AU - Mark Boyett
AU - Michael Colman
AU - Steven Niederer
AU - András Varró
AU - Gwilym Morris
AU - István Baczkó
AU - Alicia D’souza
PY - 2026
DA - 2026/05/25
JO - European Heart Journal
DO - 10.1093/eurheartj/ehag358
UR - https://hal.science/hal-05845239v1
AB - 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.
SN - 0195-668X
SN - 1522-9645
ER -