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

  1. Luca Soattin
  2. Leila Topal
  3. Roman Tikhomirov
  4. Daniele Lagomarsino-Oneto
  5. Sami Al-Othman
  6. Sushant Saluja
  7. Tibor Hornyik
  8. Zoltán Husti
  9. Jenő Antal Pintér
  10. Aiman Saleh A Mohammed
  11. Matthew Smith
  12. Alice J Francis
  13. Megan McKie
  14. Eleonora Torre
  15. Alexandra Polyák
  16. Attila Farkas
  17. Bo Hjorth Bentzen
  18. Bernard Keavney
  19. Norbert Nagy
  20. Norbert Jost
  21. Barbara Casadei
  22. Matteo Elia Mangoni
  23. Mark Richard Boyett
  24. András Varró
  25. Gwilym Matthew Morris
  26. István Baczkó
  27. Alicia D’Souza
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Abstract

BACKGROUND

Atrial fibrillation (AF) susceptibility is heightened in endurance athletes but the underlying mechanisms are incompletely understood. Because pulmonary vein (PV) myocyte triggers are critical determinants of AF, we investigated PV electrophysiological remodelling in animal models of the athlete’s heart.

METHODS

The following experiments were performed in canines and mice after 16 or 6 weeks, respectively, of daily exercise training (ExT), and compared to sedentary (Sed) controls: ECG recording, echocardiography, pharmacological autonomic block, extrastimulus pacing, multielectrode array mapping, monophasic and intracellular action potential (AP) recording with custom-designed pattern recognition analysis, histology, RNAseq and spatial in situ transcriptomics.

RESULTS

AF propensity was significantly increased in ExT animals. Mapping studies identified heightened rotational activity in the PV-left atrial (LA) junction of ExT vs . Sed canines in vivo, and enhanced automaticity, triggered activity and AP duration variability ex vivo in ExT canines and mice. Intracellular recordings in mouse PV cardiomyocytes determined at least six AP subtypes with increased frequency of pacemaker-like APs in ExT PV, concomitant with increased expression of pacemaking HCN4, Ca v 1.3 and Ca v 3.1 channels. PV spontaneous excitability was also significantly enhanced. Subcellular resolution spatial transcriptomics in mouse PV-LA identified diffuse ion channel remodelling and activation of established AF-promoting pro-inflammatory and pro-fibrotic cytokines and chemokines in ExT PV cardiomyocytes. Conduction slowing in the ExT PV-LA junction was attributable to: gap junction remodelling, reduced Na + channel expression and increased extracellular matrix deposition with enhanced myofibroblast number and proximity to PV cardiomyocytes.

CONCLUSIONS

Endurance exercise elicits proarrhythmic electro-anatomical remodelling of the PV-LA junction with enhanced pacemaking ion channel expression and immune-inflammatory pathway activation in PV myocytes as prominent contributors.

CLINICAL PERSPECTIVE

What is new?

  • This work is the first demonstration that endurance training results in proarrhythmic electrophysiological remodelling of PV sleeve myocytes and extracellular matrix deposition in the PV-LA junction.

  • We register electrical and molecular heterogeneity of the PV-LA junction at single cell and subcellular resolution, and for the first time identify the molecular events that underlie increased proarrhythmic activity of the trained PV. These include enhanced pacemaking ion channel expression (e.g., HCN4, Ca v 1.3, and Ca v 3.1), pro-inflammatory cytokine activation (e.g., TNFα, IL-6), increased myofibroblasts and extracellular matrix deposition.

What are the clinical implications?

  • We identify the molecular determinants of PV proarrhythmic activity in the trained heart and present new therapeutic targets for AF prevention in athletes.

  • Our findings provide mechanistic rationale for the efficacy of pulmonary vein isolation for AF in athletes.

Article activity feed

  1. Version published to 10.1101/2025.02.12.638004v1 on bioRxiv