title: Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model.
abstract: OBJECTIVE
  The goal of this study was to assess mechanisms underlying atrial fibrillation (AF) promotion by exercise training in an animal model.
  
  
  BACKGROUND
  High-level exercise training promotes AF, but the underlying mechanisms are unclear.
  
  
  METHODS
  AF susceptibility was assessed by programmed stimulation in rats after 8 (Ex8) and 16 (Ex16) weeks of daily 1-h treadmill training, along with 4 and 8 weeks after exercise cessation and time-matched sedentary (Sed) controls. Structural remodeling was evaluated by using serial echocardiography and histopathology, autonomic nervous system with pharmacological tools, acetylcholine-regulated potassium current (IKACh) with patch clamp recording, messenger ribonucleic acid expression with quantitative polymerase chain reaction, and regulators of G protein-signaling (RGS) 4 function in knockout mice.
  
  
  RESULTS
  AF inducibility increased after 16 weeks of training (e.g., AF >30 s in 64% of Ex16 rats vs 15% of Sed rats; p < 0.01) and rapidly returned to baseline levels with detraining. Atropine restored sinus rhythm in 5 of 5 Ex rats with AF sustained >15 min. Atrial dilation and fibrosis developed after 16 weeks of training and failed to fully recover with exercise cessation. Parasympathetic tone was increased in Ex16 rats and normalized within 4 weeks of detraining. Baroreflex heart rate responses to phenylephrine-induced blood pressure elevation and IKACh sensitivity to carbachol were enhanced in Ex16 rats, implicating both central and end-organ mechanisms in vagal enhancement. Ex rats showed unchanged cardiac adrenergic and cholinergic receptor and IKACh-subunit gene expression, but significant messenger ribonucleic acid downregulation of IKACh-inhibiting RGS proteins was present at 16 weeks. RGS4 knockout mice showed significantly enhanced sensitivity to AF induction in the presence of carbachol.
  
  
  CONCLUSIONS
  Chronic endurance exercise increased AF susceptibility in rats, with autonomic changes, atrial dilation, and fibrosis identified as potential mechanistic contributors. Vagal promotion is particularly important and occurs via augmented baroreflex responsiveness and increased cardiomyocyte sensitivity to cholinergic stimulation, possibly due to RGS protein downregulation.
authors.affiliation: Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Eduard
authors.initials: E
authors.lastname: Guasch
authors.forename: Begoña
authors.initials: B
authors.lastname: Benito
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qi
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifelli
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Shi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mighiu
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Artavazd
authors.initials: A
authors.lastname: Tadevosyan
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.forename: Yu-Ki
authors.initials: YK
authors.lastname: Iwasaki
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Lluis
authors.initials: L
authors.lastname: Mont
authors.forename: Scott
authors.initials: S
authors.lastname: Heximer
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005080:Exercise Test / Q000009:adverse effects / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000009:adverse effects / Q000379:methods* / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar