Atrial Fibrillation Promotion by Endurance Exercise: Demonstration and Mechanistic Exploration in an Animal Model

• Published in: Journal of the American College of Cardiology 2013-07, Vol.62 (1), p.68-77
• Main Authors: GUASCH, Eduard, BENITO, Begoña, GILLIS, Marc-Antoine, YU-KI IWASAKI, DOBREV, Dobromir, MONT, Lluis, HEXIMER, Scott, NATTEL, Stanley, XIAOYAN QI, CIFELLI, Carlo, NAUD, Patrice, YANFEN SHI, MIGHIU, Alexandra, TARDIF, Jean-Claude, TADEVOSYAN, Artavazd, YU CHEN
• Format: Article
• Language: English
• Subjects: Animals; Atrial Fibrillation - etiology; Atrial Fibrillation - physiopathology; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Disease Models, Animal; Exercise Test - adverse effects; Exercise Test - methods; Heart; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Physical Conditioning, Animal - adverse effects; Physical Conditioning, Animal - methods; Physical Conditioning, Animal - physiology; Physical Endurance - physiology; Random Allocation; Rats; Rats, Wistar
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2013.01.091

The goal of this study was to assess mechanisms underlying atrial fibrillation (AF) promotion by exercise training in an animal model. High-level exercise training promotes AF, but the underlying mechanisms are unclear. 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. 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. 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.