Atrial fibrillation (AF) is a supraventricular tachyarrhythmia that is strongly associated with cardiovascular (CV) disease and sedentary lifestyles. Despite the benefits of exercise on overall health, AF incidence in high-level endurance athletes rivals that of CV disease patients, suggesting a J-shaped relationship with AF. To investigate the dependence of AF vulnerability on exercise, we varied daily swim durations (120, 180 or 240 min day^-1 ) in 7-week-old male CD1 mice. We assessed mice after performing equivalent amounts of cumulative work during swimming (i.e. ∼700 L O₂ kg^-1 ), as determined from O₂ consumption rates ( V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ ). The mean V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ during exercise increased progressively throughout the training period and was indistinguishable between the swim groups. Consistent with similar improvements in aerobic conditioning induced by swimming, skeletal muscle mitochondria content increased (P = 0.027) indistinguishably between exercise groups. Physiological ventricular remodelling, characterized by mild hypertrophy and left ventricular dilatation, was also similar between exercised mice without evidence of ventricular arrhythmia inducibility. By contrast, prolongation of daily swim durations caused progressive and vagal-dependent heart rate reductions (P = 0.008), as well as increased (P = 0.005) AF vulnerability. As expected, vagal inhibition prolonged (P = 0.013) atrial refractoriness, leading to reduced AF vulnerability, although still inducible in the 180 and 240 min swim groups. Accordingly, daily swim dose progressively increased atrial hypertrophy (P = 0.003), fibrosis (P < 0.001) and macrophage accumulation (P = 0.006) without differentially affecting the ventricular tissue properties. Thus, increasing daily exercise duration drives progressively adverse atrial-specific remodelling and vagal-dependent AF vulnerability despite robust and beneficial aerobic conditioning and physiological remodelling of ventricles and skeletal muscle. KEY POINTS: Previous studies have suggested that a J-shaped dose-response relationship exists between physical activity and cardiovascular health outcomes, with moderate exercise providing protection against many cardiovascular disease conditions, whereas chronic endurance exercise can promote atrial fibrillation (AF). We found that AF vulnerability increased alongside elevated atrial hypertrophy, fibrosis and inflammation as daily swim exercise durations in mice were prolonged (i.e. ≥180 min day^-1 for 6 weeks). The MET-h week^-1 (based on O₂ measurements during swimming) needed to induce increased AF vulnerability mirrored the levels linked to AF in athletes. These adverse atria effects associated with excessive daily exercise occurred despite improved aerobic conditioning, skeletal muscle adaptation and physiological ventricular remodelling. We suggest that atrial-specific changes observed with exercise arise from excessive elevations in venous filling pressures during prolonged exercise bouts, which we argue has implications for all AF patients because elevated atrial pressures occur in most cardiovascular disease conditions as well as ageing which are linked to AF.

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