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Despite the benefits of exercise on overall health, AF incidence in high\u2010level endurance athletes rivals that of CV disease patients, suggesting a J\u2010shaped relationship with AF. To investigate the dependence of AF vulnerability on exercise, we varied daily swim durations (120, 180 or 240\u00a0min\u00a0day<jats:sup>\u20131<\/jats:sup>) in 7\u2010week\u2010old male CD1\u00a0mice. We assessed mice after performing equivalent amounts of cumulative work during swimming (i.e. \u223c700\u00a0L O<jats:sub>2<\/jats:sub>\u00a0kg<jats:sup>\u20131<\/jats:sup>), as determined from O<jats:sub>2<\/jats:sub> consumption rates (). The mean  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 (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.027) 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\u2010dependent heart rate reductions (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.008), as well as increased (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.005) AF vulnerability. As expected, vagal inhibition prolonged (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.013) atrial refractoriness, leading to reduced AF vulnerability, although still inducible in the 180 and 240\u00a0min swim groups. Accordingly, daily swim dose progressively increased atrial hypertrophy (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.003), fibrosis (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and macrophage accumulation (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.006) without differentially affecting the ventricular tissue properties. Thus, increasing daily exercise duration drives progressively adverse atrial\u2010specific remodelling and vagal\u2010dependent AF vulnerability despite robust and beneficial aerobic conditioning and physiological remodelling of ventricles and skeletal muscle.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15904-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Previous studies have suggested that a J\u2010shaped dose\u2013response 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).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We found that AF vulnerability increased alongside elevated atrial hypertrophy, fibrosis and inflammation as daily swim exercise durations in mice were prolonged (i.e. \u2265180\u00a0min\u00a0day<jats:sup>\u20131<\/jats:sup> for 6\u00a0weeks).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The MET\u2010h\u00a0week<jats:sup>\u20131<\/jats:sup> (based on O<jats:sub>2<\/jats:sub>\u00a0measurements during swimming) needed to induce increased AF vulnerability mirrored the levels linked to AF in athletes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These adverse atria effects associated with excessive daily exercise occurred despite improved aerobic conditioning, skeletal muscle adaptation and physiological ventricular remodelling.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We suggest that atrial\u2010specific 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.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285697","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T06:37:49Z","timestamp":1707287869000},"page":"569-596","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The effects of daily dose of intense exercise on cardiac responses and atrial fibrillation"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9580-9807","authenticated-orcid":false,"given":"Ren\u00e9e A.","family":"Gorman","sequence":"first","affiliation":[{"name":"Department of Biology York University  Toronto ON Canada"},{"name":"Muscle Health Research 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