{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:26:17Z","timestamp":1791822377462,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The \u201cathlete\u2019s heart\u201d phenotype, featuring resting bradycardia, has traditionally been viewed as a benign adaptation. However, emerging evidence associates prolonged, high-intensity endurance training with an increased risk of clinical sinoatrial node dysfunction. This systematic review synthesizes evidence on exercise-induced intrinsic Sinoatrial Node (SAN) electrophysiological remodelling and evaluates its dual nature along the adaptation\u2013pathology continuum. Following PRISMA guidelines, a systematic search of PubMed, Web of Science, and Google Scholar (2000\u20132025) identified 17 eligible studies. Analysis revealed that in humans, rodents, and rabbits, exercise induces intrinsic SAN electrophysiological remodelling\u2014a \u201cmembrane clock\u201d reset characterized by coordinated downregulation of pacemaker currents, notably Hyperpolarization-activated cyclic nucleotide-gated cation channel (If), via the Nkx2.5-miR-423-5p transcription factor pathway. Evidence for \u201ccalcium clock\u201d involvement remains inconsistent. In contrast, large animal models (e.g., dogs, horses) show only parasympathetic-mediated bradycardia without intrinsic remodelling. Training loads may induce structural changes (e.g., fibrosis), providing an anatomical substrate for pathology. Moderating factors such as training type and ageing contribute to a phenotype of \u201cacquired SAN reserve reduction. Exercise-induced intrinsic SAN remodelling is a physiological adaptation mechanism that, under certain conditions, can cross a threshold to become a pathological cause of clinical dysfunction. Recognizing this continuum is essential for risk stratification and future therapeutic innovation.<\/jats:p>","DOI":"10.3390\/ijms262412052","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:32:37Z","timestamp":1765805557000},"page":"12052","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Dual Nature of Sinoatrial Node Remodelling in Athletes: A Systematic Review of Electrophysiological Adaptations and the Pathological Tipping Point"],"prefix":"10.3390","volume":"26","author":[{"given":"Liang","family":"Yue","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaying","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henggui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"},{"name":"Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK"},{"name":"Beijing Academy of Artificial Intelligence, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","first-page":"1455","article-title":"Athlete\u2019s heart","volume":"89","author":"Fagard","year":"2003","journal-title":"Heart (Br. 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