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Here, we aim to test the hypothesis that diastolic sarcoplasmic reticulum (SR) Ca2+ leak in atrial myocytes, induced by mechanical stretch due to elevated pressure in the left atrium (LA), plays an essential role in the AF development in pressure-overloaded hearts.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Isolated mouse atrial myocytes subjected to acute axial stretch displayed an immediate elevation of SR Ca2+ leak. Using a mouse model of transverse aortic constriction (TAC), the relation between stretch, SR Ca2+ leak, and AF susceptibility was further tested. At 36\u2009h post-TAC, SR Ca2+ leak in cardiomyocytes from the LA (with haemodynamic stress), but not right atrium (without haemodynamic stress), significantly increased, which was further elevated at 4\u2009weeks post-TAC. Accordingly, AF susceptibility to atrial burst pacing in the 4-week TAC mice were also significantly increased, which was unaffected by inhibition of atrial fibrosis or inflammation via deletion of galectin-3. Western blotting revealed that type 2 ryanodine receptor (RyR2) in left atrial myocytes of TAC mice was oxidized due to activation and up-regulation of Nox2 and Nox4. Direct rescue of dysfunctional RyR2 with dantrolene or rycal S107 reduced diastolic SR Ca2+ leak in left atrial myocytes and prevented atrial burst pacing stimulated AF.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our study demonstrated for the first time the increased SR Ca2+ leak mediated by enhanced oxidative stress in left atrial myocytes that is causatively associated with higher AF susceptibility in pressure-overloaded hearts.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa163","type":"journal-article","created":{"date-parts":[[2020,6,5]],"date-time":"2020-06-05T11:16:56Z","timestamp":1591355816000},"page":"1091-1102","source":"Crossref","is-referenced-by-count":49,"title":["Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts"],"prefix":"10.1093","volume":"117","author":[{"given":"Yi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an, Shaanxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Qi","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, No. 28 West Xianning Road, Xi\u2019an, Shaanxi 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Jing","family":"Li","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, No. 28 West Xianning Road, Xi\u2019an, Shaanxi 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Jin","family":"He","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, No. 28 West Xianning Road, Xi\u2019an, Shaanxi 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hang","family":"Gao","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University, No. 28 West Xianning Road, Xi\u2019an, Shaanxi 710049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-003X","authenticated-orcid":false,"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical 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