{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:45:05Z","timestamp":1791121505374,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2008,10,10]]},"abstract":"<jats:p>\n            Atrial tachycardia (AT) downregulates L-type Ca\n            <jats:sup>2+<\/jats:sup>\n            current (\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            ) and causes atrial fibrillation\u2013promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            and transient outward current (\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>to<\/jats:sub>\n            ), unchanged\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaT<\/jats:sub>\n            ,\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>Kr<\/jats:sub>\n            , and\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>Ks<\/jats:sub>\n            , and reduced action potential duration (APD).\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            was unchanged in P3 at 2 and 8 hours but decreased by 55\u00b16% at 24 hours. Tachypacing caused Ca\n            <jats:sup>2+<\/jats:sup>\n            <jats:sub>\n              <jats:italic>i<\/jats:italic>\n            <\/jats:sub>\n            accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca\n            <jats:sup>2+<\/jats:sup>\n            <jats:italic>i<\/jats:italic>\n            returned to baseline. Ca\n            <jats:sub>v<\/jats:sub>\n            1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32\u00b14% and 48\u00b14%, respectively) and protein expression was decreased (47\u00b18%) at 24 hours only. Suppressing Ca\n            <jats:sup>2+<\/jats:sup>\n            <jats:sub>\n              <jats:italic>i<\/jats:italic>\n            <\/jats:sub>\n            increases during tachypacing with the\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            blocker nimodipine or the Ca\n            <jats:sup>2+<\/jats:sup>\n            chelator BAPTA-AM prevented\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca\n            <jats:sup>2+<\/jats:sup>\n            -dependent signaling was probed with inhibitors of Ca\n            <jats:sup>2+<\/jats:sup>\n            \/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            downregulation. Significant APD reductions (\u224830%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca\n            <jats:sup>2+<\/jats:sup>\n            loading, which activates the Ca\n            <jats:sup>2+<\/jats:sup>\n            -dependent calmodulin\u2013calcineurin\u2013NFAT system to cause transcriptional downregulation of\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>CaL<\/jats:sub>\n            , restoring Ca\n            <jats:sup>2+<\/jats:sup>\n            <jats:italic>i<\/jats:italic>\n            to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.\n          <\/jats:p>","DOI":"10.1161\/circresaha.108.175463","type":"journal-article","created":{"date-parts":[[2008,8,22]],"date-time":"2008-08-22T02:18:33Z","timestamp":1219371513000},"page":"845-854","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":179,"title":["Cellular Signaling Underlying Atrial Tachycardia Remodeling of L-type Calcium Current"],"prefix":"10.1161","volume":"103","author":[{"given":"Xiao Yan","family":"Qi","sequence":"first","affiliation":[{"name":"From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Universite\u0301 de Montre\u0301al, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) Tao-Yuan, Taiwan; Department of Radiation and Stress Cell Biology, Department of Clinical Pharmacology (B.J.J.M.B.), University Groningen, The Netherlands; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Hsin","family":"Yeh","sequence":"additional","affiliation":[{"name":"From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Universite\u0301 de Montre\u0301al, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) Tao-Yuan, Taiwan; Department of Radiation and Stress Cell Biology, Department of Clinical Pharmacology (B.J.J.M.B.), University Groningen, The Netherlands; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Xiao","sequence":"additional","affiliation":[{"name":"From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Universite\u0301 de Montre\u0301al, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) Tao-Yuan, Taiwan; Department of Radiation and Stress Cell Biology, Department of Clinical Pharmacology (B.J.J.M.B.), University Groningen, The Netherlands; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Burstein","sequence":"additional","affiliation":[{"name":"From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Universite\u0301 de Montre\u0301al, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) Tao-Yuan, Taiwan; Department of Radiation and Stress Cell Biology, Department of Clinical Pharmacology (B.J.J.M.B.), University Groningen, The Netherlands; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ange","family":"Maguy","sequence":"additional","affiliation":[{"name":"From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Universite\u0301 de Montre\u0301al, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) 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Tao-Yuan, Taiwan; Department of Radiation and Stress Cell Biology, Department of Clinical Pharmacology (B.J.J.M.B.), University Groningen, The Netherlands; and..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis R.","family":"Villeneuve","sequence":"additional","affiliation":[{"name":"From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Universite\u0301 de Montre\u0301al, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) 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