{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:48:56Z","timestamp":1791946136966,"version":"4.3.4"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2011,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Mutations in the cardiac Na\n              <jats:sup>+<\/jats:sup>\n              channel gene (\n              <jats:italic>SCN5A<\/jats:italic>\n              ) can adversely affect electric function in the heart, but effects can be age dependent. We explored the interacting effects of\n              <jats:italic>Scn5a<\/jats:italic>\n              disruption and aging on the pathogenesis of sinus node dysfunction in a heterozygous\n              <jats:italic>Scn5a<\/jats:italic>\n              knockout (\n              <jats:italic>Scn5a<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              ) mouse model.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We compared functional, histological, and molecular features in young (3 to 4 month) and old (1 year) wild type and\n              <jats:italic>Scn5a<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice. Both\n              <jats:italic>Scn5a<\/jats:italic>\n              disruption and aging were associated with decreased heart rate variability, reduced sinoatrial node automaticity, and slowed sinoatrial conduction. They also led to increased collagen and fibroblast levels and upregulated transforming growth factor-\u03b2\n              <jats:sub>1<\/jats:sub>\n              (TGF-\u03b2\n              <jats:sub>1<\/jats:sub>\n              ) and vimentin transcripts, providing measures of fibrosis and reduced Nav1.5 expression. All these effects were most noticeable in old\n              <jats:italic>Scn5a<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice. Na\n              <jats:sup>+<\/jats:sup>\n              channel inhibition by Nav1.5-E3 antibody directly increased TGF-\u03b2\n              <jats:sub>1<\/jats:sub>\n              production in both cultured human cardiac myocytes and fibroblasts. Finally, aging was associated with downregulation of a wide range of ion channel and related transcripts and, again, was greatest in old\n              <jats:italic>Scn5a<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice. The quantitative results from these studies permitted computer simulations that successfully replicated the observed sinoatrial node phenotypes shown by the different experimental groups.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              These results implicate a tissue degeneration triggered by Nav1.5 deficiency manifesting as a TGF-\u03b2\n              <jats:sub>1<\/jats:sub>\n              -mediated fibrosis accompanied by electric remodeling in the sinus node dysfunction associated with\n              <jats:italic>Scn5a<\/jats:italic>\n              disruption or aging. The latter effects interact to produce the most severe phenotype in old\n              <jats:italic>Scn5a<\/jats:italic>\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice. In demonstrating this, our findings suggest a novel regulatory role for Nav1.5 in cellular biological processes in addition to its electrophysiologic function.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.110.960807","type":"journal-article","created":{"date-parts":[[2011,4,15]],"date-time":"2011-04-15T03:20:41Z","timestamp":1302837641000},"page":"397-406","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":104,"title":["TGF-\u03b2\n            <sub>1<\/sub>\n            -Mediated Fibrosis and Ion Channel Remodeling Are Key Mechanisms in Producing the Sinus Node Dysfunction Associated With\n            <i>SCN5A<\/i>\n            Deficiency and Aging"],"prefix":"10.1161","volume":"4","author":[{"given":"Xiaojin","family":"Hao","sequence":"first","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmin","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhao","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Nirmalan","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Davies","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Konstantinou","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yin","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halina","family":"Dobrzynski","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Grace","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henggui","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Boyett","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; and Departments of Biochemistry and Physiology, University of Cambridge, Cambridge, UK (Y.Z., A.G., C.L.-H.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.-H.","family":"Huang","sequence":"additional","affiliation":[{"name":"From the School of Biomedicine (X.H., M.N., L.D., D.K., F.Y., H.D., M.R.B., M.L.), School of Physics and Astronomy (X.Z., H.Z.), and Faculty of Life Sciences (X.W.), University of Manchester, Manchester, UK; 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