{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:28:21Z","timestamp":1790645301118,"version":"4.1.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              STIM1 (stromal interaction molecule 1) is a calcium (Ca\n              <jats:sup>2+<\/jats:sup>\n              ) sensor that regulates cardiac hypertrophy by triggering store-operated Ca\n              <jats:sup>2+<\/jats:sup>\n              entry. Because STIM1 binding to phospholamban increases sarcoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              load independent of store-operated Ca\n              <jats:sup>2+<\/jats:sup>\n              entry, we hypothesized that it controls electrophysiological function and arrhythmias in the adult heart.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Inducible myocyte-restricted STIM1-KD (STIM1 knockdown) was achieved in adult mice using an \u03b1MHC (\u03b1-myosin heavy chain)-MerCreMer system. Mechanical and electrophysiological properties were examined using echocardiography in vivo and optical action potential (AP) mapping ex vivo in tamoxifen-induced STIM1\n              <jats:sup>flox\/flox<\/jats:sup>\n              -Cre\n              <jats:sup>tg<\/jats:sup>\n              <jats:sup>\/\u2212<\/jats:sup>\n              (STIM1-KD) and littermate controls for STIM1\n              <jats:sup>flox\/flox<\/jats:sup>\n              (referred to as STIM1-Ctl) and for Cre\n              <jats:sup>tg\/\u2212<\/jats:sup>\n              without STIM deletion (referred to as Cre-Ctl).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              STIM1-KD mice (N=23) exhibited poor survival compared with STIM1-Ctl (N=22) and Cre-Ctl (N=11) with &gt;50% mortality after only 8-days of cardiomyocyte-restricted STIM1-KD. STIM1-KD but not STIM1-Ctl or Cre-Ctl hearts exhibited a proclivity for arrhythmic behavior, ranging from frequent ectopy to pacing-induced ventricular tachycardia\/ventricular fibrillation (VT\/VF). Examination of the electrophysiological substrate revealed decreased conduction velocity and increased AP duration (APD) heterogeneity in STIM1-KD. These features, however, were comparable in VT\/VF(+) and VT\/VF(\u2212) hearts. We also uncovered a marked increase in the magnitude of APD alternans during rapid pacing, and the emergence of a spatially discordant alternans profile in STIM1-KD hearts. Unlike conduction velocity slowing and APD heterogeneity, the magnitude of APD alternans was greater (by 80%,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05) in VT\/VF(+) versus VT\/VF(\u2212) STIM1-KD hearts. Detailed phase mapping during the initial beats of VT\/VF identified one or more rotors that were localized along the nodal line separating out-of-phase alternans regions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>In an adult murine model with inducible and myocyte-specific STIM1 depletion, we demonstrate for the first time the regulation of spatially discordant alternans by STIM1. Early mortality in STIM1-KD mice is likely related to enhanced susceptibility to VT\/VF secondary to discordant APD alternans.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.119.007382","type":"journal-article","created":{"date-parts":[[2019,11,15]],"date-time":"2019-11-15T10:00:20Z","timestamp":1573812020000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans"],"prefix":"10.1161","volume":"12","author":[{"given":"Marine","family":"Cacheux","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Strauss","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Raad","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeki","family":"Ilkan","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Benard","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Feske","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University School of Medicine (S.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Sebastien","family":"Hulot","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., F.G.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi G.","family":"Akar","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Division of Cardiology, Icahn School of Medicine at Mount Sinai (M.C., B.S., N.R., Z.I., J.H., L.B., J.-S.H., 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