{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:41:53Z","timestamp":1784774513807,"version":"3.55.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Arrhythmia and Electrophysiology"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Arrhythmia syndromes associated with\n              <jats:italic>KCNJ2<\/jats:italic>\n              mutations have been described clinically; however, little is known of the underlying arrhythmia mechanism. We create the first patient inspired\n              <jats:italic>KCNJ2<\/jats:italic>\n              transgenic mouse and study effects of this mutation on cardiac function,\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>K1<\/jats:sub>\n              , and Ca\n              <jats:sup>2+<\/jats:sup>\n              handling, to determine the underlying cellular arrhythmic pathogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              A cardiac-specific\n              <jats:italic>KCNJ2<\/jats:italic>\n              -R67Q mouse was generated and bred for heterozygosity (R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              ). Echocardiography was performed at rest, under anesthesia. In vivo ECG recording and whole heart optical mapping of intact hearts was performed before and after adrenergic stimulation in wild-type (WT) littermate controls and R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice.\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>K1<\/jats:sub>\n              measurements, action potential characterization, and intracellular Ca\n              <jats:sup>2+<\/jats:sup>\n              imaging from isolated ventricular myocytes at baseline and after adrenergic stimulation were performed in WT and R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice (n=17) showed normal cardiac function, structure, and baseline electrical activity compared with WT (n=10). Following epinephrine and caffeine, only the R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              mice had bidirectional ventricular tachycardia, ventricular tachycardia, frequent ventricular ectopy, and\/or bigeminy and optical mapping demonstrated high prevalence of spontaneous and sustained ventricular arrhythmia. Both R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              (n=8) and WT myocytes (n=9) demonstrated typical n-shaped\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>K1<\/jats:sub>\n              <jats:italic>IV<\/jats:italic>\n              relationship; however, following isoproterenol, max outward\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>K1<\/jats:sub>\n              increased by \u224820% in WT but decreased by \u224824% in R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01). R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              myocytes (n=5) demonstrated prolonged action potential duration at 90% repolarization and after 10 nmol\/L isoproterenol compared with WT (n=7;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05). Ca\n              <jats:sup>2+<\/jats:sup>\n              transient amplitude, 50% decay rate, and sarcoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              content were not different between WT (n=18) and R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              (n=16) myocytes. R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              myocytes (n=10) under adrenergic stimulation showed frequent spontaneous development of early afterdepolarizations that occurred at phase 3 of action potential repolarization.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              <jats:italic>KCNJ2<\/jats:italic>\n              mutation R67Q\n              <jats:sup>+\/\u2212<\/jats:sup>\n              causes adrenergic-dependent loss of\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>K1<\/jats:sub>\n              during terminal repolarization and vulnerability to phase 3 early afterdepolarizations. This model clarifies a heretofore unknown arrhythmia mechanism and extends our understanding of treatment implications for patients with\n              <jats:italic>KCNJ2<\/jats:italic>\n              mutation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circep.120.008638","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T15:35:32Z","timestamp":1596555332000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Genetic Loss of\n            <i>I<\/i>\n            <sub>K1<\/sub>\n            Causes Adrenergic-Induced Phase 3 Early Afterdepolariz ations and Polymorphic and Bidirectional Ventricular Tachycardia"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-1708","authenticated-orcid":true,"given":"Louise","family":"Reilly","sequence":"first","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0552-9029","authenticated-orcid":true,"given":"Francisco J.","family":"Alvarado","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Lang","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Abozeid","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Van Ert","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordell","family":"Spellman","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrett","family":"Warden","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan C.","family":"Makielski","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-9688","authenticated-orcid":true,"given":"Alexey V.","family":"Glukhov","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin-Madison."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5792-064X","authenticated-orcid":true,"given":"Lee L.","family":"Eckhardt","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Arrhythmia Research Program, Division of Cardiovascular Medicine, Department of Medicine, University of 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