{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T03:56:07Z","timestamp":1790135767280,"version":"4.0.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,11,17]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in\n              <jats:italic>CALM1<\/jats:italic>\n              resulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy. The objectives of the present study were to determine if mice carrying the N98S mutation knocked into\n              <jats:italic>Calm1<\/jats:italic>\n              replicate the human arrhythmia phenotype and to examine arrhythmia mechanisms.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Mouse lines heterozygous for the Calm1\n              <jats:sup>N98S<\/jats:sup>\n              allele (Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              ) were generated using CRISPR\/Cas9 technology. Adult mutant mice and their wildtype littermates (Calm1\n              <jats:sup>+\/+<\/jats:sup>\n              ) underwent electrocardiographic monitoring. Ventricular de- and repolarization was assessed in isolated hearts using optical voltage mapping. Action potentials and whole-cell currents and [Ca\n              <jats:sup>2+<\/jats:sup>\n              ]\n              <jats:sub>i<\/jats:sub>\n              , as well, were measured in single ventricular myocytes using the patch-clamp technique and fluorescence microscopy, respectively. The microelectrode technique was used for in situ membrane voltage monitoring of ventricular conduction fibers.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Two biologically independent knock-in mouse lines heterozygous for the Calm1\n              <jats:sup>N98S<\/jats:sup>\n              allele were generated. Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              mice of either sex and line exhibited sinus bradycardia, QT\n              <jats:sub>c<\/jats:sub>\n              interval prolongation, and catecholaminergic bidirectional ventricular tachycardia. Male mutant mice also showed QRS widening. Pharmacological blockade and activation of \u03b2-adrenergic receptors rescued and exacerbated, respectively, the long-QT phenotype of Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              mice. Optical and electric assessment of membrane potential in isolated hearts and single left ventricular myocytes, respectively, revealed \u03b2-adrenergically induced delay of repolarization. \u03b2-Adrenergic stimulation increased peak density, slowed inactivation, and left-shifted the activation curve of\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Ca.L<\/jats:sub>\n              significantly more in Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              versus Calm1\n              <jats:sup>+\/+<\/jats:sup>\n              ventricular myocytes, increasing late\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Ca.L<\/jats:sub>\n              in the former. Rapidly paced Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              ventricular myocytes showed increased propensity to delayed afterdepolarization-induced triggered activity, whereas in situ His-Purkinje fibers exhibited increased susceptibility for pause-dependent early afterdepolarizations. Epicardial mapping of Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              hearts showed that both reentry and focal mechanisms contribute to arrhythmogenesis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Heterozygosity for the\n              <jats:italic>Calm1<\/jats:italic>\n              <jats:sup>N98S<\/jats:sup>\n              mutation is causative of an arrhythmia syndrome characterized by sinus bradycardia, QRS widening, adrenergically mediated QTc interval prolongation, and bidirectional ventricular tachycardia. \u03b2-Adrenergically induced\n              <jats:italic>I<\/jats:italic>\n              <jats:sub>Ca.L<\/jats:sub>\n              dysregulation contributes to the long-QT phenotype. Pause-dependent early afterdepolarizations and tachycardia-induced delayed afterdepolarizations originating in the His-Purkinje network and ventricular myocytes, respectively, constitute potential sources of arrhythmia in Calm1\n              <jats:sup>N98S\/+<\/jats:sup>\n              hearts.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.120.046450","type":"journal-article","created":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T09:00:37Z","timestamp":1600160437000},"page":"1937-1955","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S\n            <i>Calm1<\/i>\n            Mutation"],"prefix":"10.1161","volume":"142","author":[{"given":"Wen-Chin","family":"Tsai","sequence":"first","affiliation":[{"name":"The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (W.-C.T., S.G., M.A.O., J.Y., C.-P.C. P.-S.C., M.R.), Indiana University School of Medicine, Indianapolis."},{"name":"Department of Cardiology, Cardiovascular Research Center, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan (W.-C.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Guo","sequence":"additional","affiliation":[{"name":"The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (W.-C.T., S.G., M.A.O., J.Y., C.-P.C. P.-S.C., M.R.), Indiana University School of Medicine, Indianapolis."},{"name":"Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China (S.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Olaopa","sequence":"additional","affiliation":[{"name":"The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (W.-C.T., S.G., M.A.O., J.Y., C.-P.C. P.-S.C., M.R.), Indiana University School of Medicine, Indianapolis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5434-6187","authenticated-orcid":true,"given":"Loren J.","family":"Field","sequence":"additional","affiliation":[{"name":"Wells Center for Pediatric Research, Department of Pediatrics (L.J.F., M.R.), Indiana University School of Medicine, Indianapolis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (W.-C.T., S.G., M.A.O., J.Y., C.-P.C. P.-S.C., M.R.), Indiana University School of Medicine, Indianapolis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyu","family":"Shen","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (C.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8790-3445","authenticated-orcid":true,"given":"Ching-Pin","family":"Chang","sequence":"additional","affiliation":[{"name":"The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (W.-C.T., S.G., M.A.O., J.Y., C.-P.C. P.-S.C., M.R.), Indiana University School of Medicine, Indianapolis."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine (W.-C.T., S.G., M.A.O., J.Y., C.-P.C. 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