{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T17:45:20Z","timestamp":1774460720332,"version":"3.50.1"},"reference-count":77,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2016,1,15]],"date-time":"2016-01-15T00:00:00Z","timestamp":1452816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Cardiac alternans \u2013 periodic beat\u2010to\u2010beat alternations in contraction, action potential (AP) morphology or cytosolic calcium transient (CaT) amplitude \u2013 is a high risk indicator for cardiac arrhythmias and sudden cardiac death. However, it remains an unresolved issue whether beat\u2010to\u2010beat alternations in intracellular Ca<jats:sup>2+<\/jats:sup> ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) or AP morphology are the primary cause of pro\u2010arrhythmic alternans.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Here we show that in atria AP alternans occurs secondary to CaT alternans.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>CaT alternans leads to complex beat\u2010to\u2010beat changes in Ca<jats:sup>2+<\/jats:sup>\u2010regulated ion currents that determine alternans of AP morphology.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We report the novel finding that alternans of AP morphology is largely sustained by the activity of Ca<jats:sup>2+<\/jats:sup>\u2010activated Cl<jats:sup>\u2212<\/jats:sup> channels (CaCCs). Suppression of the CaCCs significantly reduces AP alternans, while CaT alternans remains unaffected.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The demonstration of a major role of CaCCs in the development of AP alternans opens new possibilities for atrial alternans and arrhythmia prevention.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Cardiac alternans, described as periodic beat\u2010to\u2010beat alternations in contraction, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude, is a high risk indicator for cardiac arrhythmias and sudden cardiac death. We investigated mechanisms of cardiac alternans in single rabbit atrial myocytes. CaTs were monitored simultaneously with membrane currents or APs recorded with the patch clamp technique. Beat\u2010to\u2010beat alternations of AP morphology and CaT amplitude revealed a strong quantitative correlation. Application of voltage clamp protocols in the form of pre\u2010recorded APs (AP\u2010clamp) during pacing\u2010induced CaT alternans revealed a Ca<jats:sup>2+<\/jats:sup>\u2010dependent current consisting of a large outward component (4.78\u00a0\u00b1\u00a00.58\u00a0pA\u00a0pF<jats:sup>\u20131<\/jats:sup> in amplitude) coinciding with AP phases 1 and 2 that was followed by an inward current (\u22120.42\u00a0\u00b1\u00a00.03\u00a0pA\u00a0pF<jats:sup>\u20131<\/jats:sup>; <jats:italic>n<\/jats:italic>\u00a0=\u00a021) during AP repolarization. Approximately 90% of the initial outward current was blocked by substitution of Cl<jats:sup>\u2212<\/jats:sup> ions or application of the Cl<jats:sup>\u2212<\/jats:sup> channel blocker DIDS identifying it as a Ca<jats:sup>2+<\/jats:sup>\u2010activated Cl<jats:sup>\u2212<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub>CaCC<\/jats:sub>). The prominent AP prolongation at action potential duration at 30% repolarization level during the small alternans CaT was due to reduced <jats:italic>I<\/jats:italic><jats:sub>CaCC<\/jats:sub>. Inhibition of Cl<jats:sup>\u2212<\/jats:sup> currents abolished AP alternans, but failed to affect CaT alternans, indicating that disturbances in Ca<jats:sup>2+<\/jats:sup> signalling were the primary event leading to alternans, and <jats:italic>I<\/jats:italic><jats:sub>CaCC<\/jats:sub> played a decisive role in shaping the beat\u2010to\u2010beat alternations in AP morphology observed during alternans.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp271887","type":"journal-article","created":{"date-parts":[[2015,12,11]],"date-time":"2015-12-11T09:42:56Z","timestamp":1449826976000},"page":"699-714","source":"Crossref","is-referenced-by-count":19,"title":["Calcium\u2010activated chloride current determines action potential morphology during calcium alternans in atrial myocytes"],"prefix":"10.1113","volume":"594","author":[{"given":"Giedrius","family":"Kanaporis","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Physiology Rush University Medical Center  Chicago IL 60612 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lothar A.","family":"Blatter","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Physiology Rush University Medical Center  Chicago IL 60612 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,1,15]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.067959"},{"key":"e_1_2_6_3_1","volume-title":"Patch Clamp Tecnique","author":"Chen\u2010Izu 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