{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:06:20Z","timestamp":1778717180360,"version":"3.51.4"},"reference-count":32,"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":[[2009,6]]},"abstract":"<jats:p><jats:bold><jats:italic>Background\u2014<\/jats:italic><\/jats:bold>Sustained bradycardia is associated with long-QT syndrome in human beings and causes spontaneous torsades de pointes in rabbits with chronic atrioventricular block (CAVB), at least partly by downregulating delayed-rectifier K<jats:sup>+<\/jats:sup>-current to cause action potential (AP) prolongation. We addressed the importance of altered Ca<jats:sup>2+<\/jats:sup>handling, studying underlying mechanisms and consequences.<\/jats:p><jats:p><jats:bold><jats:italic>Methods and Results\u2014<\/jats:italic><\/jats:bold>We measured ventricular cardiomyocyte [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>(Indo1-AM), L-type Ca<jats:sup>2+<\/jats:sup>-current (<jats:italic>I<\/jats:italic><jats:sub>CaL<\/jats:sub>) and APs (whole-cell perforated-patch), and Ca<jats:sup>2+<\/jats:sup>-handling protein expression (immunoblot). CAVB increased AP duration, cell shortening, systolic [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>transients, and caffeine-induced [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>release, and CAVB cells showed spontaneous early afterdepolarizations (EADs).<jats:italic>I<\/jats:italic><jats:sub>CaL<\/jats:sub>density was unaffected by CAVB, but inactivation was shifted to more positive voltages, increasing the activation-inactivation overlap zone for<jats:italic>I<\/jats:italic><jats:sub>CaL<\/jats:sub>window current. Ca<jats:sup>2+<\/jats:sup>-calmodulin\u2013dependent protein kinase-II (CaMKII) autophosphorylation was enhanced in CAVB, indicating CaMKII activation. CAVB also enhanced CaMKII-dependent phospholamban-phosphorylation and accelerated [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>-transient decay, consistent with phosphorylation-induced reductions in phospholamban inhibition of sarcoplasmic reticulum (SR) Ca<jats:sup>2+<\/jats:sup>-ATPase as a contributor to enhanced SR Ca<jats:sup>2+<\/jats:sup>loading. The CaMKII-inhibitor KN93 reversed CAVB-induced changes in caffeine-releasable [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>and<jats:italic>I<\/jats:italic><jats:sub>CaL<\/jats:sub>inactivation voltage and suppressed CAVB-induced EADs. Similarly, the calmodulin inhibitor W7 suppressed CAVB-induced<jats:italic>I<\/jats:italic><jats:sub>CaL<\/jats:sub>inactivation voltage shifts and EADs, and a specific CaMKII inhibitory peptide prevented<jats:italic>I<\/jats:italic><jats:sub>CaL<\/jats:sub>inactivation voltage shifts. The SR Ca<jats:sup>2+<\/jats:sup>-uptake inhibitor thapsigargin and the SR Ca<jats:sup>2+<\/jats:sup>release inhibitor ryanodine also suppressed CAVB-induced EADs, consistent with an important role for SR Ca<jats:sup>2+<\/jats:sup>loading and release in arrhythmogenesis. AP-duration changes reached a maximum after 1 week of bradypacing, but peak alterations in CaMKII and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>required 2 weeks, paralleling the EAD time course.<\/jats:p><jats:p><jats:bold><jats:italic>Conclusions\u2014<\/jats:italic><\/jats:bold>CAVB-induced remodeling enhances [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>load and activates the Ca<jats:sup>2+<\/jats:sup>-calmodulin-CaMKII system, producing [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>-handling abnormalities that contribute importantly to CAVB-induced arrhythmogenic afterdepolarizations.<\/jats:p>","DOI":"10.1161\/circep.108.815654","type":"journal-article","created":{"date-parts":[[2009,4,18]],"date-time":"2009-04-18T00:44:32Z","timestamp":1240015472000},"page":"295-304","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":56,"title":["The Calcium\/Calmodulin\/Kinase System and Arrhythmogenic Afterdepolarizations in Bradycardia-Related Acquired Long-QT Syndrome"],"prefix":"10.1161","volume":"2","author":[{"given":"XiaoYan","family":"Qi","sequence":"first","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung-Hsin","family":"Yeh","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denis","family":"Chartier","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Xiao","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiomi","family":"Tsuji","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca J.J.M.","family":"Brundel","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itsuo","family":"Kodama","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley","family":"Nattel","sequence":"additional","affiliation":[{"name":"From the Department of Medicine and Research Center, Montreal Heart Institute and Universite\u0301 de Montre\u0301al (X.Y.Q., Y.-H.Y., D.C., L.X., S.N.), Montreal, Quebec, Canada; the Department of Pharmacology and Therapeutics, McGill University (L.X., S.N.), Montreal, Quebec, Canada; First Cardiovascular Division, Chang Gung Memorial Hospital and Chang Gung University (Y.-H.Y.), Tao-Yuan, Taiwan; the Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University,..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0033-0620(88)90014-X"},{"key":"e_1_3_2_2_2","first-page":"iv4","year":"2007","unstructured":"Antzelevitch C. 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