{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T09:28:00Z","timestamp":1774344480355,"version":"3.50.1"},"reference-count":57,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,12,2]],"date-time":"2014-12-02T00:00:00Z","timestamp":1417478400000},"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":[[2015,3,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Atrial fibrillation is often initiated and perpetuated by abnormal electrical pulses repetitively originating from regions outside the heart's natural pacemaker.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>In this study we examined the causal role of abnormal calcium releases from the sarcoplasmic reticulum in producing repetitive electrical discharges in atrial cells and tissues.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Calsequestrin2 is a protein that stabilizes the closed state of calcium release channels, i.e. the ryanodine receptors. In the atria from mice predisposed to abnormal calcium releases secondary to the absence of calsequestrin2, we observed abnormal repetitive electrical discharges that may lead to atrial fibrillation.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Here, we report a novel pathological rhythm generator. Specifically, abnormal calcium release leads to electrical activation, which in turn results in another abnormal calcium release. This process repeats itself and thus sustains the repetitive electrical discharges.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>These results suggest that improving the stability of ryanodine receptors might be useful to treat atrial fibrillation.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Aberrant diastolic calcium (Ca) release due to leaky ryanodine receptors (RyR2s) has been recently associated with atrial fibrillation (AF) and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, it remains unclear how diastolic Ca release contributes to the rising of rapid repetitive focal activity, which is considered as a common AF triggering mechanism. To address this question, we conducted simultaneous voltage\/Ca optical mapping in atrial tissue and one\u2010\/two\u2010dimensional confocal imaging in atrial tissue and myocytes from wild\u2010type (WT,<jats:italic>n<\/jats:italic>\u00a0=\u00a015) and CPVT mice lacking calsequestrin 2 (<jats:italic>Casq2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>,<jats:italic>n<\/jats:italic>\u00a0=\u00a045), which promotes diastolic Ca release. During \u03b2\u2010adrenergic stimulation (100\u00a0n<jats:sc>m<\/jats:sc>isoproterenol), only<jats:italic>Casq2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>\u00a0atrial myocytes showed pacing\u2010induced self\u2010sustained repetitive activity (31\u00a0\u00b1\u00a021\u00a0s<jats:italic>vs<\/jats:italic>. none in WT). Importantly, in atrial tissue, this repetitive activity could translate to Ca\u2010dependent focal arrhythmia. Ectopic action potential (AP) firing during repetitive activity occurred only when diastolic Ca release achieved a sufficient level of synchronization. The AP, in turn, synchronized subsequent diastolic Ca release by temporally aligning multiple sources of Ca waves both within individual myocytes and throughout the atrial tissue. This alternating interplay between AP and diastolic Ca release perpetuates the self\u2010sustaining repetitive activity. In fact, pharmacological disruption of synchronized diastolic Ca release (by ryanodine) prevented aberrant APs; and vice versa, the inhibition of AP (by TTX or 0 Na, 0 Ca solution) de\u2010synchronized diastolic Ca release. Taken together, these results suggest that a cyclical interaction between synchronized diastolic Ca release and AP forms a pathological rhythm generator that is involved in Ca\u2010dependent atrial arrhythmias in CPVT.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.280784","type":"journal-article","created":{"date-parts":[[2014,11,11]],"date-time":"2014-11-11T05:09:21Z","timestamp":1415682561000},"page":"1443-1458","source":"Crossref","is-referenced-by-count":24,"title":["Alternating membrane potential\/calcium interplay underlies repetitive focal activity in a genetic model of calcium\u2010dependent atrial arrhythmias"],"prefix":"10.1113","volume":"593","author":[{"given":"Qing","family":"Lou","sequence":"first","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andriy E.","family":"Belevych","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Przemys\u0142aw B.","family":"Radwa\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"},{"name":"Division of Pharmacy Practice and Administration College of Pharmacy The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuradha","family":"Kalyanasundaram","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bjorn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Vanderbilt University Nashville TN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vadim V.","family":"Fedorov","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e1ndor","family":"Gy\u00f6rke","sequence":"additional","affiliation":[{"name":"Department of Physiology &amp; Cell Biology, College of Medicine The Ohio State University Columbus OH USA"},{"name":"Davis Heart &amp; Lung Research Institute The Ohio State University Columbus OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,12,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.73.5.813"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.260455"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.65.1.115"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.70.113006.100455"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.711606"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1996.tb15505.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300052110"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-1-18"},{"key":"e_1_2_6_10_1","first-page":"1940","article-title":"Calmodulin kinase II\u2010mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice","volume":"119","author":"Chelu MG","year":"2009","journal-title":"J Clin Invest"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60096-7"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.113.000994"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.12.047"},{"key":"e_1_2_6_14_1","article-title":"Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex","author":"Glukhov AV","year":"2013","journal-title":"Eur Heart J"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.285.18.2370"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0b013e31828124ad"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199809033391003"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/309453a0"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt233"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.9.725"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000141296.59876.87"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.11.014"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.95.3.572"},{"key":"e_1_2_6_24_1","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0031-6997(25)00019-5","article-title":"Delayed afterdepolarizations in heart muscle: mechanisms and relevance","volume":"40","author":"January CT","year":"1988","journal-title":"Pharmacol Rev"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1978.sp012416"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2011.02.003"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12006"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00025.2003"},{"key":"e_1_2_6_29_1","first-page":"2510","article-title":"Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia","volume":"116","author":"Knollmann BC","year":"2006","journal-title":"J Clin Invest"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.206078"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.264689"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.989707"},{"key":"e_1_2_6_33_1","first-page":"A10945","article-title":"Calsequestrin 2 deletion causes abnormal atrial automaticity and conduction associated with degenerative fibrosis of the sinoatrial node pacemaker complex","volume":"126","author":"Lou Q","year":"2012","journal-title":"Circulation"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01118.2008"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.595140"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.279638"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.262345"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehs079"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.203836"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2008.01211.x"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.10.008"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.772715"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.87.9.774"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/303535a0"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.273342"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.71.1606"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2006"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000032490.04207.BD"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000252828.17939.00"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvm009"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.006641"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.067306"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46315"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.229294"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2006.12.021"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.41.4.434"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2010.06.042"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.183236"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.2014.280784","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.2014.280784","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T16:35:49Z","timestamp":1747154149000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.2014.280784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,2]]},"references-count":57,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,3,15]]}},"alternative-id":["10.1113\/jphysiol.2014.280784"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.2014.280784","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,2]]}}}