{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:06:53Z","timestamp":1778717213282,"version":"3.51.4"},"reference-count":56,"publisher":"AIP Publishing","issue":"9","funder":[{"name":"Bridge Funds from the School of Medicine to GS"},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["NSF-1602841"],"award-info":[{"award-number":["NSF-1602841"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,9,1]]},"abstract":"<jats:p>Abnormal Ca2+ handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca2+ release from Ca2+-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca2+-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca2+ elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca2+ dynamics in bradycardia and LQT2. Abnormal systolic Ca2+-oscillations and EADs caused by SR Ca2+-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca2+ while a third gate senses luminal junctional SR Ca2+. The model predicts EADs in bradycardia and low extracellular [K+] and cessation of SR Ca2+-release terminate salvos of EADs. Ca2+-waves, systolic cell-synchronous Ca2+-release, and multifocal diastolic Ca2+ release seen in subcellular Ca2+-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca2+-overload, abnormal SR Ca2+-release, and the subsequent activation of the electrogenic Na+\/Ca2+-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.<\/jats:p>","DOI":"10.1063\/1.5000711","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T14:59:13Z","timestamp":1506437953000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":17,"title":["A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome"],"prefix":"10.1063","volume":"27","author":[{"given":"Dan","family":"Wilson","sequence":"first","affiliation":[{"name":"Department of Mathematics, University of Pittsburgh 1 , Pittsburgh, Pennsylvania 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bard","family":"Ermentrout","sequence":"additional","affiliation":[{"name":"Department of Mathematics, University of Pittsburgh 1 , Pittsburgh, Pennsylvania 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"N\u011bmec","sequence":"additional","affiliation":[{"name":"Department of Medicine, Heart and Vascular Institute, University of Pittsburgh 2 , Pittsburgh, Pennsylvania 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5306-8178","authenticated-orcid":false,"given":"Guy","family":"Salama","sequence":"additional","affiliation":[{"name":"Department of Medicine, Heart and Vascular Institute, University of Pittsburgh 2 , Pittsburgh, Pennsylvania 15261, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"317","published-online":{"date-parts":[[2017,9,26]]},"reference":[{"key":"2023070318213601300_c1","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1161\/CIRCEP.114.002214","article-title":"Synchronous systolic subcellular Ca2+-elevations underlie ventricular arrhythmia in drug-induced long QT type 2","volume":"8","year":"2015","journal-title":"Circ.: Arrhythmia Electrophysiol."},{"key":"2023070318213601300_c2","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation-contraction coupling","volume":"415","year":"2002","journal-title":"Nature"},{"key":"2023070318213601300_c3","first-page":"243","article-title":"Excitation-contraction coupling and regulation of contractility studied on isolated adult myocardial cells","volume":"27","year":"1972","journal-title":"Acta Cardiol."},{"key":"2023070318213601300_c4","first-page":"210A","article-title":"Isolated myocardial cells of adult mammals. 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