{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:25:32Z","timestamp":1791491132192,"version":"4.3.4"},"reference-count":41,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["NHLBI R35 HL144980 (BCK),NHLBI R01 HL151223"],"award-info":[{"award-number":["NHLBI R35 HL144980 (BCK),NHLBI R01 HL151223"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,8]]},"abstract":"<jats:p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmia syndrome caused by gene mutations that render RYR2 Ca release channels hyperactive, provoking spontaneous Ca release and delayed afterdepolarizations (DADs). What remains unknown is the cellular source of ventricular arrhythmia triggered by DADs: Purkinje cells in the conduction system or ventricular cardiomyocytes in the working myocardium. To answer this question, we used a genetic approach in mice to knock out cardiac calsequestrin either in Purkinje cells or in ventricular cardiomyocytes. Total loss of calsequestrin in the heart causes a severe CPVT phenotype in mice and humans. We found that loss of calsequestrin only in ventricular myocytes produced a full-blown CPVT phenotype, whereas mice with loss of calsequestrin only in Purkinje cells were comparable to WT mice. Subendocardial chemical ablation or restoration of calsequestrin expression in subendocardial cardiomyocytes neighboring Purkinje cells was sufficient to protect against catecholamine-induced arrhythmias. In silico modeling demonstrated that DADs in ventricular myocardium can trigger full action potentials in the Purkinje fiber, but not vice versa. Hence, ectopic beats in CPVT are likely generated at the Purkinje\u2013myocardial junction via a heretofore unrecognized tissue mechanism, whereby DADs in the ventricular myocardium trigger full action potentials in adjacent Purkinje cells.<\/jats:p>","DOI":"10.1172\/jci.insight.151893","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T12:00:36Z","timestamp":1641470436000},"source":"Crossref","is-referenced-by-count":34,"title":["The Purkinje\u2013myocardial junction is the anatomic origin of ventricular arrhythmia in CPVT"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-1792","authenticated-orcid":true,"given":"Daniel J.","family":"Blackwell","sequence":"first","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Faggioni","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1198-2834","authenticated-orcid":true,"given":"Matthew J.","family":"Wleklinski","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA."},{"name":"Department of Pharmacology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nieves","family":"Gomez-Hurtado","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghav","family":"Venkataraman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea E.","family":"Gibbs","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Washington, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz J.","family":"Baudenbacher","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiaoching","family":"Gong","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Rockefeller University, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenn I.","family":"Fishman","sequence":"additional","affiliation":[{"name":"Leon H. 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