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The most common form of CPVT is caused by autosomal\u2010dominant variants in the cardiac ryanodine receptor type\u20102 (<jats:italic>RYR2)<\/jats:italic> gene. Mutations in <jats:italic>RYR2<\/jats:italic> promote calcium (Ca<jats:sup>2+<\/jats:sup>) leak from the sarcoplasmic reticulum (SR), triggering lethal arrhythmias. Recently, it was demonstrated that tetracaine derivative EL20 specifically inhibits mutant RyR2, normalizes Ca<jats:sup>2+<\/jats:sup> handling and suppresses arrhythmias in a CPVT mouse model. The objective of this study was to determine whether EL20 normalizes SR Ca<jats:sup>2+<\/jats:sup> handling and arrhythmic events in induced pluripotent stem cell\u2010derived cardiomyocytes (iPSC\u2010CMs) from a CPVT patient. Blood samples from a child carrying RyR2 variant RyR2 variant Arg\u2010176\u2010Glu (R176Q) and a mutation\u2010negative relative were reprogrammed into iPSCs using a Sendai virus system. iPSC\u2010CMs were derived using the Stemdiff<jats:sup>TM<\/jats:sup> kit. Confocal Ca<jats:sup>2+<\/jats:sup> imaging was used to quantify RyR2 activity in the absence and presence of EL20. iPSC\u2010CMs harbouring the R176Q variant demonstrated spontaneous SR Ca<jats:sup>2+<\/jats:sup> release events, whereas administration of EL20 diminished these abnormal events at low nanomolar concentrations (IC<jats:sub>50<\/jats:sub>\u00a0=\u00a082\u00a0nM). Importantly, treatment with EL20 did not have any adverse effects on systolic Ca<jats:sup>2+<\/jats:sup> handling in control iPSC\u2010CMs. Our results show for the first time that tetracaine derivative EL20 normalized SR Ca<jats:sup>2+<\/jats:sup> handling and suppresses arrhythmogenic activity in iPSC\u2010CMs derived from a CPVT patient. Hence, this study confirms that this RyR2\u2010inhibitor represents a promising therapeutic candidate for treatment of CPVT.<\/jats:p>","DOI":"10.1111\/jcmm.16521","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T23:09:27Z","timestamp":1623366567000},"page":"6115-6124","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell\u2010derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia"],"prefix":"10.1111","volume":"25","author":[{"given":"Tarah A.","family":"Word","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology &amp; Biophysics Cardiovascular Research Institute Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann P.","family":"Quick","sequence":"additional","affiliation":[{"name":"Section of Cardiology Department of Pediatrics Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Y.","family":"Miyake","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology &amp; Biophysics Cardiovascular Research Institute Baylor College of Medicine Houston TX USA"},{"name":"Section of Cardiology Department of Pediatrics Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra K.","family":"Shak","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology &amp; Biophysics Cardiovascular Research Institute Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolu","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology &amp; Biophysics Cardiovascular Research Institute Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Cellular Biology Stem Cells and Regenerative Medicine Center Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh D.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Cellular Biology Stem Cells and Regenerative Medicine Center Baylor College of Medicine Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Sibrian\u2010Vazquez","sequence":"additional","affiliation":[{"name":"Elex Biotech Inc Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Strongin","sequence":"additional","affiliation":[{"name":"Department of Chemistry Portland State University Portland OR USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1878-9631","authenticated-orcid":false,"given":"Andrew P.","family":"Landstrom","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Cardiology Duke University School of Medicine Durham NC USA"},{"name":"Department of Cell Biology Duke University School of Medicine Durham NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5044-672X","authenticated-orcid":false,"given":"Xander H. 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