{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:30:12Z","timestamp":1791387012858,"version":"4.3.3"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R35-HL144980"],"award-info":[{"award-number":["R35-HL144980"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["9SFRN34830019"],"award-info":[{"award-number":["9SFRN34830019"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2021,2,5]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale:<\/jats:title>\n                    <jats:p>The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide\u2019s efficacy in CPVT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>To determine whether RyR2 block independently contributes to flecainide\u2019s efficacy for suppressing spontaneous sarcoplasmic reticulum Ca release and for preventing ventricular tachycardia in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      We synthesized N-methylated flecainide analogues (QX-flecainide and\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -methyl flecainide) and showed that\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -methylation reduces flecainide\u2019s inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers.\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -methylation did not alter flecainide\u2019s inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2\u2212\/\u2212) CPVT mouse model. In membrane-permeabilized Casq2\u2212\/\u2212 cardiomyocytes\u2014lacking intact sarcolemma and devoid of sodium channel contribution\u2014flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2\u2212\/\u2212 cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2\u2212\/\u2212 mice, whereas\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      -methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.120.316819","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T05:02:53Z","timestamp":1607576573000},"page":"321-331","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT"],"prefix":"10.1161","volume":"128","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0427-6587","authenticated-orcid":true,"given":"Dmytro O.","family":"Kryshtal","sequence":"first","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.O.K., D.J.B., C.L.E., B.C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-1792","authenticated-orcid":true,"given":"Daniel J.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.O.K., D.J.B., C.L.E., B.C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1755-7142","authenticated-orcid":true,"given":"Christian L.","family":"Egly","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.O.K., D.J.B., C.L.E., B.C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-1835","authenticated-orcid":true,"given":"Abigail N.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN (A.N.S., S.M.B., J.N.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2150-7516","authenticated-orcid":true,"given":"Suzanne M.","family":"Batiste","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN (A.N.S., S.M.B., J.N.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0885-636X","authenticated-orcid":true,"given":"Jeffrey N.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN (A.N.S., S.M.B., J.N.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9919-7661","authenticated-orcid":true,"given":"Derek R.","family":"Laver","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW, Australia (D.R.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-9735","authenticated-orcid":true,"given":"Bjorn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (D.O.K., D.J.B., C.L.E., B.C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000020013.73106.d8"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/324565"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000038886.18992.6b"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.08.015"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.303391"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06799"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.91.5.1512"},{"key":"e_1_3_6_9_2","volume-title":"Goodman & Gilman\u2019s the Pharmacological Basis of Therapeutics","author":"Brunton LL","year":"2018","unstructured":"Brunton, LL, Knollmann, BC, Hilal-Dandan, R. 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