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Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload

dc.contributor.authorHwang, Hyun Seok
dc.contributor.authorBaldo, Marcelo P.
dc.contributor.authorRodriguez, Jose Pindado
dc.contributor.authorFaggioni, Michela
dc.contributor.authorKnollmann, Bjorn C.
dc.identifier.citationHwang HS, Baldo MP, Rodriguez JP, Faggioni M and Knollmann BC (2019) Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload. Front. Physiol. 10:992. doi: 10.3389/fphys.2019.00992en_US
dc.description.abstractBackground: The dual Na+ and cardiac Ca2+-release channel inhibitor, Flecainide (FLEC) is effective in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by mutations in cardiac Ca2+ -release channels (RyR2), calsequestrin (Casq2), or calmodulin. FLEC suppresses spontaneous Ca2+ waves in Casq2-knockout (Casq2(-/-) ) cardiomyocytes, a CPVT model. However, a report failed to find FLEC efficacy against Ca2+ waves in another CPVT model, RyR2-R4496C heterozygous mice (RyR2(R)(4496)(C+/-)), raising the possibility that FLEC efficacy may be mutation dependent. Objective: To address this controversy, we compared FLEC in Casq2(-/-) and RyR2(R)(4496)(C+ /-) cardiomyocytes and mice under identical conditions. Methods: After 30 min exposure to FLEC (6 mu M) or vehicle (VEH), spontaneous Ca2+ waves were quantified during a 40 s pause after 1 Hz pacing train in the presence of isoproterenol (ISO, 1 mu M). FLEC efficacy was also tested in vivo using a low dose (LOW: 3 mg/kg ISO + 60 mg/kg caffeine) or a high dose catecholamine challenge (HIGH: 3 mg/kg ISO + 120 mg/kg caffeine). Results: In cardiomyocytes, FLEC efficacy was dependent on extracellular [Ca2+]. At 2 mM [Ca2+], only Casq2(-/-) myocytes exhibited Ca2+ waves, which were strongly suppressed by FLEC. At 3 mM [Ca2+] both groups exhibited Ca2+ waves that were suppressed by FLEC. At 4 mM [Ca2+], FLEC no longer suppressed Ca2+ waves in both groups. Analogous to the results in myocytes, RyR2(R)(4496C)(+/- )mice (n = 12) had significantly lower arrhythmia scores than Casq2(-/-) mice (n = 9), but the pattern of FLEC efficacy was similar in both groups (i.e., reduced FLEC efficacy after HIGH dose catecholamine challenge). Conclusion: FLEC inhibits Ca2+ waves in RyR2(R4496)(C+/-) cardiomyocytes, indicating that RyR2 channel block by FLEC is not mutation-specific. However, FLEC efficacy is reduced by Ca2+ overload in vitro or by high dose catecholamine challenge in vivo, which could explain conflicting literature reports.en_US
dc.description.sponsorshipThis work was partly supported by the U.S. National Institutes of Health (R35HL144980, R01HL124935 to BK), the American Heart Association Strategically Focused Research Network on Arrhythmia and Sudden Cardiac Death (19SFRN34910022 to BK), Scientist Development Grant (12SDG12050597 to HH), and the Leducq Foundation (18CVD05 to BK).en_US
dc.publisherFrontiers in Physiologyen_US
dc.rightsCopyright © 2019 Hwang, Baldo, Rodriguez, Faggioni and Knollmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.subjectcatecholaminergic polymorphic ventricular tachycardiaen_US
dc.subjectcalcium overloaden_US
dc.subjectcalsequestrin (Casq2)en_US
dc.subjectcardiac ryanodine receptor (RyR2)en_US
dc.titleEfficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overloaden_US

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