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• W2075799570 abstract "HomeCirculation ResearchVol. 109, No. 6Mechanism of Antiarrhythmic Effects of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBMechanism of Antiarrhythmic Effects of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Hiroshi Watanabe, Derek S. Steele and Björn C. Knollmann Hiroshi WatanabeHiroshi Watanabe Search for more papers by this author , Derek S. SteeleDerek S. Steele Search for more papers by this author and Björn C. KnollmannBjörn C. Knollmann Search for more papers by this author Originally published2 Sep 2011https://doi.org/10.1161/CIRCRESAHA.111.251322Circulation Research. 2011;109:712–713To The Editor:We read with interest the recent article by Liu et al, in Circulation Research, on the mechanism underlying the antiarrhythmic effects of flecainide in catecholaminergic polymorphic ventricular tachycardia (CPVT).1 They conclude that Na+ channel block but not inhibition of the cardiac ryanodine receptor (RyR2) has a key role in the antiarrhythmic effects of flecainide in CPVT, because they found flecainide suppresses triggered activity without a reduction of Ca2+ waves in RyR2R4496C+/− mice. However, we have previously reported that flecainide directly inhibits RYR2 and thereby prevents CPVT.2 Evidence that flecainide reduces the frequency of triggered beats to a greater extent than that of spontaneous Ca2+ waves in cardiac calsequestrin Casq2 null (Casq2−/−) mice, another model of CPVT, led us to propose a dual mode of flecainide action in CPVT: suppression of spontaneous Ca2+ release from sarcoplasmic reticulum by RyR2 inhibition and suppression of triggered beats by Na+ channel block.2Our studies with a range of sodium channel blockers support a role for RyR2 block in this setting. In our first report, we found that lidocaine, which does not inhibit RyR2, fails to suppress CPVT at a dose that produces similar Na+ channel block to a dose of flecainide that completely suppresses CPVT,2 which supports a direct role for RyR2 inhibition in this setting. The importance of RyR2 inhibition is further corroborated by our recent study, which tested the effects of all class I antiarrhythmic drugs clinically available in the Unites States in Casq2−/− mice.3 We found that RyR2 inhibition and Ca2+ wave suppression in vitro determined the antiarrhythmic efficacy against CPVT in vivo.3 The importance of RyR2 inhibition for preventing CPVT has also been confirmed by the recent report of the Chen group.4One of the points of difference between the data of Liu et al and our work is the effect of flecainide on sarcoplasmic reticulum Ca2+ sparks: no apparent effect in RyR2R4496C+/− cells in the study by Liu et al1 and an increase in Ca2+ spark frequency and reduction of spark amplitude, width, and overall spark mass in mouse and rat myocytes in our studies.5,6 The discrepancy may relate to experimental conditions, because the basal Ca2+ spark frequency in the experiments by Liu et al is several fold higher than that of our experiments.1,5 If Ca2+ spark frequency is already very high, it may be difficult to detect any further increases caused by flecainide.Another possible explanation for the reported discrepancy is that flecainide may be less effective against mutant RyR2R4496C+/− channels than wild-type RyR2 channels in the setting of Casq2 deletion. However, the Fishman group7 has reported that flecainide is effective in suppressing Ca2+ waves in Purkinje cells from the same RyR2R4496C+/− mouse model studied by Liu et al.1 Furthermore, we reported that flecainide and propafenone (which also blocks RyR2 channels) were effective in CPVT patients carrying mutations in RYR2,2,3 whereas other sodium channel blockers that did not inhibit RyR2 in our experiments were ineffective in CPVT patients.8–10Taken together, these clinical and experimental findings suggest that both Na+ channel block and RyR2 inhibition are important for the antiarrhythmic effects of flecainide in CPVT. The interesting results reported by Liu et al1 show that more experiments are needed to fully define the mechanisms of drug action in CPVT patients.Hiroshi Watanabe Division of Cardiology Niigata University Graduate School of Medical and Dental Sciences Niigata, Japan E-mail [email protected]Derek S. Steele Institute of Membrane and Systems Biology Faculty of Biological Sciences University of Leeds Leeds, United KingdomBjürn C. Knollmann Oates Institute for Experimental Therapeutics Vanderbilt University School of Medicine Nashville, TNSources of FundingSupported by National Institutes of Health grants HL88635 and HL71670 (B.C.K), and grants from Ministries of Health, Labor, and Welfare of Japan (2010-145) and Education, Culture, Sports, Science and Technology of Japan (2010-22790696; H.W).DisclosuresNone.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment. References 1. Liu N, Denegri M, Ruan Y, Avelino-Cruz JE, Perissi A, Negri S, Napolitano C, Coetzee WA, Boyden PA, Priori SG. Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res. 2011; 109:291–295.LinkGoogle Scholar2. Watanabe H, Chopra N, Laver D, Hwang HS, Davies SS, Roach DE, Duff HJ, Roden DM, Wilde AA, Knollmann BC. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009; 15:380–383.CrossrefMedlineGoogle Scholar3. Hwang HS, Hasdemir C, Laver D, Mehra D, Turhan K, Faggioni M, Yin H, Knollmann BC. Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol. 2011; 4:128–135.LinkGoogle Scholar4. Zhou Q, Xiao J, Jiang D, Wang R, Vembaiyan K, Wang A, Smith CD, Xie C, Chen W, Zhang J, Tian X, Jones PP, Zhong X, Guo A, Chen H, Zhang L, Zhu W, Yang D, Li X, Chen J, Gillis AM, Duff HJ, Cheng H, Feldman AM, Song LS, Fill M, Back TG, Chen SR. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca(2+) release. Nat Med. Published online before print July 10, 2011. doi:10.1038/nm.2406. http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2406.html.Google Scholar5. Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ, Chopra N, Piston DW, Huke S, Knollmann BC. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J Mol Cell Cardiol. 2010; 48:293–301.CrossrefMedlineGoogle Scholar6. Savio-Galimberti E, Knollmann BC. Efficacy and potency of class I antiarrhythmic drugs for suppression of Ca2+ waves in permeabilized myocytes lacking calsequestrin. J Mol Cell Cardiol. Published online before print July 12, 2011. doi:10.1016/j.yjmcc.2011.07.002. http://www.sciencedirect.com/science/article/pii/S0022282811002665.Google Scholar7. Kang G, Giovannone SF, Liu N, Liu FY, Zhang J, Priori SG, Fishman GI. Purkinje cells from RyR2 mutant mice are highly arrhythmogenic but responsive to targeted therapy. Circ Res. 2010; 107:512–519.LinkGoogle Scholar8. van der Werf C, Kannankeril PJ, Sacher F, Krahn AD, Viskin S, Leenhardt A, Shimizu W, Sumitomo N, Fish FA, Bhuiyan ZA, Willems AR, van der Veen MJ, Watanabe H, Laborderie J, Haissaguerre M, Knollmann BC, Wilde AA. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011; 57:2244–2254.CrossrefMedlineGoogle Scholar9. Sumitomo N, Harada K, Nagashima M, Yasuda T, Nakamura Y, Aragaki Y, Saito A, Kurosaki K, Jouo K, Koujiro M, Konishi S, Matsuoka S, Oono T, Hayakawa S, Miura M, Ushinohama H, Shibata T, Niimura I. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart. 2003; 89:66–70.CrossrefMedlineGoogle Scholar10. De Rosa G, Delogu AB, Piastra M, Chiaretti A, Bloise R, Priori SG. Catecholaminergic polymorphic ventricular tachycardia: successful emergency treatment with intravenous propranolol. Pediatr Emerg Care. 2004; 20:175–177.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByKryshtal D, Blackwell D, Egly C, Smith A, Batiste S, Johnston J, Laver D and Knollmann B (2020) RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT, Circulation Research, 128:3, (321-331), Online publication date: 5-Feb-2021. Vagos M, van Herck I, Sundnes J, Arevalo H, Edwards A and Koivumäki J (2018) Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges, Frontiers in Physiology, 10.3389/fphys.2018.01221, 9 Darbar D (2018) Standard Antiarrhythmic Drugs Cardiac Electrophysiology: From Cell to Bedside, 10.1016/B978-0-323-44733-1.00112-7, (1062-1075), . Maizels L, Huber I, Arbel G, Tijsen A, Gepstein A, Khoury A and Gepstein L (2017) Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2, Circulation: Arrhythmia and Electrophysiology, 10:6, Online publication date: 1-Jun-2017. Arnaiz-Cot J, Cleemann L and Morad M (2016) Xanthohumol Modulates Calcium Signaling in Rat Ventricular Myocytes: Possible Antiarrhythmic Properties, Journal of Pharmacology and Experimental Therapeutics, 10.1124/jpet.116.236588, 360:1, (239-248), Online publication date: 1-Jan-2017. Enriquez A, Antzelevitch C, Bismah V and Baranchuk A (2016) Atrial fibrillation in inherited cardiac channelopathies: From mechanisms to management, Heart Rhythm, 10.1016/j.hrthm.2016.06.008, 13:9, (1878-1884), Online publication date: 1-Sep-2016. Yang P, Moreno J, Miyake C, Vaughn‐Behrens S, Jeng M, Grandi E, Wehrens X, Noskov S and Clancy C (2015) In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia , The Journal of Physiology, 10.1113/JP271282, 594:3, (567-593), Online publication date: 1-Feb-2016. Steinfurt J, Dechant M, Böckelmann D, Zumhagen S, Stiller B, Schulze-Bahr E, Bode C and Odening K (2015) High-dose flecainide with low-dose β-blocker therapy in catecholaminergic polymorphic ventricular tachycardia: A case report and review of the literature, Journal of Cardiology Cases, 10.1016/j.jccase.2014.08.009, 11:1, (10-13), Online publication date: 1-Jan-2015. Driessen H, Bourgonje V, van Veen T and Vos M (2014) New antiarrhythmic targets to control intracellular calcium handling, Netherlands Heart Journal, 10.1007/s12471-014-0549-5, 22:5, (198-213), Online publication date: 1-May-2014. Darbar D (2014) Standard Antiarrhythmic Drugs Cardiac Electrophysiology: From Cell to Bedside, 10.1016/B978-1-4557-2856-5.00111-4, (1095-1110), . Aistrup G (2014) Cellular Pharmacology of Cardiac Automaticity and Conduction: Implications in Antiarrhythmic Drug Assessment Cardiac Arrhythmias, 10.1007/978-1-4471-5316-0_24, (305-333), . Steele D, Hwang H and Knollmann B (2013) Triple mode of action of flecainide in catecholaminergic polymorphic ventricular tachycardia, Cardiovascular Research, 10.1093/cvr/cvt059, 98:2, (326-327), Online publication date: 1-May-2013. (2012) 不整脈学研究の進歩(循環器学2012年の進歩), Journal of JCS Cardiologists, 10.1253/jjcsc.20.2_342, 20:2, (342-346), Online publication date: 25-Sep-2012. Lee Y, Maruyama M, Chang P, Park H, Rhee K, Hsieh Y, Hsueh C, Shen C, Lin S, Hwang H, Yin H, Knollmann B and Chen P (2012) Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles, Heart Rhythm, 10.1016/j.hrthm.2012.02.031, 9:7, (1125-1132), Online publication date: 1-Jul-2012. Liu N, Napolitano C, Venetucci L and Priori S (2012) Flecainide and Antiarrhythmic Effects in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia, Trends in Cardiovascular Medicine, 10.1016/j.tcm.2012.06.008, 22:2, (35-39), Online publication date: 1-Feb-2012. September 2, 2011Vol 109, Issue 6 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.111.251322PMID: 21885838 Originally publishedSeptember 2, 2011 PDF download Advertisement SubjectsPharmacology" @default.
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