ArticlePloS one2015
Channel Activity of Cardiac Ryanodine Receptors (RyR2) Determines Potency and Efficacy of Flecainide and R-Propafenone against Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 33 citations in OpenAlex.
- Long-Term Serial Exercise Stress Testing in Catecholaminergic Polymorphic Ventricular Tachycardia on Beta-Blocker and Flecainide Therapy.Journal of cardiovascular electrophysiology · 2026Article
- Introduction of a single carboxylic acid converts the cyclic oligomeric depsipeptide ent-verticilide from a ryanodine receptor 2 (RyR2) inhibitor to RyR2 activator.Molecular pharmacology · 2025Article
- Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.Circulation · 2023Article
- Flecainide induces a sustained countercurrent dependent effect on RyR2 in permeabilized WT ventricular myocytes but not in intact cells.Frontiers in pharmacology · 2023Article
- How does flecainide impact RyR2 channel function?The Journal of general physiology · 2022Article
- The Antiarrhythmic Mechanisms of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia.Frontiers in physiology · 2022Review
- The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1.Physiological reports · 2021Article
- Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function.Cardiovascular research · 2021Article
- Is the Debate on the Flecainide Action on the RYR2 in CPVT Closed?Circulation research · 2021Article
- RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT.Circulation research · 2021Article
- Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia.The Journal of physiology · 2020Review
- TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle.Circulation research · 2020Article
- Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure.Expert opinion on therapeutic targets · 2020Review
- Electrophysiological and Contractile Effects of Disopyramide in Patients With Obstructive Hypertrophic Cardiomyopathy: A Translational Study.JACC. Basic to translational science · 2019Article
- A 35-year effective treatment of catecholaminergic polymorphic ventricular tachycardia with propafenone.HeartRhythm case reports · 2019Article
- Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload.Frontiers in physiology · 2019Article
- Projection length stimulated by oxytocin is modulated by the inhibition of calcium signaling in U-87MG cells.Journal of neural transmission (Vienna, Austria : 1996) · 2018Article
- Multiple targets for flecainide action: implications for cardiac arrhythmogenesis.British journal of pharmacology · 2018Review
- Reply from Pei-Chi Yang, Jonathan D. Moreno, Mao-Tsuen Jeng, Xander H. T. Wehrens, Sergei Noskov and Colleen E. Clancy.The Journal of physiology · 2016Article
- Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor.British journal of pharmacology · 2016Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Flecainide blocks ryanodine receptor type 2 (RyR2) channels in the open state, suppresses arrhythmogenic Ca2+ waves and prevents catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice and humans. We hypothesized that differences in RyR2 activity induced by CPVT mutations determines the potency of open-state RyR2 blockers like flecainide (FLEC) and R-propafenone (RPROP) against Ca2+ waves in cardiomyocytes. Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits). Consistent with increased RyR2 activity, Ca2+ spark and wave frequencies were significantly higher in CPVT compared to WT mouse myocytes. We next obtained concentration-response curves of Ca2+ wave inhibition for FLEC, RPROP (another open-state RyR2 blocker), and tetracaine (TET) (a state-independent RyR2 blocker). Both FLEC and RPROP inhibited Ca2+ waves with significantly higher potency (lower IC50) and efficacy in CPVT compared to WT. In contrast, TET had similar potency in all groups studied. Increasing RyR2 activity of permeabilized WT myocytes by exposure to caffeine (150 µM) increased the potency of FLEC and RPROP but not of TET. RPROP and FLEC were also significantly more potent in rabbit ventricular myocytes that intrinsically exhibit higher Ca2+ spark rates than WT mouse ventricular myocytes. In conclusion, RyR2 activity determines the potency of open-state blockers FLEC and RPROP for suppressing arrhythmogenic Ca2+ waves in cardiomyocytes, a mechanism likely relevant to antiarrhythmic drug efficacy in CPVT.
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