Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S hearts

Cardiac ryanodine receptor mutations are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), and some, including RyR2‐P2328S, also predispose to atrial fibrillation. Recent work associates reduced atrial Nav1.5 currents in homozygous RyR2‐P2328S (RyR2S/S) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Nav1.5 blocker flecainide reduces ventricular arrhythmogenicity in CPVT. We aimed to determine whether, and how, flecainide influences atrial arrhythmogenicity in RyR2S/S mice and their wild‐type (WT) littermates.

• Publication year

  2015

• Venue

  Acta Physiologica

• Publication date

  2015-04-23

• Fields of study

  Medicine

• Identifiers
  DOI 10.1111/apha.12505PMID 25850710PMCID 4510817
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1.

  2015cited by this paper
• Suppression of Spontaneous Ca Elevations Prevents Atrial Fibrillation in Calsequestrin 2-Null Hearts

  2014cited by this paper
• Ryanodine Receptor–Mediated Calcium Leak Drives Progressive Development of an Atrial Fibrillation Substrate in a Transgenic Mouse Model

  2014influential reference
• Arrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/− hearts

  2014cited by this paper
• CaMKII-dependent regulation of cardiac Na+ homeostasis

  2014cited by this paper
• Determinants of myocardial conduction velocity: implications for arrhythmogenesis

  2013influential reference
• Atrial arrhythmia, triggering events and conduction abnormalities in isolated murine RyR2‐P2328S hearts

  2013influential reference
• Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current

  2013influential reference
• Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia.

  2013cited by this paper
• Loss of Nav1.5 expression and function in murine atria containing the RyR2-P2328S gain-of-function mutation.

  2013influential reference
• Abnormal Ca2+ homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2 modification

  2013influential reference
• Conduction Slowing Contributes to Spontaneous Ventricular Arrhythmias in Intrinsically Active Murine RyR2‐P2328S Hearts

  2013influential reference
• Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia

  2012cited by this paper
• Prevalence of atrial fibrillation in the general population and in high-risk groups: the ECHOES study.

  2012cited by this paper
• Flecainide-Induced Proarrhythmia Is Attributed to Abnormal Changes in Repolarization and Refractoriness in Perfused Guinea-Pig Heart

  2012cited by this paper
• Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia.

  2011cited by this paper
• Reactive Oxygen Species–Activated Ca/Calmodulin Kinase II&dgr; Is Required for Late INa Augmentation Leading to Cellular Na and Ca Overload

  2011cited by this paper
• Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model.

  2011cited by this paper
• Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.

  2011cited by this paper
• Short Communication: Flecainide Exerts an Antiarrhythmic Effect in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia by Increasing the Threshold for Triggered Activity

  2011cited by this paper
• Efficacy and potency of class I antiarrhythmic drugs for suppression of Ca2+ waves in permeabilized myocytes lacking calsequestrin.

  2011cited by this paper
• Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature.

  2011influential reference
• Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia

  2011influential reference
• Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca2+ entry depends on intracellular Ca2+ stores

  2010influential reference
• Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass.

  2010influential reference
• Acute atrial arrhythmogenicity and altered Ca2+ homeostasis in murine RyR2-P2328S hearts

  2010influential reference
• Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans

  2009influential reference
• High-Density Substrate Mapping in Brugada Syndrome: Combined Role of Conduction and Repolarization Heterogeneities in Arrhythmogenesis

  2009cited by this paper
• Intracellular calcium modulation of voltage-gated sodium channels in ventricular myocytes.

  2009cited by this paper
• Physiological consequences of the P2328S mutation in the ryanodine receptor (RyR2) gene in genetically modified murine hearts

  2008influential reference
• The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts

  2007cited by this paper
• Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/− murine hearts modelling the Brugada syndrome

  2007cited by this paper
• Association of atrial arrhythmia and sinus node dysfunction in patients with catecholaminergic polymorphic ventricular tachycardia.

  2007cited by this paper
• Expanding Spectrum of Human RYR2-Related Disease: New Electrocardiographic, Structural, and Genetic Features

  2007cited by this paper
• Calcium signalling during excitation-contraction coupling in mammalian atrial myocytes

  2006cited by this paper
• Cardiovascular Physiology

  2005cited by this paper
• The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction

  2004cited by this paper
• A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study.

  2002cited by this paper
• Predetermined recruitment of calcium release sites underlies excitation‐contraction coupling in rat atrial myocytes

  2001cited by this paper
• Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia

  2001cited by this paper
• Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.

  1999cited by this paper
• Compared effects of sotalol, flecainide and propafenone on ventricular repolarization in patients free of underlying structural heart disease.

  1998cited by this paper
• Impact of atrial fibrillation on the risk of death: the Framingham Heart Study.

  1998cited by this paper
• Comparison of the effects of class I anti-arrhythmic drugs, cibenzoline, mexiletine and flecainide, on the delayed rectifier K+ current of guinea-pig ventricular myocytes.

  1996cited by this paper
• Effects of intracellular calcium on sodium current density in cultured neonatal rat cardiac myocytes.

  1995cited by this paper
• Effect of flecainide on atrial and ventricular refractoriness and conduction in patients with normal left ventricle. Implications for possible antiarrhythmic and proarrhythmic mechanisms.

  1995cited by this paper
• Class I and IV antiarrhythmic drugs and cytosolic calcium regulate mRNA encoding the sodium channel alpha subunit in rat cardiac muscle.

  1992cited by this paper
• Proarrhythmic Effects of Flecainide: Experimental Evidence for Increased Susceptibility to Reentrant Arrhythmias

  1991cited by this paper
• Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

  1991cited by this paper
• Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes.

  1990cited by this paper
• Use dependence of sodium current inhibition by tetrodotoxin in rat cardiac muscle: influence of channel state

  1990cited by this paper
• Electrical activity, cAMP, and cytosolic calcium regulate mRNA encoding sodium channel alpha subunits in rat muscle cells.

  1989cited by this paper
• Electrical activity, cAMP, and cytosolic calcium regulate mRNA encoding sodium channel α subunits in rat muscle cells

  1989cited by this paper
• Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.

  1989cited by this paper
• Distribution and Mobility of Voltage‐gated Ion Channels in Skeletal Muscle a

  1986cited by this paper
• Lateral distribution of sodium and potassium channels in frog skeletal muscle: measurements with a patch‐clamp technique.

  1983cited by this paper
• Photobleaching through glass micropipettes: sodium channels without lateral mobility in the sarcolemma of frog skeletal muscle.

  1982cited by this paper
• Inactivation of the sodium channel. I. Sodium current experiments

  1977cited by this paper
• The effect of internal and external potassium concentration on the membrane potential of frog muscle

  1956influential reference

• The modernized classification of cardiac anti-arrhythmic drugs: its application to clinical practice.

  2025cites this paper
• Cardiac arrhythmogenesis: roles of ion channels and their functional modification

  2024cites this paper
• Exenatide reduces atrial fibrillation susceptibility by inhibiting hKv1.5 and hNav1.5 channels

  2024cites this paper
• Loose-patch clamp analysis applied to voltage-gated ionic currents following pharmacological ryanodine receptor modulation in murine hippocampal cornu ammonis-1 pyramidal neurons

  2024cites this paper
• Advances in basic and translational research in atrial fibrillation

  2023cites this paper
• Feedback contributions to excitation–contraction coupling in native functioning striated muscle

  2023cites this paper
• How does flecainide impact RyR2 channel function?

  2022cites this paper
• Ca2+-dependent modulation of voltage-gated myocyte sodium channels

  2021cites this paper
• Flecainide Paradoxically Activates Cardiac Ryanodine Receptor Channels under Low Activity Conditions: A Potential Pro-Arrhythmic Action

  2021cites this paper
• Is the Debate on the Flecainide Action on the RYR2 in CPVT Closed?

  2021cites this paper
• Protein expression profiles in murine ventricles modeling catecholaminergic polymorphic ventricular tachycardia: effects of genotype and sex

  2020cites this paper
• Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

  2020cites this paper
• Nitro-fatty acids suppress ischemic ventricular arrhythmias by preserving calcium homeostasis

  2020cites this paper
• Safety and efficacy of flecainide for patients with catecholaminergic polymorphic ventricular tachycardia

  2019cites this paper
• Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

  2019cites this paper
• Ion channel gating in cardiac ryanodine receptors from the arrhythmic RyR2-P2328S mouse

  2019cites this paper
• Mechanisms of ventricular arrhythmogenesis in the age dependent Pgc-1β -/- model of mitochondrial dysfunction.

  2019cites this paper
• Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β−/− atrial preparations

  2018cites this paper
• Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β−/−) murine hearts

  2018cites this paper
• Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

  2018influential citation
• Modernized Classification of Cardiac Antiarrhythmic Drugs

  2018cites this paper
• Ageing, the autonomic nervous system and arrhythmia: From brain to heart.

  2018cites this paper
• Reduced cardiomyocyte Na+ current in the age‐dependent murine Pgc‐1β −/− model of ventricular arrhythmia

  2018cites this paper
• Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

  2017cites this paper
• Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1β−/− hearts

  2017cites this paper
• Murine Electrophysiological Models of Cardiac Arrhythmogenesis.

  2017cites this paper
• Nationwide experience of catecholaminergic polymorphic ventricular tachycardia caused by RyR2 mutations

  2017cites this paper
• Response to: Depolarization vs. repolarization: what is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts?

  2016cites this paper
• Salt: a matter of balance

  2016cites this paper
• The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles

  2015influential citation
• Linking ryanodine receptor Ca2+ leak and Na+ current in heart: a day in the life of flecainide

  2015cites this paper