R222Q SCN5A Mutation Is Associated With Reversible Ventricular Ectopy and Dilated Cardiomyopathy

Mann, Stefan A.; Castro, M. Leticia; Ohanian, Monique; Guo, Guanglan; Zodgekar, Poonam; Sheu, Angela; Stockhammer, Kathryn; Thompson, T.; Playford, David; Subbiah, Rajesh N.; Kuchar, Dennis L.; Aggarwal, Anu G.; Vandenberg, Jamie I.; Fatkin, Diane

doi:10.1016/j.jacc.2012.05.050

Cited by 131 publications

(162 citation statements)

References 38 publications

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“…Fourth, patch-clamp experiments show that the introduction of the mutation causes hyperexcitability of the Na v 1.5 channels. Finally, computational analyses of I Na and AP in single cells imply that the biophysical changes caused by the p.I141V mutation both include an acceleration of the spontaneous depolarization rate in the Purkinje cell model, which is similar to what was reported for a multifocal ectopic Purkinje-related premature contractionlinked p.R222Q mutation by Mann et al, 2 and a reduction of the threshold for cardiac cell excitability.…”

Section: Evidence For Na V 15 Pi141v Causality In Exerciseinduced Psupporting

confidence: 74%

“…[2][3][4] In the current study, the clinical phenotype, associating with the p.I141V mutation, was characterized by a distinct hyperexcitability without evidence of conduction abnormalities or QT interval prolongation. Although the p.I141V and the p.R222Q mutation both associate with atrial arrhythmias, the clinical characteristics of the individuals carrying the p.I141V mutation differ from the phenotype described in p.R222Q-carriers.…”

Section: Gain-of-function Mutations In Na V 15 and The Clinical Phenmentioning

confidence: 68%

“…Moreover, carriers of p.R222Q show frequent PVCs, with both left and right bundle-branch block patterns triggered from Purkinje fibers at low heart rates, but disappearance of PVCs during exercise, and dilated cardiomyopathy. 2,3 In p.I141V mutation carriers, the burden of PVCs was much lower, which may explain why they did not display any abnormalities in ventricular structure or contractility.…”

Section: Gain-of-function Mutations In Na V 15 and The Clinical Phenmentioning

confidence: 99%

“…Also, in a previous study, flecainide has been shown to induce a dramatic reduction in PVCs and recovery of normal left ventricular function in SCN5A p.R222Q mutation carriers,. 2 Although flecainide may directly act on RyR2 channels, [30][31][32] it has recently been suggested that the drug may reduce sodium channel availability, which would increase the channel threshold for triggered activity. 33 Recently, using a rat cardiomyocyte model, Sikkel et al 34 showed that flecainide reduces calcium sparks by a mechanism involving reduction of I Na , that is, through increased Ca2+ efflux via the sodium-calcium exchanger across the sarcolemma and reduced Ca2+ concentration in the vicinity of the RyR2.…”

Section: Mechanistic Considerationsmentioning

confidence: 99%

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Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Swan

Amarouch

Leinonen

et al. 2014

Circ Cardiovasc Genet

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Background-Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family. Methods and Results-A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Na v 1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells. Conclusions-Gain

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Section: Evidence For Na V 15 Pi141v Causality In Exerciseinduced Psupporting

confidence: 74%

Section: Gain-of-function Mutations In Na V 15 and The Clinical Phenmentioning

confidence: 68%

Section: Gain-of-function Mutations In Na V 15 and The Clinical Phenmentioning

confidence: 99%

Section: Mechanistic Considerationsmentioning

confidence: 99%

See 2 more Smart Citations

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Swan

Amarouch

Leinonen

et al. 2014

Circ Cardiovasc Genet

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“…Both gain-of-function and loss-offunction Na + channel dysfunctions are associated with familial dilated cardiomyopathy, and persistent Na + current is associated with acquired diastolic and systolic dysfunction and electrical instability. For instance, an R222Q SCN5A gain-of-function variant, which left-shifted the steady state parameters of activation and inactivation, caused reversible ventricular ectopy and a dilated cardiomyopathy, which were substantially reversed with amiodarone or flecainide (37). The F1759A-dTG mice mimic many of these structural and functional abnormalities, including cardiac enlargement and ventricular dysfunction, and our studies reveal, at least in part, the downstream mechanisms by which gain-of-function SCN5A mutants cause a dilated cardiomyopathy and substrates for both atrial and ventricular arrhythmogenesis.…”

Section: Discussionmentioning

confidence: 99%

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

Wan¹,

Abrams²,

Weinberg³

et al. 2015

Journal of Clinical Investigation

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A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation

et al. 2020

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SCN5A gene mutations are described in 2% of patients with dilated cardiomyopathy (DCM) and different rhythm disturbances, including multifocal ectopic Purkinje-related premature contractions. Recent data indicate that sodium channel blockers are particularly effective monotherapy in carriers of the R222Q SCN5A variant. Our purpose is to describe the effectiveness of antiarrhythmic treatment in a family with genetically determined arrhythmogenic DCM associated with the R814W variant in the SCN5A gene. We examined a family with arrhythmogenic DCM (multifocal ectopic Purkinje-related premature contractions phenotype, atrial tachyarrhythmias, automatism, and conduction disorders) and described antiarrhythmic treatment efficacy in heart failure symptoms reduction and myocardial function improvement. We found a heterozygotic mutation R814W in SCN5A by whole exome sequencing in the proband and confirmed its presence in all affected subjects. There were two sudden cardiac deaths and one heart transplantation among first-degree relatives. The 58-year-old father and his 37-year-old daughter had full spectrum of symptoms associated with R814W SCN5A mutation. Both had implanted cardioverter defibrillator. In the father, adding mexiletine to quinidine therapy reduced ventricular arrhythmia (50-60% → 6-8% of whole rhythm) and reverted long-standing atrial fibrillation to sinus rhythm. In the daughter, mexiletine and overdrive pacing were effective in ventricular arrhythmia reduction (25% → 0.01%). Because of a growing number of atrial fibrillation recurrences, a reduced dose of quinidine (subsequently flecainide) was added, resulting in arrhythmia significant reduction. In both cases, antiarrhythmic effectiveness correlated with clinical improvement. In SCN5A R814W-associated DCM, a combination of Class I antiarrhythmics and overdrive pacing is an effective treatment of severe ventricular and atrial arrhythmias.

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R222Q SCN5A Mutation Is Associated With Reversible Ventricular Ectopy and Dilated Cardiomyopathy

Abstract: The R222Q SCN5A variant has an activating effect on sodium channel function and is associated with reversible ventricular ectopy and DCM. Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented.

Cited by 131 publications

References 38 publications

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice

A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation

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