Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na v 1.5 gain-of-function mutation (G213D)

Calloe, Kirstine; Broendberg, Anders Krogh; Christensen, Alex Hørby; Pedersen, Lisbeth Nørum; Olesen, Morten S.; Tejada, Maria de los Angeles; Friis, Søren; Thomsen, Morten B.; Bundgaard, Henning; Jensen, Henrik

doi:10.1016/j.ijcard.2017.11.095

Cited by 29 publications

(41 citation statements)

References 31 publications

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“…Likewise previously reported in the MEPPC syndrome (Beckermann et al, 2014; Calloe et al, 2018; Laurent et al, 2012; Mann et al, 2012; Nair et al, 2012; ter Bekke et al, 2018; Zakrzewska‐Koperska et al, 2018), our patient presented incessant multifocal polymorphic PVCs originating from the fascicular‐Purkinje system, atrial ectopic beats, and junctional rhythm responsible for DCM and left ventricular dysfunction. Concerning the molecular mechanisms leading to DCM, we can only speculate, like others (Bezzina & Remme, 2008), on a role for altered calcium homeostasis as a consequence of alterations in intracellular sodium concentrations.…”

Section: Discussionsupporting

confidence: 87%

“…Nevertheless, the underlying mechanism of the Na + -current increase seems to be different in these two Na + -channelopathies, since long QT syndrome subtype 3 is mainly associated with the appearance of a persistent Na + current. To date, there are only a few reports on the MEPPC syndrome; however, an increase in the Na +window current leading to Purkinje-related PVCs seems to be the electrophysiological hallmark of this syndrome (Beckermann et al, 2014;Calloe et al, 2018;Laurent et al, 2012;Mann et al, 2012;Nair et al, 2012;ter Bekke et al, 2018), as confirmed by the present study.…”

Section: Functional Characteristics Of the Na V 15-a204e Mutationsupporting

confidence: 87%

“…Likewise previously reported in the MEPPC syndrome (Beckermann et al, 2014;Calloe et al, 2018;Laurent et al, 2012;Mann et al, 2012;Nair et al, 2012;ter The rapid reversal of DCM was in favor of PVC-induced cardiomyopathy. Indeed, the risk of developing DCM increases with PVC burden, with a cutoff value of >10% for reversible cardiomyopathy (Baman et al, 2010).…”

Section: Clinical Phenotypesupporting

confidence: 82%

“…Interestingly, the PVCs originated from sites located near the scar border. Among SCN5A mutations reported in MEPPC, the main reported mechanism of the associated DCM is arrhythmia‐induced cardiomyopathy, as patients recover a normal cardiac function under effective antiarrhythmic treatment of PVCs (Beckermann et al, 2014; Calloe et al, 2018; Laurent et al, 2012; Mann et al, 2012; ter Bekke et al, 2018; Zakrzewska‐Koperska et al, 2018). However, the presence of an area of LV scars in our young patient raises the hypothesis that sodium‐channel dysfunction can also cause structural alterations of the myocardium and/or that the arrhythmia‐induced cardiomyopathy can progress to structural cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

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A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions

et al. 2020

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Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje‐related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit‐sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav1.5‐A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild‐type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC‐associated Nav1.5 mutations revealed a common electrophysiological pattern of abnormal voltage‐dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular‐Purkinje system observed in patients with MEPPC.

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Section: Discussionsupporting

confidence: 87%

Section: Functional Characteristics Of the Na V 15-a204e Mutationsupporting

confidence: 87%

Section: Clinical Phenotypesupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions

et al. 2020

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“…The occurrence of paroxysmal AF can be a result of TBX5 gain-of-function mutations and overexpressions of Nppa, Cx40, Kcnj2 and Tbx3 genes [7]. Na v 1.5 gain-of-function mutation is proved to be associated with an increased risk of multifocal atrial and ventricular ectopies and dilated cardiomyopathy [8].…”

Section: Introductionmentioning

confidence: 99%

Fetal arrhythmias: prenatal evaluation and intrauterine therapeutics

Yuan

2020

Ital J Pediatr

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Introduction: Fetal arrhythmias are a common phenomenon with rather complicated etiologies. Debates remain regarding prenatal diagnosis and treatment of fetal arrhythmias. Methods:The literature reporting on prenatal diagnosis and treatment of fetal arrhythmias published in the recent two decades were retrieved, collected and analyzed. Results: Both fetal magnetocardiogram and electrocardiogram provide information of cardiac time intervals, including the QRS and QT durations. M-mode ultrasound detects the AV and VA intervals, fetal heart rate, and AV conduction. By using Doppler ultrasound, simultaneous recording of the atrial and ventricular waves can be obtained. Benign fetal arrhythmias, including premature contractions and sinus tachycardia, do not need any treatment before and after birth. Sustained fetal arrhythmias that predispose to the occurrence of hydrops fetalis, cardiac dysfunction or eventual fetal demise require active treatments. Intrauterine therapy of fetal tachyarrhythmias has been carried out by the transplacental route. If maternal transplacental treatment fails, intraumbilical, intraperitoneal, or direct fetal intramuscular injection of antiarrhythmic agents can be attempted. Conclusions: The outcomes of intrauterine therapy of fetal tachyarrhythmias depend on the types or etiology of fetal arrhythmias and fetal conditions. Most are curable to a transplacental treatment by the first-line antiarrhythmic agents. Fetal cardiac pacings are effective methods to restore sinus rhythm in drug-resistant or hemodynamically compromised cases. Immediate postnatal pacemaker implantation is warranted in refractory cases.

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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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Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Na v 1.5 gain-of-function mutation (G213D)

Cited by 29 publications

References 31 publications

A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions

A novel gain‐of‐function mutation in SCN5A responsible for multifocal ectopic Purkinje‐related premature contractions

Fetal arrhythmias: prenatal evaluation and intrauterine therapeutics

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

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