Reduced Na
            <sup>+</sup>
            Current in Native Cardiomyocytes of a Brugada Syndrome Patient Associated With β-2-Syntrophin Mutation

Schmidt, Constanze; Wiedmann, Felix; El‐Battrawy, Ibrahim; Fritz, Markus; Ratte, Antonius; Beller, Carsten J.; Lang, Siegfried; Rudic, Boris; Schimpf, Rainer; Akın, İbrahim; Kretzler, Matthias; Borggrefe, Martin; Katus, Hugo A.; Zhou, X.E.; Thomas, Dierk

doi:10.1161/circgen.118.002263

Cited by 11 publications

(7 citation statements)

References 5 publications

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“…Through a diminishing of the natrium inward current or a reinforcement of the potassium outward current, the balance of the otherwise elaborate process of the action potential is disturbed as positive ions are increasingly lost to the outer cellular membrane (El-Battrawy et al, 2019;Schmidt et al, 2018). This and a possible loss of the plateau phase physiologically maintained by the calcium channels that is either caused by a loss of function mutation or the fact that the aggravated repolarization through the potassium and sodium channels prevent the activation of the calcium channels lead to a shortening of the action potential, which makes the myocard susceptible to the development of a reentry and with that, that of an extrasystole which might be the start of a arrhythmogenic event.…”

Section: Discussionmentioning

confidence: 99%

Arrhythmic events in Brugada syndrome patients induced by fever

Roterberg

El‐Battrawy

Veith

et al. 2019

Noninvasive Electrocardiol

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Introduction The Brugada syndrome is associated with arrhythmic events, which may even lead to sudden cardiac death (SCD) as it causes arrhythmic events. A typical Brugada syndrome ECG type I can be triggered at fever situations. The aim of this pooled meta‐analysis is to further explore the baseline characteristics and the association of fever to BrS‐related arrhythmic events. Methods We compiled data from a search of databases (PubMed, Web of Science, Cochrane Library, and Google Scholar). We included 17 studies including 14 case reports and a total of 53 patients. Results Our population including 53 patients showed a male predominance of 92% with a mean age of 40.6 ± 17.7 years. 58% of patients had a family history of SCD or BrS. Genetic screening was performed in 14 patients (26%) and revealed a SCN5A mutation in 21% of the patients. ICD implantation was initiated in six patients. 75% (n = 39) of patients did not have symptoms before the fever event. Symptoms at fever included life‐threatening arrhythmia such as ventricular fibrillation (VF) or ventricular tachycardia (VT; 17%), syncope (13%), and cardiac arrest or aborted SCD (13%). One patient developed electrical storm which led to not aborted SCD. Conclusion Fever is a great risk factor for arrhythmia events in BrS patients. Patients with known fever triggered Brugada syndrome should be surveilled closely during fever and be started on antipyretic therapy as soon as possible.

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Section: Discussionmentioning

confidence: 99%

Arrhythmic events in Brugada syndrome patients induced by fever

Roterberg

El‐Battrawy

Veith

et al. 2019

Noninvasive Electrocardiol

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“…A recent study investigated the functional roles of a mutation in SNTB2 (β‐2‐syntrophin) ( SNTB2 ‐N167K) in native cardiomyocytes obtained from right atrial tissue of a patient with BrS. 17 Cardiomyocytes with the SNTB2 ‐N167K mutation showed reduced peak I Na and late I Na and shortened action potential duration. The results were consistent with findings in the coexpression of Nav1.5 with WT SNTB2 and SNTB2 ‐N167K or with SNTB2 ‐N167K alone in Xenopus oocytes, which showed a significant reduction in I Na in both homozygous and heterozygous conditions.…”

Section: Experimental Models Of Brsmentioning

confidence: 99%

“…Although the human heart is the best choice for building models, animal and cellular models have been chosen by most researchers because of the difficulty in obtaining human heart tissues and ethical limitations. Several models have been used to simulate the disease, including transgenic mice and porcine, canine, and rabbit heart preparations, and various cellular models with expression of mutant SCN5A and human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) 17 (Table 1 ). Another difficulty is the current technological inability to study the detailed impulse propagation mechanisms of the syndrome in vivo.…”

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confidence: 99%

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

Lang

Akın

et al. 2022

JAHA

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Brugada syndrome (BrS) is an inherited and rare cardiac arrhythmogenic disease associated with an increased risk of ventricular fibrillation and sudden cardiac death. Different genes have been linked to BrS. The majority of mutations are located in the SCN5A gene, and the typical abnormal ECG is an elevation of the ST segment in the right precordial leads V1 to V3. The pathophysiological mechanisms of BrS were studied in different models, including animal models, heterologous expression systems, and human‐induced pluripotent stem cell–derived cardiomyocyte models. Currently, only a few BrS studies have used human‐induced pluripotent stem cell–derived cardiomyocytes, most of which have focused on genotype–phenotype correlations and drug screening. The combination of new technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR associated protein 9)‐mediated genome editing and 3‐dimensional engineered heart tissues, has provided novel insights into the pathophysiological mechanisms of the disease and could offer opportunities to improve the diagnosis and treatment of patients with BrS. This review aimed to compare different models of BrS for a better understanding of the roles of human‐induced pluripotent stem cell–derived cardiomyocytes in current BrS research and personalized medicine at a later stage.

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“…Besides the role of the sodium channel ancillary subunits, additional SCN5A/Na v 1.5 interacting proteins have been reported in BrS. Mutations in Plakophilin (PKP2) [260,371] MOG1 [9,201,[372][373][374][375], FGF13 [376], syntrophin (SNTA1) [377], NEDD4 [378,379], Tmem168 [379] and telethonin [285,286] are identified in BrS patients and their implication to sodium channel function has been reported. Distinct Na v 1.5 interacting protein mutants lead to I Na deficit [261,286,375,377] while others influence Na v trafficking and thus subcellular localization [201,379].…”

Section: Brugada Syndromementioning

confidence: 99%

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Daimi

Lozano-Velasco

Aránega

et al. 2022

IJMS

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Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways.

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Reduced Na ⁺ Current in Native Cardiomyocytes of a Brugada Syndrome Patient Associated With β-2-Syntrophin Mutation

Cited by 11 publications

References 5 publications

Arrhythmic events in Brugada syndrome patients induced by fever

Arrhythmic events in Brugada syndrome patients induced by fever

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

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Reduced Na + Current in Native Cardiomyocytes of a Brugada Syndrome Patient Associated With β-2-Syntrophin Mutation

Cited by 11 publications

References 5 publications

Arrhythmic events in Brugada syndrome patients induced by fever

Arrhythmic events in Brugada syndrome patients induced by fever

Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

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Reduced Na ⁺ Current in Native Cardiomyocytes of a Brugada Syndrome Patient Associated With β-2-Syntrophin Mutation