iPSC-Cardiomyocyte Models of Brugada Syndrome—Achievements, Challenges and Future Perspectives

Nijak, Aleksandra; Saenen, Johan; Labro, Alain J.; Schepers, Dorien; Loeys, Bart; Alaerts, Maaike

doi:10.3390/ijms22062825

Cited by 20 publications

(8 citation statements)

References 131 publications

(262 reference statements)

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“…Functional studies of SCN5A variants found in case 8 (p.Trp1345_Ser1349delinsPhe/p.Pro1730Leu) and in case 13 (p.Asp1741Glyfs*48/ p.Val240Met), both individually and in co-expression, are pending, as are functional studies of three of the missense variants here identified (p.Arg811Cys; p.Pro1730Leu, p.Ala1778Asp). While these models have a number of shortcomings, as they do not closely reproduce human heart physiology and clinical manifestations [ 45 , 46 ], functional and pharmacological studies in induced pluripotent cell (iPSC)-derived cardiomyocytes have overcome several of these shortcomings and have become a promising option for precision medicine [ 47 ]. These functional studies, together with careful and detailed clinical characterization of patients and apparently asymptomatic mutation carriers, are crucial to understand the complexities of SCN5A channelopathies.…”

Section: Discussionmentioning

confidence: 99%

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts

Villarreal-Molina

García-Ordóñez

Reyes-Quintero

et al. 2021

Genes

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Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

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Section: Discussionmentioning

confidence: 99%

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts

Villarreal-Molina

García-Ordóñez

Reyes-Quintero

et al. 2021

Genes

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“…A main limitation of our investigation is the use of the HEK293 cell model ( 22 ). This cell type displays significant differences from ventricular cardiomyocytes, given that human cardiomyocytes are highlighted by their high level of differentiation and exclusive expression of certain types of ion channels and cellular structural proteins.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel Scn3b mutation in a Chinese Brugada syndrome pedigree: implications for Nav1.5 electrophysiological properties and intracellular distribution of Nav1.5 and Navβ3

Fan,

Wang,

Cao

et al. 2024

Front. Cardiovasc. Med.

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BackgroundThe Scn3b gene encodes for Navβ3, a pivotal regulatory subunit of the fast sodium channel in cardiomyocytes. However, its mutation status in the Chinese population suffering from Brugada Syndrome (BrS) has not been characterized, and the contributory pathophysiological mechanisms to disease pathology remain undefined.Methods and ResultsA Scn3b (c.260C>T, p.P87l) mutation was identified in a patient with BrS of Chinese descent. Functional analyses demonstrated that sodium channel activation for the wild type, mutant samples, and co-expression of both commenced at −55 mv and peaked at −25 mv. The mutant group exhibited a notable reduction, approximately 60%, in peak sodium channel activation current (INa) at −25 mv. The parameters for half-maximal activation voltages (V1/2) and slope factors (k) showed no significant differences when comparing wild type, mutant, and combined expression groups (P = 0.98 and P = 0.65, respectively). Additionally, no significant disparities were evident in terms of the steady-state sodium channel inactivation parameters V1/2 and k (with P-values of 0.85 and 0.25, respectively), nor were there significant differences in the activation time constant τ (P = 0.59) and late sodium current density (P = 0.23) across the wild-type, mutant, and co-expressed groups. Confocal imaging and Western blot analysis demonstrated decreased plasma membrane localization of SCN3B and SCN5A in the P87l group. Computational simulations of cardiac action potentials suggested that SCN3B P87l can alter the morphology of the action potentials within the endocardium and epicardium while reducing the peak of depolarization.ConclusionsThe pathogenic impact of the Scn3b P87l mutation predominantly originates from a reduction in peak INa activation current coupled with decreased cell surface expression of Nav1.5 and Navβ3. These alterations may influence cardiac action potential configurations and contribute to the risk of ventricular arrhythmias in individuals with BrS.

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“…The availability of autologous cells that can differentiate into all cell types directly from patients has allowed the possibility of investigating the aetiology of BrS directly on patients’ cardiomyocytes without the need for invasive biopsies to obtain primary cells. These cells provide a sufficient amount of biological material that can be sustained in vitro for a long time, with a more complex and physiological expression profile compared to that of immortalised cell lines and free of species-to-species differences inherent in animal-derived models [ 60 ]. Davis and colleagues were among the pioneers in the adoption of iPSC technology for the study of BrS.…”

Section: Brugada Syndrome Experimental Modelsmentioning

confidence: 99%

Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome

Melgari

Calamaio

Frosio

et al. 2023

IJMS

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The development of high-throughput automated patch-clamp technology is a recent breakthrough in the field of Brugada syndrome research. Brugada syndrome is a heart disorder marked by abnormal electrocardiographic readings and an elevated risk of sudden cardiac death due to arrhythmias. Various experimental models, developed either in animals, cell lines, human tissue or computational simulation, play a crucial role in advancing our understanding of this condition, and developing effective treatments. In the perspective of the pathophysiological role of ion channels and their pharmacology, automated patch-clamp involves a robotic system that enables the simultaneous recording of electrical activity from multiple single cells at once, greatly improving the speed and efficiency of data collection. By combining this approach with the use of patient-derived cardiomyocytes, researchers are gaining a more comprehensive view of the underlying mechanisms of heart disease. This has led to the development of more effective treatments for those affected by cardiovascular conditions.

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iPSC-Cardiomyocyte Models of Brugada Syndrome—Achievements, Challenges and Future Perspectives

Cited by 20 publications

References 131 publications

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts

Identification of a novel Scn3b mutation in a Chinese Brugada syndrome pedigree: implications for Nav1.5 electrophysiological properties and intracellular distribution of Nav1.5 and Navβ3

Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome

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