Research

9 pages, 1137 KiB

Open AccessArticle

Left Axis Deviation in Brugada Syndrome: Vectorcardiographic Evaluation during Ajmaline Provocation Testing Reveals Additional Depolarization Abnormalities

by Martijn H. van der Ree, Jeroen Vendrik, Jan A. Kors, Ahmad S. Amin, Arthur A. M. Wilde, Hanno L. Tan and Pieter G. Postema

Int. J. Mol. Sci. 2021, 22(2), 484; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020484 - 06 Jan 2021

Cited by 4 | Viewed by 1995

Abstract

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation [...] Read more.

Patients with Brugada syndrome (BrS) can show a leftward deviation of the frontal QRS-axis upon provocation with sodium channel blockers. The cause of this axis change is unclear. In this study, we aimed to determine (1) the prevalence of this left axis deviation and (2) to evaluate its cause, using the insights that could be derived from vectorcardiograms. Hence, from a large cohort of patients who underwent ajmaline provocation testing (n = 1430), we selected patients in whom a type-1 BrS-ECG was evoked (n = 345). Depolarization and repolarization parameters were analyzed for reconstructed vectorcardiograms and were compared between patients with and without a >30° leftward axis shift. We found (1) that the prevalence of a left axis deviation during provocation testing was 18% and (2) that this left axis deviation was not explained by terminal conduction slowing in the right ventricular outflow tract (4th QRS-loop quartile: +17 ± 14 ms versus +13 ± 15 ms, nonsignificant) but was associated with a more proximal conduction slowing (1st QRS-loop quartile: +12[8;18] ms versus +8[4;12] ms, p < 0.001 and 3rd QRS-loop quartile: +12 ± 10 ms versus +5 ± 7 ms, p < 0.001). There was no important heterogeneity of the action potential morphology (no difference in the ventricular gradient), but a left axis deviation did result in a discordant repolarization (spatial QRS-T angle: 122[59;147]° versus 44[25;91]°, p < 0.001). Thus, although the development of the type-1 BrS-ECG is characterized by a terminal conduction delay in the right ventricle, BrS-patients with a left axis deviation upon sodium channel blocker provocation have an additional proximal conduction slowing, which is associated with a subsequent discordant repolarization. Whether this has implications for risk stratification is still undetermined. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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Review

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25 pages, 6405 KiB

Open AccessReview

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

by Aleksandra Nijak, Johan Saenen, Alain J. Labro, Dorien Schepers, Bart L. Loeys and Maaike Alaerts

Int. J. Mol. Sci. 2021, 22(6), 2825; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062825 - 10 Mar 2021

Cited by 10 | Viewed by 4018

Abstract

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those [...] Read more.

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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10 pages, 1247 KiB

Open AccessReview

Fibrosis and Conduction Abnormalities as Basis for Overlap of Brugada Syndrome and Early Repolarization Syndrome

by Bastiaan J. Boukens, Mark Potse and Ruben Coronel

Int. J. Mol. Sci. 2021, 22(4), 1570; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041570 - 04 Feb 2021

Cited by 11 | Viewed by 3046

Abstract

Brugada syndrome and early repolarization syndrome are both classified as J-wave syndromes, with a similar mechanism of arrhythmogenesis and with the same basis for genesis of the characteristic electrocardiographic features. The Brugada syndrome is now considered a conduction disorder based on subtle structural [...] Read more.

Brugada syndrome and early repolarization syndrome are both classified as J-wave syndromes, with a similar mechanism of arrhythmogenesis and with the same basis for genesis of the characteristic electrocardiographic features. The Brugada syndrome is now considered a conduction disorder based on subtle structural abnormalities in the right ventricular outflow tract. Recent evidence suggests structural substrate in patients with the early repolarization syndrome as well. We propose a unifying mechanism based on these structural abnormalities explaining both arrhythmogenesis and the electrocardiographic changes. In addition, we speculate that, with increasing technical advances in imaging techniques and their spatial resolution, these syndromes will be reclassified as structural heart diseases or cardiomyopathies. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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19 pages, 1273 KiB

Open AccessReview

Role of Non-Coding Variants in Brugada Syndrome

by Adrian Pérez-Agustín, Mel·lina Pinsach-Abuin and Sara Pagans

Int. J. Mol. Sci. 2020, 21(22), 8556; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228556 - 13 Nov 2020

Cited by 7 | Viewed by 2512

Abstract

Brugada syndrome (BrS) is an inherited electrical heart disease associated with a high risk of sudden cardiac death (SCD). The genetic characterization of BrS has always been challenging. Although several cardiac ion channel genes have been associated with BrS, SCN5A is the only [...] Read more.

Brugada syndrome (BrS) is an inherited electrical heart disease associated with a high risk of sudden cardiac death (SCD). The genetic characterization of BrS has always been challenging. Although several cardiac ion channel genes have been associated with BrS, SCN5A is the only gene that presents definitive evidence for causality to be used for clinical diagnosis of BrS. However, more than 65% of diagnosed cases cannot be explained by variants in SCN5A or other genes. Therefore, in an important number of BrS cases, the underlying mechanisms are still elusive. Common variants, mostly located in non-coding regions, have emerged as potential modulators of the disease by affecting different regulatory mechanisms, including transcription factors (TFs), three-dimensional organization of the genome, or non-coding RNAs (ncRNAs). These common variants have been hypothesized to modulate the interindividual susceptibility of the disease, which could explain incomplete penetrance of BrS observed within families. Altogether, the study of both common and rare variants in parallel is becoming increasingly important to better understand the genetic basis underlying BrS. In this review, we aim to describe the challenges of studying non-coding variants associated with disease, re-examine the studies that have linked non-coding variants with BrS, and provide further evidence for the relevance of regulatory elements in understanding this cardiac disorder. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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10 pages, 585 KiB

Open AccessReview

Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?

by Oscar Campuzano, Georgia Sarquella-Brugada, Sergi Cesar, Elena Arbelo, Josep Brugada and Ramon Brugada

Int. J. Mol. Sci. 2020, 21(19), 7155; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197155 - 28 Sep 2020

Cited by 32 | Viewed by 3270

Abstract

Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than [...] Read more.

Brugada syndrome is a rare inherited arrhythmogenic disease leading to ventricular fibrillation and high risk of sudden death. In 1998, this syndrome was linked with a genetic variant with an autosomal dominant pattern of inheritance. To date, rare variants identified in more than 40 genes have been potentially associated with this disease. Variants in regulatory regions, combinations of common variants and other genetic alterations are also proposed as potential origins of Brugada syndrome, suggesting a polygenic or oligogenic inheritance pattern. However, most of these genetic alterations remain of questionable causality; indeed, rare pathogenic variants in the SCN5A gene are the only established cause of Brugada syndrome. Comprehensive analysis of all reported genetic alterations identified the origin of disease in no more than 40% of diagnosed cases. Therefore, identifying the cause of this rare arrhythmogenic disease in the many families without a genetic diagnosis is a major current challenge in Brugada syndrome. Additional challenges are interpretation/classification of variants and translation of genetic data into clinical practice. Further studies focused on unraveling the pathophysiological mechanisms underlying the disease are needed. Here we provide an update on the genetic basis of Brugada syndrome. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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20 pages, 1618 KiB

Open AccessReview

Mechanisms of Arrhythmias in the Brugada Syndrome

by Michiel Blok and Bastiaan J. Boukens

Int. J. Mol. Sci. 2020, 21(19), 7051; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197051 - 25 Sep 2020

Cited by 20 | Viewed by 5382

Abstract

Arrhythmias in Brugada syndrome patients originate in the right ventricular outflow tract (RVOT). Over the past few decades, the characterization of the unique anatomy and electrophysiology of the RVOT has revealed the arrhythmogenic nature of this region. However, the mechanisms that drive arrhythmias [...] Read more.

Arrhythmias in Brugada syndrome patients originate in the right ventricular outflow tract (RVOT). Over the past few decades, the characterization of the unique anatomy and electrophysiology of the RVOT has revealed the arrhythmogenic nature of this region. However, the mechanisms that drive arrhythmias in Brugada syndrome patients remain debated as well as the exact site of their occurrence in the RVOT. Identifying the site of origin and mechanism of Brugada syndrome would greatly benefit the development of mechanism-driven treatment strategies. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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19 pages, 268 KiB

Open AccessReview

Brugada Syndrome: Oligogenic or Mendelian Disease?

by Michelle M. Monasky, Emanuele Micaglio, Giuseppe Ciconte and Carlo Pappone

Int. J. Mol. Sci. 2020, 21(5), 1687; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051687 - 01 Mar 2020

Cited by 42 | Viewed by 4126

Abstract

Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic [...] Read more.

Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70–85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant’s frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype–phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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8 pages, 3169 KiB

Open AccessCase Report

Novel SCN5A p.V1429M Variant Segregation in a Family with Brugada Syndrome

by Michelle M. Monasky, Emanuele Micaglio, Giuseppe Ciconte, Valeria Borrelli, Luigi Giannelli, Gabriele Vicedomini, Andrea Ghiroldi, Luigi Anastasia, Emanuela T. Locati, Sara Benedetti, Chiara Di Resta, Giorgio Casari and Carlo Pappone

Int. J. Mol. Sci. 2020, 21(16), 5902; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165902 - 17 Aug 2020

Cited by 5 | Viewed by 1877

Abstract

Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is SCN5A, which some argue is the only gene that has been definitively confirmed to cause BrS, [...] Read more.

Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is SCN5A, which some argue is the only gene that has been definitively confirmed to cause BrS, while the potential causative effect of other genes is still under debate. While the issue of BrS genetics is currently a hot topic, current knowledge is not able to result in molecular confirmation of over half of BrS cases. Therefore, it is difficult to develop research models with wide potential. Instead, the clinical genetics first need to be better understood. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.4285G>A (p.Val1429Met) in the SCN5A gene, and demonstrate its segregation with BrS, suggesting a pathogenic effect. These results provide the first disease association with this variant and are crucial clinical data to communicate to basic scientists, who could perform functional studies to better understand the molecular effects of this clinically-relevant variant in BrS. Full article

(This article belongs to the Special Issue Brugada Syndrome: Causes, Diagnosis, and Treatment)

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