Cardiac Histological Substrate in Patients With Clinical Phenotype of Brugada Syndrome

Frustaci, Andrea; Priori, Silvia G.; Pieroni, Maurizio; Chimenti, Cristina; Napolitano, Carlo; Rivolta, Ilaria; Sanna, Tommaso; Bellocci, Fulvio; Russo, Matteo Antonio

doi:10.1161/circulationaha.105.520999

Cited by 324 publications

(253 citation statements)

References 28 publications

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“…Some microscopic myocardial alterations have been reported, suggesting that the channelopathy may induce cardiomyopathic changes in some patients. 11,12 Thus, the presence of important structural alterations should suggest an alternative diagnosis.…”

Section: Clinical Diagnosis Diagnostic Criteriamentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

128

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Review ARticleMore than 20 years ago, eight individuals were resuscitated from sudden cardiac death (SCD) caused by documented ventricular fibrillation (VF); all showed a characteristic ST segment elevation in the right precordial leads and a structurally normal heart. 1 In 1996, the term "Brugada syndrome" (BrS) was used to describe what was previously known as "right bundle branch block, persistent ST segment elevation, and sudden death syndrome. " 2 A year later, BrS was reported to be the same disease as sudden unexplained nocturnal death syndrome (SUNDS). In other countries, BrS has different names: Lai Tai (Thailand), Pokkuri (Japan), and Bangungut (Philippines). Currently, the prevalence of BrS is estimated at ~3-5 in 10,000 people, and it is higher in young men of Southeast Asian origin. It is the main cause of death among young healthy men in Southeast Asia. 3 Recent reports suggest that BrS could be responsible for 4% of all SCD and up to 12% of sudden death in patients with structurally normal hearts. The clinical phenotype manifests in adulthood, at a mean age of 41 years, and it is 8-to 10-times more frequent in males. Frequently, sudden death can be the first manifestation of the disease. 4 In 1998, the genetic basis of BrS was established when the sodium channel protein type V subunit α gene (SCN5A), which encodes the α-subunit of the voltage-gated Na v 1.5 cardiac sodium channel responsible for regulating rapid sodium current (I Na ), was associated with the disease. 5 Currently, BrS is recognized as a rare, inherited cardiac channelopathy caused by an alteration of ionic currents that leads to ventricular arrhythmias and SCD. It is clinically characterized by ST segment elevation in leads V1-V3 of the electrocardiogram, but incomplete penetrance and variable expressivity confound the diagnosis. 6 Despite the identification of 18 associated genes, 65-70% of clinically diagnosed cases remain without an identifiable genetic cause. 4 CLINICAL DIAGNOSIS Diagnostic criteriaThe clinical diagnosis of BrS requires the identification of the ST segment elevation in the right precordial leads at baseline or after the use of sodium blockers. Three different electrocardiographic (ECG) patterns can be often observed in families with BrS: type I, which consists of a coved-type ST segment elevation greater than 2 mm followed by a descending negative T wave in at least two right precordial leads (V1 to V3); type II ST elevation, saddleback-shaped patterns with a high initial increase followed by an ST elevation greater than 2 mm; and saddleback-shaped patterns with a high initial increase followed by an ST elevation less than 2 mm (Figure 1). The second Brugada Consensus Report proposed that only type I is diagnostic for BrS 7 and, in 2013, it was proposed that a definitive diagnosis of BrS considers both spontaneous type I pattern and a provoked type I pattern (with a baseline type II or III pattern) in at least one right precordial lead (V1 or V2). 8 The diagnosis of BrS is currently accepted in those patients ...

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Section: Clinical Diagnosis Diagnostic Criteriamentioning

confidence: 99%

Brugada syndrome: clinical and genetic findings

Sarquella-Brugada

Campuzano

Arbelo

et al. 2016

Genetics in Medicine

128

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“…27) Frustaci, et al and our colleagues Ohkubo, et al documented structural abnormalities, including right ventricular myocarditis, right ventricular cardiomyopathy, and cardiomyopathic changes in endomyocardial biopsy samples. 16,18) Furthermore, Coronel, et al described histopathologic features of a heart explanted from a Brugada syndrome patient, and showed that right ventricular hypertrophy and fibrosis with epicardial fatty infiltration as well as conduction slowing were based on interstitial fibrosis, not transmural repolarization differences, and that these features caused the ECG signs and explained the VF. 7) Recent work in the same laboratory confirmed that local depolarization abnormalities are the dominant pathophysiologic mechanism for the type 1 Brugada electrogram.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11][12][13][14][15] Furthermore, structural abnormalities in the right ventricle are reported in Brugada syndrome. [16][17][18] We conducted a single-center case-control electroanatomic mapping study in patients with and without Brugada syndrome to identify the arrhythmogenic substrates in Brugada syndrome.…”

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confidence: 99%

Clarifying the Arrhythmogenic Substrate for Brugada Syndrome Electroanatomic Mapping Study of the Right Ventricle

et al. 2011

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SummaryThe right ventricular outflow tract (RVOT) is considered the arrhythmogenic region that gives rise to Brugada syndrome. To obtain a better understanding of this substrate, we performed electroanatomic mapping of the right ventricle (RV) in patients with Brugada syndrome.The RV was mapped electroanatomically with the CARTO system in 11 patients with asymptomatic Brugada syndrome but in whom ventricular fibrillation was induced by programmed ventricular stimulation, and in 5 control patients. The low voltage zone area (< 1.5 mV) was larger (16.1% versus 7.8%, P < 0.01) and the bipolar electrogram duration was greater (81.6 ± 7.8 ms versus 53.4 ± 5.6 ms, P < 0.01) in the patients with Brugada syndrome versus the control patients; the bipolar electrogram duration was greater in the septal portion and free wall of the RVOT.Our data suggest that regional endocardial conduction slowing based on structural abnormalities exists at the RVOT in Brugada syndrome. (Int Heart J 2011; 52: 290-294)

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“…In some aspects, this phenotype resembles PCCD, although in the later fibrosis was found to be limited to the conduction system area (Lenègre and Moreau, 1963;Lev, 1964). However, it is worth noting that fibrosis has also been observed in patients with the Brugada syndrome (Coronel et al, 2005;Frustaci et al, 2005). More recently, it was shown that Scn5a ± mice display variable degrees of conduction defects when young (10 weeks old): some mice have only mild prolongation of the QRS interval while others have more severe QRS prolongation associated with RR or SS patterns (Leoni et al, 2010).…”

Section: A Model For the Brugada Syndrome And Conduction Disorders: Tmentioning

confidence: 97%

Mouse models of SCN5A-related cardiac arrhythmias

Charpentier

Bourgé

Mérot

2008

Progress in Biophysics and Molecular Biology

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Mutations of SCN5A gene, which encodes the α-subunit of the voltage-gated Na channel Na V 1.5, underlie hereditary cardiac arrhythmic syndromes such as the type 3 long QT syndrome, cardiac conduction diseases, the Brugada syndrome, the sick sinus syndrome, a trial standstill, and numerous overlap syndromes. Patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases. However, they could not clarify how SCN5A mutations can be responsible for such a large spectrum of diseases, for the late age of onset or the progressiveness of some of these diseases and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological mechanisms of cardiac SCN5A-related arrhythmic syndromes and several mouse models have been established. This review presents the results obtained on these models that, for most of them, recapitulate the clinical phenotypes of the patients. This includes two models knocked out for Nav1.5 β1 and β3 auxiliary subunits that are also discussed. Despite their own limitations that we point out, the mouse models still appear as powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the secondary cellular consequences of SCN5A mutations such as the expression remodeling of other genes. This points out the potential role of these genes in the overall human phenotype. Finally, they constitute useful tools for addressing the role of genetic and environmental modifiers on cardiac electrical activity.

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Cardiac Histological Substrate in Patients With Clinical Phenotype of Brugada Syndrome

Cited by 324 publications

References 28 publications

Brugada syndrome: clinical and genetic findings

Brugada syndrome: clinical and genetic findings

Clarifying the Arrhythmogenic Substrate for Brugada Syndrome Electroanatomic Mapping Study of the Right Ventricle

Mouse models of SCN5A-related cardiac arrhythmias

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