Abnormal expression of cardiac neural crest cells in heart development: A different hypothesis for the etiopathogenesis of Brugada syndrome

Elizari, Marcelo V.; Levi, Raúl J.; Acunzo, Rafael S.; Chiale, Pablo A.; Civetta, María M.; Ferreiro, Marcela; Sicouri, Serge

doi:10.1016/j.hrthm.2006.10.026

Cited by 71 publications

(47 citation statements)

References 31 publications

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“…The embryological origin (contributions of the second heart field, neural crest cells) of the right ventricle differs from left ventricle and has been suggested to predispose the right ventricle to arrhythmias in adulthood. 75,76 The adult right Figure 2. Illustration depicting the role of the cardiac sodium (I Na ), L-type calcium (I CaL ) and transient outward current (I to ) and the extent of structural abnormalities in conduction block by current-to-load mismatch, which can result in excitation failure or activation delay of the subepicardium.…”

Section: A Unifying Hypothesis Of the Brugada Syndrome: Two Conspirinmentioning

confidence: 99%

The Brugada ECG Pattern

Hoogendijk

Opthof

Postema

et al. 2010

Circ: Arrhythmia and Electrophysiology

130

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I n 1992, Brugada and Brugada introduced a new clinical entity characterized by right precordial ST-segment elevation followed by a negative T-wave and a high incidence of ventricular fibrillation (VF) in the absence of structural heart disease. 1 The typical ECG anomaly is currently known as the Brugada ECG pattern and the conglomerate of features as the Brugada syndrome. Over the years, the Brugada syndrome has been recognized as an important cause of sudden cardiac death in young men, especially in Southeast Asia, 2 and has attracted much attention from researchers and clinicians alike. This has led to substantial progress in identification of modulating factors of the Brugada ECG pattern, the associated ventricular arrhythmias, and in the risk stratification of patients. 3 However, the development of effective therapeutic strategies has lagged behind. Currently, symptomatic treatment with implantable cardioverterdefibrillators (ICDs) is the mainstay in the prevention of sudden cardiac death, 3 although it is costly and associated with a high risk of complications. 4 The pathophysiological mechanism of the Brugada syndrome remains elusive, 5 and no single causal factor appears to link all patients. The Brugada ECG pattern is modulated by genetic mutations and pharmacological agents that alter the function of ion channels active during the early phases of the action potential. Furthermore, signs of right ventricular structural abnormalities are often found in patients with Brugada syndrome. The aim of this study is to review the available literature on the Brugada syndrome in an attempt to provide a unifying hypothesis of the mechanism of the Brugada syndrome. This unifying hypothesis should be able to explain the ECG pattern, the arrhythmogenic mechanism, their modulation by ion channels, and the relation of structural abnormalities to the Brugada syndrome. Is the Brugada Syndrome a Channelopathy?The Brugada syndrome was introduced shortly after the first demonstration of statistical linkage between the long-QT syndrome (LQTS) and a gene locus. 6 Since then, genetic mutations that alter ion channel functions and prolong the QT duration were linked with the LQTS. 7 These observations defined the LQTS as a channelopathy. In analogy with the LQTS, a hereditary pattern was suspected in half the Brugada syndrome cases. Additionally, no structural heart disease was demonstrated, suggesting that the Brugada syndrome also was a channelopathy. 1 Over the years, this analogy was substantiated by further observations of similarity with the LQTS. GeneticsGenetic mutations that alter ion channel functions have been identified in patients with Brugada syndrome. The first identified mutations were located in SCN5A, the gene encoding the ␣-subunit of the cardiac sodium channel, leading to reduced cardiac sodium current (I Na ). 8 The prevalence of SCN5A mutations is Ϸ20% 9 and is higher in patients with than without a family history of Brugada syndrome. 10 Recently, mutations in GPD1L 11 , a gene probably involved in the tra...

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Section: A Unifying Hypothesis Of the Brugada Syndrome: Two Conspirinmentioning

confidence: 99%

The Brugada ECG Pattern

Hoogendijk

Opthof

Postema

et al. 2010

Circ: Arrhythmia and Electrophysiology

130

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“…The neural crest theory (development abnormality) underlines the complex nature of the RV [33]. Abnormal RVOT tissue may affect gap junctions and/or ionic currents, may change action potential and, under provoking factors, result in local slow conduction and/or heterogenous repolarization (Figure 2) [33]. This hypothesis is consistent with possible somatic mutations in BrS and explains cases of non-familial BrS occurrence [28].…”

Section: Mechanisms In Brs Pathogenesismentioning

confidence: 81%

“…Interestingly, the depolarization theory is also supported by a local 2:1 conduction block which was observed during VF/ventricular flutter over the right ventricle (RV) [32]. Cardiac neural crest cells are required in the development of RVOT [33]. The neural crest theory (development abnormality) underlines the complex nature of the RV [33].…”

Section: Mechanisms In Brs Pathogenesismentioning

confidence: 99%

“…Cardiac neural crest cells are required in the development of RVOT [33]. The neural crest theory (development abnormality) underlines the complex nature of the RV [33]. Abnormal RVOT tissue may affect gap junctions and/or ionic currents, may change action potential and, under provoking factors, result in local slow conduction and/or heterogenous repolarization (Figure 2) [33].…”

Section: Mechanisms In Brs Pathogenesismentioning

confidence: 99%

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Brugada syndrome: current diagnostics, epidemiology, genetic data and novel mechanisms (RCD code: V-1A.1)

Matusik

Pudło

Rydlewska

et al. 2017

Journal of Rare Cardiovascular Diseases

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Brugada syndrome (BrS) is a cardiac channelopathy associated with ventricular arrhythmias and sudden cardiac death. Diagnosis of BrS is based on type 1 BrS electrocardiogram (ECG) pattern (coved pattern) presence, observed spontaneously or after provocation test. The worldwide prevalence of BrS ECG patterns is estimated to reach 0.4% and strongly depends on the population studied. BrS results from various genetic mutations of sodium, calcium and potassium channels and/or associated proteins affecting ion currents. SCN5A mutations are the most prevalent in BrS. Pathogenesis of BrS is explained by the depolarization theory, the repolarization theory and the neural crest theory, which seem to be complimentary, at least partially. This review summarizes current diagnostic criteria of BrS and epidemiology of BrS ECG patterns. We also discuss the recent understanding of BrS pathophysiology and the role of genetic testing in BrS. JRCD 2017; 3 (3): 73-80

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“…Abnormal expression of cardiac neural crest cells in the heart development was regarded as the etiopathogenesis of Brugada syndrome, reported by Elizari et al [68]. The studies had shown that conditional knockout of Cx43 in neural crest cells led to selective dilatation of the outflow tracts in the mouse, reported by Ewart et al [69].…”

Section: Ventricular Tachyarrhythmogenesis and Automatic Nervous Actimentioning

confidence: 99%

Spontaneous high-frequency action potential

Shen

Choe

2011

Sci. China Life Sci.

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Action potential, which is the foundation of physiology and electrophysiology, is most vital in physiological research. This work starts by detecting cardiac electrophysiology (tachyarrhythmias), combined with all spontaneous discharge phenomena in vivo such as wound currents and spontaneous neuropathic pain, elaborates from generation, induction, initiation, to all of the features of spontaneous high-frequency action potential--SSL action potential mechanism, i.e., connecting-end hyperpolarization initiates spontaneous depolarization and action potential in somatic membrane. This work resolves the conundrums of in vivo spontaneous discharge in tachyarrhythmias, wounds, denervation supersensitivity, neurogenic pain (hyperalgesia and allodynia), epileptic discharge and diabetic pain in pathophysiological and clinical researches that have puzzled people for a hundred years. action potential, spontaneous high-frequency action potential, tachyarrhythmias, atrial fibrillation, wound, denervation supersensitivity, neurogenic pain, hyperalgesia and allodynia, epileptic discharge, diabetic pain, regeneration and development Citation:Shen H Y, Choe W C. Spontaneous high-frequency action potential. Sci China Life Sci, 2011Sci, , 54: 311 -335, doi: 10.1007 Wound, nerve disconnection, and atrial fibrillation (AF) induced by the excessive atrial dilation, are commonly characterized by the spontaneous repetitive discharge. Their common induction is the disconnection of intercellular connection, and their common result is the initiation of spontaneous high-frequency discharge, which discloses the existence of the special action of intercellular connection.The Hodgkin-Huxley model has predicted, and the computer models in applied mathematics have well demonstrated, that potassium leakage causes persistent spontaneous electrifying state with spontaneous oscillation of high-frequency action potential. The sustained disconnection of connecting-end space induces potassium leakage in the connecting-end and consequently the sustained reduction of [K + ] i , which induces in vivo spontaneous high-frequency action potential in plasmalemma.To form an intercellular conduction, connecting-end space exerts action on ion diffusions, the alteration of the space alters ion diffusions (i.e., ionic permeability) in the connecting-end. The abolishment of connecting-end space action causes K + leakage and consequently the reduction of intracellular positive electropotential (IPE) (i.e., the increase of intracellular negative potential), which elevates resting somatic membrane potential and initiates action potential in somatic membrane. SSL action potential is named to the course from the initiation (i.e., connecting-end hyperpolarization) to the termination of somatic membrane action potential.Tachyarrhythmias that are characterized by spontaneous discharge have been most deeply studied. Their inductions contain both mechanical actions and chemical actions, and their courses contain the transformation from traditional action potential to SSL-ty...

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Abnormal expression of cardiac neural crest cells in heart development: A different hypothesis for the etiopathogenesis of Brugada syndrome

Cited by 71 publications

References 31 publications

The Brugada ECG Pattern

The Brugada ECG Pattern

Brugada syndrome: current diagnostics, epidemiology, genetic data and novel mechanisms (RCD code: V-1A.1)

Spontaneous high-frequency action potential

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