Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch

Hoogendijk, Mark G.; Potse, Mark; Linnenbank, André C.; Verkerk, Arie O.; Ruijter, Hester M. den; Amersfoorth, Shirley C.M. van; Klaver, Eva C.; Beekman, Leander; Bezzina, Connie R.; Postema, Pieter G.; Tan, Hanno L.; Reimer, Annette; Wal, Allard C. van der; Harkel, Arend D J Ten; Dalinghaus, Michiel; Vinet, Alain; Wilde, Arthur A.M.; Bakker, Jacques M.T. de; Coronel, Ruben

doi:10.1016/j.hrthm.2009.10.007

Cited by 116 publications

(98 citation statements)

References 30 publications

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“…(25) We agree with others who have hypothesized that RV fibrosis, undetectable using current imaging technology, is also present in these patients and explains the BrS ECG phenotype. (11,12,29) Our data therefore lend support to the depolarization hypothesis and the presence of subtle structural abnormalities in patients with BrS.…”

Section: Left Ventricular Midwall Lge In Brssupporting

confidence: 81%

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

et al. 2017

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Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?, Heart Rhythm, http://dx.doi.org/10. 1016/j.hrthm.2016.12.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Left Ventricular Midwall Lge In Brssupporting

confidence: 81%

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

et al. 2017

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“…42 The second heart came from a loss-of-function mutation carrier in SCN5A, undergoing cardiac transplantation for end-stage heart failure in dilated cardiomyopathy. 69 In this heart, sodium channel blockade provoked right-sided STsegment elevation on a pseudo-ECG. Neither early repolarization nor late activation was found as a cause of the ST-segment elevation.…”

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

confidence: 95%

“…However, the ST-segment elevation did coincide with loss of local activation at the basal right ventricular subepicardium, which contained fibrosis and fatty infiltration. 69 Fibrosis and fatty infiltration form barriers that can create sites of sudden expansion of the myocardium. At the site of "tissue expansion," few myocytes have to produce the depolarizing current to excite a large mass of neighboring myocytes and conduction may fail (current-to-load mismatch).…”

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

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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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“…The development of conduction slowing and Brugada syndrome, besides sodium channel function, may also be influenced by cardiomyocyte coupling (through gap junctions) and collagen deposition, which may, in turn, be modulated by the inheritance of other genetic factors. 32,33 In this respect, the role of oligogenic inheritance in susceptibility to these disorders is becoming increasingly clear. 34 It could also be speculated that the R1638X truncated channel is associated with a trafficking defect and fails to bind with interacting partners at the cardiomyocyte membrane, which could affect interactions of the sodium channel macromolecular complex (eg, connexins), as opposed to the W156X, which is not expressed entirely because of NMD.…”

Section: Phenotype Of Hipsc-cms Carrying Mutations R1638x and W156xmentioning

confidence: 99%

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na _v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

Kosmidis

Veerman

Casini

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background-Several compounds have been reported to induce translational readthrough of premature stop codons resulting in the production of full-length protein by interfering with ribosomal proofreading. Here we examined the effect of 2 of these compounds, gentamicin and PTC124, in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes bearing nonsense mutations in the sodium channel gene SCN5A, which are associated with conduction disease and potential lethal arrhythmias. Methods and Results-We generated hiPSC from 2 patients carrying the mutations R1638X and W156X. hiPSC-derived cardiomyocytes from both patients recapitulated the expected electrophysiological phenotype, as evidenced by reduced Na + currents and action potential upstroke velocities compared with hiPSC-derived cardiomyocytes from 2 unrelated control individuals. While we were able to confirm the readthrough efficacy of the 2 drugs in Human Embryonic Kidney 293 cells, we did not observe rescue of the electrophysiological phenotype in hiPSC-derived cardiomyocytes from the patients. Conclusions-We conclude that these drugs are unlikely to present an effective treatment for patients carrying the loss-of-function SCN5A gene mutations examined in this study. (Circ Arrhythm Electrophysiol. 2016;9:e004227.

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Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch

Cited by 116 publications

References 30 publications

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

The Brugada ECG Pattern

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na _v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

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Mechanism of right precordial ST-segment elevation in structural heart disease: Excitation failure by current-to-load mismatch

Cited by 116 publications

References 30 publications

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

Late gadolinium enhancement in Brugada syndrome: A marker for subtle underlying cardiomyopathy?

The Brugada ECG Pattern

Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A

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Product

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Readthrough-Promoting Drugs Gentamicin and PTC124 Fail to Rescue Na _v 1.5 Function of Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes Carrying Nonsense Mutations in the Sodium Channel Gene SCN5A