The complexity of genotype-phenotype relations associated with loss-of-function sodium channel mutations and the role of in silico studies

Wilde, Arthur A.M.; Coronel, Ruben

doi:10.1152/ajpheart.00494.2008

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…Furthermore, the mouse model closely reproduces many of the key human features of BrS, including ST elevation [7], and both slowed conduction and repolarization heterogeneities leading to ventricular arrhythmogenesis originating in the RV, as demonstrated in mapping experiments [8]. It also shows the complex range of further phenotypes that include sick sinus syndrome and progressive conduction disorders associated with the clinical SCN5A gene modification [9]. Finally, Scn5a+/− hearts show fibrosis and reduced connexin expression that worsens with age [2], in line with similar clinical findings [10].…”

Section: Introductionmentioning

confidence: 99%

Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

et al. 2012

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Brugada syndrome (BrS) is associated with ventricular tachycardia originating particularly in the right ventricle (RV). We explore electrophysiological features predisposing to such arrhythmic tendency and their possible RV localization in a heterozygotic Scn5a+/− murine model. Nav1.5 mRNA and protein expression were lower in Scn5a+/− than wild-type (WT), with a further reduction in the RV compared with the left ventricle (LV). RVs showed higher expression levels of Kv4.2, Kv4.3 and KChIP2 in both Scn5a+/− and WT. Action potential upstroke velocity and maximum Na+ current (INa) density were correspondingly decreased in Scn5a+/−, with a further reduction in the RV. The voltage dependence of inactivation was shifted to more negative values in Scn5a+/−. These findings are predictive of a localized depolarization abnormality leading to slowed conduction. Persistent Na+ current (IpNa) density was decreased in a similar pattern to INa. RV transient outward current (Ito) density was greater than LV in both WT and Scn5a+/−, and had larger time constants of inactivation. These findings were also consistent with the observation that AP durations were smallest in the RV of Scn5a+/−, fulfilling predictions of an increased heterogeneity of repolarization as an additional possible electrophysiological mechanism for arrhythmogenesis in BrS.

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Section: Introductionmentioning

confidence: 99%

Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

et al. 2012

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“…Our group has produced a heterozygotic Scn5a +/− mouse, which shows a 50% reduction in the transmembrane Na + current (20). While loss of function mutations in the SCN5A gene both clinically (30) and in our mouse model (20) may lead to a complex range of phenotypes, incorporating sick sinus syndrome and progressive conduction disorders, the Scn5a +/− mouse has been shown to closely reproduce many of the key human features of BrS. Thus it demonstrates ST elevation (16) and an enhanced ventricular arrhythmogenesis that is exacerbated by flecainide and relieved by quinidine (16, 17).…”

mentioning

confidence: 96%

Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/− mouse model

Martin

Guzadhur

Grace

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Two major mechanisms have been postulated for the arrhythmogenic tendency observed in Brugada Syndrome (BrS): delays in conduction or increased heterogeneities in repolarization. We use a contact mapping system to directly investigate the interacting roles of these two mechanisms in arrhythmogenesis using a genetic murine model for BrS for the first time. Electrograms were obtained from a multielectrode recording array placed against the left ventricle and right ventricle (RV) of spontaneously beating Langendorff-perfused wild type (WT) and Scn5a+/− mouse hearts. Scn5a+/− hearts showed activation waves arriving at the epicardial surface consistent with slowed conduction, which was exacerbated in the presence of flecainide. Lines of conduction block across the RV resulting from premature ventricular beats led to the formation of reentrant circuits and polymorphic ventricular tachycardia. WT hearts showed an inverse relationship between activation times and activation recovery intervals measured at the epicardial surface, which resulted in synchronicity of repolarization times. In contrast, Scn5a+/− hearts, despite having smaller mean activation recovery intervals, demonstrated a greater heterogeneity compared with WT. Isochronal maps showed that their normal activation recovery interval gradients at the epicardial surface were disrupted, leading to heterogeneity in repolarization times. We thus directly demonstrate the initiation of arrhythmia in the RV of Scn5a+/− hearts. This occurs as a result of the combination of repolarization heterogeneities leading to lines of conduction block and unidirectional conduction, with conduction slowing allowing the formation of reentrant circuits. The repolarization heterogeneities may also be responsible for the changing pattern of block, leading to the polymorphic character of the resulting ventricular tachycardia.

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“…BrS stands out as the most extensively characterized among the sodium (Na + ) channelopathy disorders linked to a decrease or loss of function in Na + channels caused by mutations within the SCN5A gene and its related proteins [26]. The primary approach to diagnosing BrS is through clinical evaluation.…”

Section: Brugada Syndromementioning

confidence: 99%

Recent Advances in Inherited Cardiac Arrhythmias and Their Genetic Testing

Huse,

Acharya,

Agrawal

et al. 2023

Cureus

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Inherited arrhythmias, encompassing conditions such as cardiomyopathies, cardiac ion channel disorders, and coronary heart disease, represent the common causes that elevate the threat of sudden cardiac death among adults. Researchers have pinpointed the genes responsible for these hereditary arrhythmias in the last 30 years. Concurrently, it has become clear that the genetic makeup underlying these conditions is more intricate than previously understood. Evolution in DNA sequencing techniques, particularly next-generation sequencing, has empowered us to learn these intricate hereditary characteristics. Genetic testing is crucial in diagnosing, assessing risk, and determining treatment for individuals with these conditions and their family members. The need for collaborative endeavors to comprehend and address these uncommon yet potentially life-threatening disorders is becoming more evident. This review aims to inform readers of the latest advances in understanding hereditary arrhythmias and provide the groundwork for collaborative genetic testing initiatives to characterize these disorders in the general population.

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The complexity of genotype-phenotype relations associated with loss-of-function sodium channel mutations and the role of in silico studies

Cited by 6 publications

References 19 publications

Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/− mouse model

Recent Advances in Inherited Cardiac Arrhythmias and Their Genetic Testing

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The complexity of genotype-phenotype relations associated with loss-of-function sodium channel mutations and the role of in silico studies

Cited by 6 publications

References 19 publications

Reduced Na + and higher K + channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Reduced Na + and higher K + channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Mapping of reentrant spontaneous polymorphic ventricular tachycardia in a Scn5a+/− mouse model

Recent Advances in Inherited Cardiac Arrhythmias and Their Genetic Testing

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Product

Resources

About

Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice

Reduced Na ⁺ and higher K ⁺ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/− mice