The implications of genetic mutations in the sodium channel gene (SCN5A)

Moric, Ewa; Herbert, Ernest; Trusz‐Gluza, Maria; Filipecki, Artur; Mazurek, Urszula; Wilczok, Tadeusz

doi:10.1016/s1099-5129(03)00085-0

Cited by 46 publications

(37 citation statements)

References 82 publications

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“…Mutations in the cardiac sodium channel gene SCN5A are responsible for type-3 long QT disease that leads to sudden cardiac death. It produces a persistent sodium current in the plateau phase of cardiac action potential and results in lethal arrhythmias (Clancy and Rudy, 1999;Chiang and Roden, 2000;Moric et al, 2003;Xiao-Li et al, 2004). It was mentioned earlier that, at the molecular level, aconitine binds to Na ϩ channels and prolongs their open-state favoring entry of a large quantity of Na ϩ into cytosol and eventually induces triggered activity (Sawanobori et al, 1987;Watano et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

Amran¹,

Hashimoto²,

Homma³

2004

J Pharmacol Exp Ther

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The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501-1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 M) suppressed abnormal electrical activity induced by aconitine, but SEA (100 M) did not show such effects. KBR (10 M) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1-100 M) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na ϩ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.

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Section: Discussionmentioning

confidence: 99%

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

Amran¹,

Hashimoto²,

Homma³

2004

J Pharmacol Exp Ther

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“…Several SCN5A review articles were also quite useful. 30,31 Brugada syndrome is characterized by ST-segment elevation in the right precordial leads (V1 to V3) and, in some patients, right bundle-branch block, with propensity for ventricular fibrillation and sudden death, often nocturnally. 32 The incidence varies between 5 and 66 persons per 10,000 in wellstudied Asian areas, but is thought to be much less in the United States and Europe.…”

Section: Disease Associationsmentioning

confidence: 99%

“…SCN5A article reviews list 67 Brugada syndrome mutations overall, of which 49 are distinct to Brugada syndrome alone, the remaining being shared with other SCN5A syndromes. 30 Four SCN5A mutations -D1114N, 14 delK1500, 31 E1784K, 14,31 and 1795insD 14 31 PCCD, also called Lenegre-Lev's disease, is one of the most common cardiac conduction disturbances, which cause disability in millions of people worldwide, often lead to pacemaker implants, and can be fatal. PCCD is characterized by progressive, age-related slowing of cardiac conduction through the His-Purkinje system, right or left bundle branch block, and prolongation of the PR rather than the QT interval.…”

Section: Disease Associationsmentioning

confidence: 99%

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

Modell

Lehmann

2006

Genetics in Medicine

147

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Long QT syndrome (LQTS) refers to a group of "channelopathies"-disorders that affect cardiac ion channels. The "family" concept of syndromes has been applied to the multiple LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT prolongation and slowed ventricular repolarization. The 470ϩ allelic mutations induce loss-of-function in the passage of mainly K ϩ ions, and gain-of-function in the passage of Na ϩ ions through their respective ion channels. Resultant early after depolarizations can lead to a polymorphic form of ventricular tachycardia known as torsade de pointes, resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted either spontaneously or with external defibrillation). LQTS may be either congenital or acquired. The genetic epidemiology of both forms can vary with subpopulation depending on the allele, but as a whole, LQTS appears in every corner of the globe. Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A

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“…SCN5A R104Q and SCN5A E1784K mutations were excluded due to being associated with both LQTS and Brugada syndrome (Moric et al, 2003). The genetic test results were reviewed in 2016.…”

Section: Participants and Proceduresmentioning

confidence: 99%

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

Wesołowska

Elovainio

Koponen

et al. 2016

Journal of Genetic Counseling

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We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships.The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, β-blockers, antidepressants, and social support (OR = 1.09, 95% CI [1.02, 1.15], p = .007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR = 1.10, 95% CI [1.03, 1.19], p = .009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.

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The implications of genetic mutations in the sodium channel gene (SCN5A)

Cited by 46 publications

References 82 publications

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

The long QT syndrome family of cardiac ion channelopathies: A HuGE review

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

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