Misplaced Brain Sodium Channels in Heart Kindle Sudden Death in Epilepsy

George, Alfred L.

doi:10.1161/circep.115.003261

Cited by 3 publications

(3 citation statements)

References 20 publications

(21 reference statements)

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“…Indeed, in a transgenic mouse model of epilepsy ( Scn2a Q54 ), the I Na-L was found to be increased significantly from 1 to 3 percent of peak I Na and importantly the specific I Na-L blocker prototype GS-967, mitigated epileptic attacks (Anderson et al, 2014 ). These findings suggest that the gating modifiers of Nav channels may be effective and target specific anti-epileptics (Anderson et al, 2014 ; George, 2015 ).…”

Section: Enhancement Of I Na−l and Late I mentioning

confidence: 99%

Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets

et al. 2017

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While recent advances clarified the molecular and cellular modes of action of antiarrhythmic drugs (AADs), their link to suppression of dynamical arrhythmia mechanisms remains only partially understood. The current classifications of AADs (Classes I, III, and IV) rely on blocking peak Na, K and L-type calcium currents (ICa,L), with Class II with dominant beta receptor blocking activity and Class V including drugs with diverse classes of actions. The discovery that the calcium and redox sensor, cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) enhances both the late Na (INa-L) and the late ICa,L in patients at high risk of VT/VF provided a new and a rational AAD target. Pathological rise of either or both of INa-L and late ICa,L are demonstrated to promote cellular early afterdepolarizations (EADs) and EAD-mediated triggered activity that can initiate VT/VF in remodeled hearts. Selective inhibition of the INa-L without affecting their peak transients with the highly specific prototype drug, GS-967 suppresses these EAD-mediated VT/VFs. As in the case of INa-L, selective inhibition of the late ICa,L without affecting its peak with the prototype drug, roscovitine suppressed oxidative EAD-mediated VT/VF. These findings indicate that specific blockers of the late inward currents without affecting their peaks (gating modifiers), offer a new and effective AAD class action i.e., “Class VI.” The development of safe drugs with selective Class VI actions provides a rational and effective approach to treat VT/VF particularly in cardiac conditions associated with enhanced CaMKII activity such as heart failure.

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Section: Enhancement Of I Na−l and Late I mentioning

confidence: 99%

Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets

et al. 2017

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“…Aberrant initiation of APs themselves could produce all three conditions for re-entry: unidirectional block, slowed conduction and a refractory core around which an AP can circulate [87] . Interestingly, in sudden unexplained death in epilepsy (SUDEP), a possible explanation is ventricular arrhythmias [88] , [89] . The proposed mechanism is AP prolongation due to increased contributions of neuronal sodium channel isoforms to the late component of I Na ( I Na, L ), similar to that of LQTS type 3 [88] , [89] .…”

Section: Sodium Channelsmentioning

confidence: 99%

Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions

Tse

Yeo

2015

IJC Heart & Vasculature

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Ventricular arrhythmias arise from disruptions in the normal orderly sequence of electrical activation and recovery of the heart. They can be categorized into disorders affecting predominantly cellular depolarization or repolarization, or those involving action potential (AP) conduction. This article briefly discusses the factors causing conduction abnormalities in the form of unidirectional conduction block and reduced conduction velocity (CV). It then examines the roles that sodium channels and gap junctions play in AP conduction. Finally, it synthesizes experimental results to illustrate molecular mechanisms of how abnormalities in these proteins contribute to such conduction abnormalities and hence ventricular arrhythmogenesis, in acquired pathologies such as acute ischaemia and heart failure, as well as inherited arrhythmic syndromes.

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“…Recent studies have implicated calmodulin mutations in patients suffering from a LQTS with previously unidentified genetic causes [17], [18], [19]. Moreover, a long QT phenotype has been implicated in sudden unexpected death in epilepsy (SUDEP), caused by increased late Na + current ( I Na, L ) mediated by neuronal Na + channel isoforms [20], [21].…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological mechanisms of long and short QT syndromes

Tse

Chan

Keung

et al. 2017

IJC Heart & Vasculature

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The QT interval on the human electrocardiogram is normally in the order of 450 ms, and reflects the summated durations of action potential (AP) depolarization and repolarization of ventricular myocytes. Both prolongation and shortening in the QT interval have been associated with ventricular tachy-arrhythmias, which predispose affected individuals to sudden cardiac death. In this article, the molecular determinants of the AP duration and the causes of long and short QT syndromes (LQTS and SQTS) are explored. This is followed by a review of the recent advances on their arrhythmogenic mechanisms involving reentry and/or triggered activity based on experiments conducted in mouse models. Established and novel clinical risk markers based on the QT interval for the prediction of arrhythmic risk and cardiovascular mortality are presented here. It is concluded by a discussion on strategies for the future rational design of anti-arrhythmic agents.

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Misplaced Brain Sodium Channels in Heart Kindle Sudden Death in Epilepsy

Cited by 3 publications

References 20 publications

Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets

Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets

Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions

Electrophysiological mechanisms of long and short QT syndromes

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