The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth, Balázs; Bers, Donald M.

doi:10.1002/2055-5822.12003

Cited by 10 publications

(15 citation statements)

References 180 publications

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“…This may be related to the well-known fact that ATX-II slows inactivation of Na + channels [33]. ATX-II is widely used for mimicking pharmacologically the consequences of an augmented I Nalate , which is often seen under pathological conditions [5] and ATX-II is a widely used pharmacological tool to model this. In canine myocytes (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, the elevation of I Na-late results in increased arrhythmia propensity (e.g. in heart failure) including prolongation of the action potential duration (APD), increased inhomogeneity of repolarization and occurrence of early as well as delayed afterdepolarizations [5,[12][13][14]. Therefore, as a new concept, intensive efforts were made recently to develop selective inhibitors of I Na-late [9,15,16].…”

Section: Introductionmentioning

confidence: 99%

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Late sodium current in human, canine and guinea pig ventricular myocardium

Horváth

Hézsô

Szentandrássy

et al. 2020

Journal of Molecular and Cellular Cardiology

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Although late sodium current (I Na-late) has long been known to contribute to plateau formation of mammalian cardiac action potentials, lately it was considered as possible target for antiarrhythmic drugs. However, many aspects of this current are still poorly understood. The present work was designed to study the true profile of I Nalate in canine and guinea pig ventricular cells and compare them to I Na-late recorded in undiseased human hearts. I Na-late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp conditions using either canonic-or self-action potentials as command signals. Under action potential voltage clamp conditions the amplitude of canine and human I Na-late monotonically decreased during the plateau (decrescendoprofile), in contrast to guinea pig, where its amplitude increased during the plateau (crescendo profile). The decrescendo-profile of canine I Na-late could not be converted to a crescendo-morphology by application of ramplike command voltages or command action potentials recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the crescendo I Na-late profile in guinea pig was due to the slower decay of I Na-late in this species. When action potentials were recorded from multicellular ventricular preparations with sharp microelectrode, action potentials were shortened by tetrodotoxin, which effect was the largest in human, while smaller in canine, and the smallest in guinea pig preparations. It is concluded that important interspecies differences exist in the behavior of I Na-late. At present canine myocytes seem to represent the best model of human ventricular cells regarding the properties of I Na-late. These results should be taken into account when pharmacological studies with I Na-late are interpreted and extrapolated to human. Accordingly, canine ventricular tissues or myocytes are suggested for pharmacological studies with I Na-late inhibitors or modifiers. Incorporation of present data to human action potential models may yield a better understanding of the role of I Na-late in action potential morphology, arrhythmogenesis, and intracellular calcium dynamics. with physiological and pathological significance recognized long ago [1-3], its pathophysiological role in LQT3 [4] and heart failure [5-8] has been emphasized only in the last decades. I Na-late-as an inward current-contributes to plateau formation and is responsible for largely

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Late sodium current in human, canine and guinea pig ventricular myocardium

Horváth

Hézsô

Szentandrássy

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…To validate the "#% model equation, simulated current-voltage relationship (I-V curve) were compared to experimental data as shown in Figure 1. The conductance of the WT "#% was chosen to be 0.5% of that of "#$ illustrated in literature [14,15]. Specifically, the model of the "#% was given by the following equation:…”

Section: Methodsmentioning

confidence: 99%

In Silico Investigation of the Functional Impact of SCN10A Mutations in Human Atrial Cells

Nemi

Zhang

2018

2018 Computing in Cardiology Conference (CinC)

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In normal conditions, action potential (AP) in cardiac myocytes is initiated by peak sodium current "#$ , which become inactivated during depolarization, leaving a less pronounce current known as late sodium current ("#%), which has a relatively smaller amplitude (~0.5%) compared to the "#$. A recent study has identified three gain-of-function mutations in the SCN10A channel (the gene encoding the voltage-gated sodium channel (1.8, "#%) that have a correlation with the subsequent development of atrial fibrillation. However, the underlying mechanism responsible for the pro-arrhythmic effect of the gene mutations is unclear. This study aims to investigate the effect of the three gene mutations on atrial electrical action potentials. Hodgkin-Huxley (HH) formulation of late sodium channel current in human atrial cells was developed and validated against experimental data obtained by voltage clamp techniques. The formulation was then implemented in Colman et al. human atrial model to simulate atrial APs for wild type (WT) and mutation conditions. It was shown that A1073 and P1092 mutations prolong the action potential duration (APD) and elevate the plateau (phase 2) potential compared to WT. Such altered AP profiles may alter tissue's spatial heterogeneity, favoring the initiation and maintenance of atrial fibrillation, which warrants future study.

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“…5 The transient mode is responsible for the peak Na + current (I Na ) during phase 0 and lasts for about 1 ms. 5,6 After the peak I Na , Na + channels quickly become inactivated, resulting in the burst and late-scattered modes responsible for a sustained current component that lasts up to 100 ms during the plateau phase of action potential and is referred to as ''late I Na '' (Figure 1). 7 The amplitude of late I Na represents 0.1% to 1% of that of peak I Na ; however, because of the relatively longer duration of plateau phase 2 compared with phase 0, the net late Na + influx is comparable with the peak Na + influx. 8,9 Role of Late I Na Current in Atrial and Ventricular Arrhythmias Enhanced late I Na in atrial myocytes has been shown to lower the threshold of action potential firing, initiate diastolic depolarization, and increase excitability, and hence the risk of atrial arrhythmias, mainly atrial fibrillation (AF; Figure 2).…”

Section: Biology Of the Sodium Channelsmentioning

confidence: 97%

“…8,9 Role of Late I Na Current in Atrial and Ventricular Arrhythmias Enhanced late I Na in atrial myocytes has been shown to lower the threshold of action potential firing, initiate diastolic depolarization, and increase excitability, and hence the risk of atrial arrhythmias, mainly atrial fibrillation (AF; Figure 2). 7 On the other side, several electrophysiological mechanisms result in the initiation of ventricular arrhythmias, including triggered activity (which is either early after depolarization [EAD] or delayed after depolarization [DAD]), abnormal automaticity, and reentry. 10 Patients with cardiomyopathies may have increased transmural dispersion of repolarization (TDR), which is considered one of the Figure 1.…”

Section: Biology Of the Sodium Channelsmentioning

confidence: 99%

Ranolazine in Cardiac Arrhythmia

Saad

Mahmoud

Elgendy

et al. 2015

Clinical Cardiology

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Ranolazine utilization in the management of refractory angina has been established by multiple randomized clinical studies. However, there is growing evidence showing an evolving role in the field of cardiac arrhythmias. Multiple experimental and clinical studies have evaluated the role of ranolazine in prevention and management of atrial fibrillation, with ongoing studies on its role in ventricular arrhythmias. In this review, we will discuss the pharmacological, experimental, and clinical evidence behind ranolazine use in the management of various cardiac arrhythmias.

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The late sodium current in heart failure: pathophysiology and clinical relevance

Cited by 10 publications

References 180 publications

Late sodium current in human, canine and guinea pig ventricular myocardium

Late sodium current in human, canine and guinea pig ventricular myocardium

In Silico Investigation of the Functional Impact of SCN10A Mutations in Human Atrial Cells

Ranolazine in Cardiac Arrhythmia

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