An Emerging Antiarrhythmic Target: Late Sodium Current

Bányász, Tamás; Szentandrássy, Norbert; Magyar, János; Szabó, Zoltán; Nánási, Péter P.; Chen‐Izu, Ye; Izu, Leighton T.

doi:10.2174/1381612820666141029111729

Cited by 11 publications

(9 citation statements)

References 246 publications

(405 reference statements)

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“…Perhaps the phenotype of Q1909R becomes manifest only in specific circumstances, which may not be apparent in healthy sedentary laboratory animals. For instance, a bevy of other cellular factors and conditions have been shown to upregulate late Na + current( 42 , 43 ), including heart failure ( 44 ), hypoxia ( 45 , 46 ), reactive oxygen species ( 45 ), CaMKII-dependent phosphorylation ( 47 , 48 ), and altered interaction with other regulatory proteins ( 49 , 50 ). It is possible that some of these processes may be linked to FHF modulation of Na V 1.5.…”

Section: Discussionmentioning

confidence: 99%

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Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Abrams¹,

Roybal²,

Chakouri³

et al. 2020

JCI Insight

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The Ca 2+ -binding protein calmodulin has emerged as a pivotal player in tuning Na + channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the Na V 1.5 interactome in regulating late Na + current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human Na V 1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na + current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human Na V 1.5 demonstrated increased late Na + current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na + current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the Na V 1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing Na V 1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na + current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na + current.

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Section: Discussionmentioning

confidence: 99%

“…Heterologous expression studies suggest that the protection is due to FGF13, which is colocalized with Na V 1.5 in murine cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na + current, a highly sought-after drug target ( 42 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Abrams¹,

Roybal²,

Chakouri³

et al. 2020

JCI Insight

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“…CARDIAC LATE NA ϩ CURRENT (I NaL ) is increased in a number of heart diseases (16,28,30). Enhanced I NaL leads to Ca 2ϩ overload via reverse mode operation of Na ϩ /Ca 2ϩ exchanger (NCX) (2,3,5,26). Cardiomyocytes obtained from animals with chronic heart failure (29) as well as from patients with hypertrophic cardiomyopathy (9) have been shown to have increased I NaL leading to increased diastolic intracellular Ca 2ϩ ([Ca 2ϩ ] i ).…”

mentioning

confidence: 99%

Inhibition of late Na⁺ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats

Chi

Belardinelli

Zeng

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Late Na(+) current (INaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of INaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent INaL inhibitor on mechanical and electrical abnormalities, were determined in an animal model of diastolic dysfunction. Dahl salt-sensitive (DSS) rats fed a high-salt (HS) diet for 8 wk, compared with a normal salt (NS) diet, had increased left ventricular (LV) mass (1,257 ± 96 vs. 891 ± 34 mg) and diastolic dysfunction [isovolumic relaxation time (IVRT): 26.8 ± 0.5 vs. 18.9 ± 0.2 ms; early transmitral flow velocity/early mitral annulus velocity (E/E') ratio: 25.5 ± 1.9 vs. 14.9 ± 0.9]. INaL in LV myocytes from HS rats was significantly increased to 0.41 ± 0.02 from 0.14 ± 0.02 pA/pF in NS rats. The action potential duration (APD) was prolonged to 136 ± 12 from 68 ± 9 ms in NS rats. QTc intervals were longer in HS vs. NS rats (267 ± 8 vs. 212 ± 2 ms). Acute and chronic treatment with GS-967 decreased the enhanced INaL to 0.24 ± 0.01 and 0.17 ± 0.02 pA/pF, respectively, vs. 0.41 ± 0.02 pA/pF in the HS group. Chronic treatment with GS-967 dose-dependently reduced LV mass, the increases in E/E' ratio, and the prolongation of IVRT by 27, 27, and 20%, respectively, at the 1.0 mg·kg(-1)·day(-1) dose without affecting blood pressure or LV systolic function. The prolonged APDs in myocytes and QTc of HS rats were significantly reduced with GS-967 treatment. These results indicate that INaL is a significant contributor to the LV diastolic dysfunction, hypertrophy, and repolarization abnormalities and thus, inhibition of this current is a promising therapeutic target for diastolic heart failure.

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“…Protein kinase C (PKC) is a group of serine-threonine protein kinases, and there are at least seven members identified in mammalian myocardium [28]. Some of them are calcium-dependent and others that are insensitive to Ca 2+ could be activated by diacylglycerol (DAG) or lipid-derived second messengers [29].…”

Section: The Mechanism Of Endogenous and Enhanced Late Inamentioning

confidence: 99%

Late sodium current associated cardiac electrophysiological and mechanical dysfunction

Huang

et al. 2017

Pflugers Arch - Eur J Physiol

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Late sodium current (I) is a small sustained inward current observed during the cardiac action potential plateau phase following decay of the early peak I. The endogenous I is relatively small in normal hearts but exerts functionally significant effects on cardiomyocyte repolarization with potentially pro-arrhythmic effects in hearts with reduced repolarization reserve. Enhanced I occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure. It may there play important roles in arrhythmogenesis and mechanical dysfunction. Experimental and clinical research suggests that I inhibition may prevent and treat cardiac arrhythmias and improve ventricular pump function. Selective I inhibitors, exemplified by ranolazine, GS-967 and GS-458967 have little or no effect on peak sodium current and/or I, and carry no or minimal pro-arrhythmic risk compared to those associated with administration of classical class I or III antiarrhythmic drugs, particularly in patients with ischemic heart disease. This increased understanding of I may be encouraging to clinicians in use of I inhibitors to treat cardiac arrhythmias and mechanical dysfunction directly associated with enhanced I such as LQTS type 3, and myocardial ischemia. This review discusses the roles of endogenous and enhanced I in arrhythmogenesis and mechanical dysfunction, and the basic and clinical research of I inhibitors.

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An Emerging Antiarrhythmic Target: Late Sodium Current

Cited by 11 publications

References 246 publications

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Inhibition of late Na⁺ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats

Late sodium current associated cardiac electrophysiological and mechanical dysfunction

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An Emerging Antiarrhythmic Target: Late Sodium Current

Cited by 11 publications

References 246 publications

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding–deficient channels

Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats

Late sodium current associated cardiac electrophysiological and mechanical dysfunction

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Inhibition of late Na⁺ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats