Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner

Sag, Can Martin; Mallwitz, Anika; Wagner, Stefan; Hartmann, Nico; Schotola, Hanna; Fischer, Thomas; Ungeheuer, Nele; Herting, Jonas; Shah, Ajay M.; Maier, Lars S.; Sossalla, Samuel; Unsöld, Bernhard

doi:10.1016/j.yjmcc.2014.08.016

Cited by 42 publications

(42 citation statements)

References 32 publications

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“…9 This drives an efflux of Na + via the Na + -Ca 2+ exchanger, with a corresponding influx of Ca +2 resulting in intracellular Ca +2 overload, 10-12 a key step in cardiac arrhythmogenesis. [13][14][15][16] Previous studies have shown that the late Na + current is unable to inactivate in the settings of myocardial ischemia and heart failure. 9,17,18 Because VF results in massive global ischemia, these ionic derangements originating from the late Na + current and Ca 2+ dynamics may serve as therapeutic targets for preventing ventricular refibrillation after LDVF.…”

Section: See Editorial By Burashnikov and Antzelevitchmentioning

confidence: 99%

“…This provides a potential substrate for various cardiac arrhythmias as demonstrated in several previous studies. 7,[13][14][15][16]20 Indeed, selective inhibition of the late Na + current with GS-967 and ranolazine have been demonstrated to reduce VF susceptibility during acute myocardial infarction in porcine models. 32,33 Bonatti et al 33 studied GS-967 and demonstrated a significant 34 selectively inhibited the late Na + current with the drug eleclazine and found that it reduced ventricular repolarization abnormalities without reducing inotropy before and during adrenergic stimulation with epinephrine.…”

Section: + Current Blockade and Vf And Refibrillationmentioning

confidence: 99%

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Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Azam

Zamiri

Massé³

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background-After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na + current to inactivate leads to intracellular Ca 2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na + current, on ventricular refibrillation. Methods and Results-Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967-treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967-treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca 2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca 2+ alternans (P=0.03). Conclusions-Late Na + current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca 2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models. (Circ Arrhythm Electrophysiol. 2017;10:e004331.

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Section: See Editorial By Burashnikov and Antzelevitchmentioning

confidence: 99%

Section: + Current Blockade and Vf And Refibrillationmentioning

confidence: 99%

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Azam

Zamiri

Massé³

et al. 2017

Circ: Arrhythmia and Electrophysiology

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“…17,29,[43][44][45] The resulting calcium overload is thought to trigger intracellular Ca 2þ release from the sarco-endoplasmic reticulum (SR), leading to cytosolic Ca 2þ oscillations, automaticity, and triggered activity. 16,35,[46][47][48] Calcium overload and oscillatory activity are able to activate forward mode NCX. 49 This carries an inward positive current, also known as the transient inward current due to NCX stoichiometry…”

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confidence: 99%

“…51,53 Pharmacological enhancement of I Na,late has been shown to induce DADs and triggered activity. 48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity. 16,48,[53][54][55] Delayed afterdepolarizations have been observed in several types of cardiac tissue, including both atrial and ventricular myocytes, where they can lead to triggered activity and tachyarrhythmias.…”

mentioning

confidence: 99%

“…48,53 Furthermore, inhibition of I Na,late by ranolazine reduces the incidence of DADs and prevents triggered activity. 16,48,[53][54][55] Delayed afterdepolarizations have been observed in several types of cardiac tissue, including both atrial and ventricular myocytes, where they can lead to triggered activity and tachyarrhythmias. 56 The second mechanism of arrhythmia in the heart is abnormal conduction and includes conduction block and reentry.…”

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confidence: 99%

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The Significance of the Late Na⁺ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

Mason

Sossalla

2016

J Cardiovasc Pharmacol Ther

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The purpose of this article is to review the basis of arrhythmogenesis, the functional and clinical role of the late Na current, and its therapeutic inhibition. Under pathological conditions such as ischemia and heart failure this current is abnormally enhanced and influences cellular electrophysiology as a proarrhythmic substrate in myocardial pathology. Ranolazine the only approved late Na current blocker has been demonstrated to produce antiarrhythmic effects in the atria and the ventricle. We summarize recent experimental and clinical studies of ranolazine and other experimental late Na current blockers and discuss the significance of the available data.

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The functional consequences of sodium channel Na_V1.8 in human left ventricular hypertrophy

Ahmad

Tirilomis

Pabel³

et al. 2018

ESC Heart Failure

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AimsIn hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV1.8 in human hypertrophied myocardium.Methods and resultsMyocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload‐induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real‐time PCR and western blot and detected a significant up‐regulation of NaV1.8 mRNA (2.34‐fold) and protein expression (1.96‐fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV1.5 protein expression was significantly reduced in parallel (0.60‐fold). Using whole‐cell patch‐clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV1.8‐specific blockers either A‐803467 (30 nM) or PF‐01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)‐Ca2+ leak and SR‐Ca2+ spark frequency after exposure to both NaV1.8 inhibitors.ConclusionsWe show for the first time that the neuronal sodium channel NaV1.8 is up‐regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of NaV1.8 reduced augmented INaL, abbreviated the action potential duration, and decreased the SR‐Ca2+ leak. The findings of our study suggest that NaV1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.

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Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner

Cited by 42 publications

References 32 publications

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

The Significance of the Late Na⁺ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

The functional consequences of sodium channel Na_V1.8 in human left ventricular hypertrophy

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Enhanced late INa induces proarrhythmogenic SR Ca leak in a CaMKII-dependent manner

Cited by 42 publications

References 32 publications

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy

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The Significance of the Late Na⁺ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

The functional consequences of sodium channel Na_V1.8 in human left ventricular hypertrophy