Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation

Justo, Fernanda; Fuller, Henrique; Nearing, Bruce D.; Rajamani, Sridharan; Belardinelli, Luiz; Verrier, Richard L.

doi:10.1016/j.hrthm.2016.06.020

Cited by 29 publications

(21 citation statements)

References 32 publications

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“…The possibility that the drug can alter cardiac electrophysiologic properties independent of an influence on coronary artery blood flow is consistent with preclinical evidence from Nieminen et al (2011) and Justo et al (2016), who demonstrated protective antiarrhythmic effects of I NaL inhibition with ranolazine and eleclazine, respectively, during flow-regulated coronary artery stenosis.…”

Section: Discussionsupporting

confidence: 78%

“…I NaL inhibition was implicated in the antiarrhythmic effect as the I Kr inhibitor E4031 decreased the ventricular fibrillation thresh-old in the same model. Recently, Justo et al (2016) demonstrated that the highly selective I NaL inhibitor eleclazine significantly decreased stenosis-induced TWH in intact porcines. Thus, the protective effect of ranolazine appears to be due to direct actions on myocardial electrical properties, as coronary artery blood flow was maintained constant.…”

Section: Discussionmentioning

confidence: 99%

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Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non–flow‐limiting coronary artery stenosis

Evaristo

Stocco

Shah

et al. 2017

Noninvasive Electrocardiol

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non–flow‐limiting coronary artery stenosis

Evaristo

Stocco

Shah

et al. 2017

Noninvasive Electrocardiol

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“…There are also data from prior studies on the reduction of atrial fibrillation with late Na + current blockade. 34,36 The induction and maintenance of atrial fibrillation are similarly affected by intracellular Ca 2+ dynamics, further supporting the mechanistic hypothesis that the inhibition of the late Na + current may modulate arrhythmogenesis by improving Ca 2+ dynamics. In our study, the use of GS-967 did not lead to significant reductions of Ca 2+ transient or Ca 2+ amplitude alternans after initial LDVF, but we observed spontaneous termination of initial VF in GS-967-treated hearts.…”

Section: Dynamics After Ldvfmentioning

confidence: 56%

“…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. Our study further supports that the late Na + current plays an important role in the maintenance and reinitiation of VF, and its blockade may both prevent refibrillation and improve defibrillation outcome.…”

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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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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“…A new selective cardiac late Na + current inhibitor confers concurrent protection against autonomically induced atrial premature beats (APBs), and dual protection against vulnerability to ischemia-induced AF, and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects [4].…”

Section: Excess Amount Of Reactive Oxygen Species (Ros) and P-wave Dumentioning

confidence: 99%

P-wave dispersion: an update

Pérez‐Riera

Abreu

Barbosa‐Barros

et al. 2016

Indian Pacing and Electrophysiology Journal

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P-wave dispersion (PWD, Pd or Pdis) is a noninvasive electrocardiographic (ECG) marker for atrial remodeling and predictor for atrial fibrillation (AF). PWD is defined as the difference between the widest and the narrowest P-wave duration recorded from the 12 ECG leads. Increased P-wave duration and PWD reflect prolongation of intraatrial and interatrial conduction time with lack of a well-coordinated conduction system within the atrial muscles, with inhomogeneous, asynchronic, pro-inflammatory and anti-inflammatory effect mediated by interleukin-6 (IL-6) in patients with the CG + GG genotype IL-6 -634C/G polymorphism [1] and discontinuous propagation of sinus impulses mainly between the left and right atria, interstitial/extracellular fibroblast activation and collagen deposition with fibrosis (via TGF-β) in atrial tissue, insufficient blood supply, significant not isotropic myoelectric activity, and thin wall thickness and consequent expansion tendency all well-known electrophysiological characteristics in patients with atrial arrhythmias and especially paroxysmal atrial fibrillation (PAF) [2].

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Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation

Cited by 29 publications

References 32 publications

Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non–flow‐limiting coronary artery stenosis

Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non–flow‐limiting coronary artery stenosis

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

P-wave dispersion: an update

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