Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

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

doi:10.1016/j.hrthm.2016.04.015

Cited by 26 publications

(14 citation statements)

References 23 publications

(35 reference statements)

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“…Interestingly, recent studies demonstrated, consistent with the results of the present study, that increased I Na-L plays a key role in the induction of rapid pacing-induced AF in mice and its suppression by GS-967 [31]. The importance of I Na-L blockade in the suppression of AF with the novel specific I Na-L blocker, eleclazine was also demonstrated in larger animals (pigs) [32] indicating the potential antiarrhythmic efficacy of this new class of drug action in humans [11]. …”

Section: Discussionsupporting

confidence: 90%

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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Background The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade. Method and Results High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial surfaces along with microelectrode recordings were performed in isolated-perfused male Fisher 344 rat hearts in Langendorff setting. Aged atria (23–24 months) manifested 10-fold increase in atrial tissue fibrosis compared to young/adult (2–4 months) atria (P<0001. Spontaneous AF arose in 39 out of 41 of the aged atria but in 0 out of 12 young/adult hearts (P<001) during arterial perfusion of with 0.1 mm of hydrogen peroxide (H2O2). Optical Action Potential (AP) activation maps showed that the AF was initiated by a focal mechanism in the LA suggestive of EAD-mediated triggered activity. Cellular AP recordings with glass microelectrodes from the LA epicardial sites showing focal activity confirmed optical AP recordings that the spontaneous AF was initiated by late phase 3 EAD-mediated triggered activity. Inhibition of CaMKII activity with KN-93 (1 μM) (N=6) or its downstream target, the enhanced INa-L with GS-967 (1 μM), a specific blocker of INa-L (N=6), potently suppressed the AF and prevented its initiation when perfused 15 min prior to H2O2 (n=6). Conclusions Increased atrial tissue fibrosis combined with acute oxidative activation of CaMK II Initiate AF by EAD-mediated triggered activity. Specific block of the INa-L with GS-967 effectively suppresses the AF. Drug therapy of oxidative AF in humans with traditional antiarrhythmic drugs remains suboptimal; suppressing INa-L offers a potential new strategy for effective suppression of oxidative human AF that remains suboptimal.

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Section: Discussionsupporting

confidence: 90%

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Pezhouman¹,

Cao

Fishbein

et al. 2018

J Hear Health

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“…Our data are consistent with the inhibition of I NaL by ELE via open channel block, as suggested in previous reports. 26 , 27 , 28 , 29 The inhibition of both I Na and I NaL by ELE has been shown to be voltage-dependent so that the IC 50 s for inhibition of the ATX-II-activated I NaL in atrial and ventricular myocytes in the present study (217 nM and 180 nM, respectively) were comparable with the value reported previously in rabbit ventricular myocytes at a corresponding HP of -80 mV (260 nM). 27 Consistent with previous reports on recordings of fast I Na from rabbit ventricular myocytes and recombinant human Na v 1.5 channels, 27 , 28 10 μM ELE produced significant use-dependent inhibition, with little difference between atrial and ventricular myocytes.…”

Section: Discussionsupporting

confidence: 89%

“… 26 , 27 ELE has been shown to inhibit fast I Na in a use-dependent manner consistent with preferential activated state block with little effect on I Kr 27 , 28 and to reduce spontaneous AF in an intact porcine model. 29 The objectives of this study were to investigate atrial-ventricular differences in the properties of I Na and its inhibition by ELE in rat cardiac myocytes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

et al. 2020

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Background Atrial-ventricular differences in voltage-gated Na + currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative antiarrhythmic drug with properties similar to the prototypical atrial-selective Na + channel blocker ranolazine that has been shown to be safe and well tolerated in patients. Objective The present study investigated atrial-ventricular differences in the biophysical properties and inhibition by eleclazine of voltage-gated Na + currents. Methods The fast and late components of whole-cell voltage-gated Na + currents (respectively, I Na and I NaL ) were recorded at room temperature (∼22°C) from rat isolated atrial and ventricular myocytes. Results Atrial I Na activated at command potentials ∼5.5 mV more negative and inactivated at conditioning potentials ∼7 mV more negative than ventricular I Na . There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I NaL activated by 3 nM ATX-II (IC 50 s ∼200 nM). Eleclazine (10 μM) inhibited I Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I Na from inactivation in both cell types. Conclusions Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I Na . The more negative voltage dependence of I Na activation/inactivation in atrial myocytes underlies differences between the 2 cell types in the voltage dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective antiarrhythmic drug.

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“…However, the mechanisms underlying alternans may differ, since calcium handling is altered between paroxysmal and chronic AF20. In paroxysmal AF, evidence suggests that SK channels40, acetylcholine-activated K + current41, and late Na + current42 may play a more prominent role in alternans propensity and arrhythmogenesis. Given the arrhythmogenic implications of APD alternans presented in this and other studies, these differences in the fundamental mechanisms underlying APD alternans in paroxysmal versus chronic AF underscore the need for further research on the diversity of AF mechanisms2, in order to develop better targeted, patient-specific therapies.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation

Chang

Trayanova

2016

Sci Rep

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The occurrence of atrial fibrillation (AF) is associated with progressive changes in the calcium handling system of atrial myocytes. Calcium cycling instability has been implicated as an underlying mechanism of electrical alternans observed in patients who experience AF. However, the extent to which calcium-induced alternation of electrical activity in the atria contributes to arrhythmogenesis is unknown. In this study, we investigated the effects of calcium-driven alternans (CDA) on arrhythmia susceptibility in a biophysically detailed, 3D computer model of the human atria representing electrical and structural remodeling secondary to chronic AF. We found that elevated propensity to CDA rendered the atria vulnerable to ectopy-induced arrhythmia. It also increased the complexity and persistence of arrhythmias induced by fast pacing, with unstable scroll waves meandering and frequently breaking up to produce multiple wavelets. Our results suggest that calcium-induced electrical instability may increase arrhythmia vulnerability and promote increasing disorganization of arrhythmias in the chronic AF-remodeled atria, thus playing an important role in the progression of the disease.

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Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

Cited by 26 publications

References 23 publications

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation

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