Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial Fibrillation

Burashnikov, Alexander; Diego, José M. Di; Zygmunt, Andrew C.; Belardinelli, Luiz; Antzelevitch, Charles

doi:10.1161/circulationaha.107.704890

Cited by 361 publications

(328 citation statements)

References 30 publications

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“…This is consistent with its ventricular effects through inhibition of the late inward sodium current I Na while possessing greater potency in modulating peak I Na in atrial cardiomyocytes 23. Increased late I Na leads to Ca 2+ overload through Na/Ca exchange in the reverse mode, leading with that way in electrophysiologic instability with action potential duration prolongation, early afterdepolarizations, and delayed afterdepolarizations 24, 25.…”

Section: Discussionsupporting

confidence: 71%

Impact of ranolazine on ventricular arrhythmias – A systematic review

Bazoukis

Tse

Letsas

et al. 2018

Journal of Arrhythmia

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Ranolazine is a new medication for the treatment of refractory angina. However, except its anti‐anginal properties, it has been found to act as an anti‐arrhythmic. The aim of our systematic review is to present the existing data about the impact of ranolazine in ventricular arrhythmias. We searched MEDLINE and Cochrane databases as well clinicaltrials.gov until September 1, 2017 to find all studies (clinical trials, observational studies, case reports/series) reported data about the impact of ranolazine in ventricular arrhythmias. Our search revealed 14 studies (3 clinical trials, 2 observational studies, 8 case reports, 1 case series). These data reported a beneficial impact of ranolazine in ventricular tachycardia/fibrillation, premature ventricular beats, and ICD interventions in different clinical settings. The existing data highlight the anti‐arrhythmic properties of ranolazine in ventricular arrhythmias.

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Section: Discussionsupporting

confidence: 71%

Impact of ranolazine on ventricular arrhythmias – A systematic review

Bazoukis

Tse

Letsas

et al. 2018

Journal of Arrhythmia

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“…Accordingly, atrial selective peak I Na inhibition would be an attractive approach. In light of this, it has been shown that ranolazine acts as an atrial selective peak I Na inhibitor without possible adverse effects on ventricular electrophysiology due to consequences of peak I Na inhibition [3]. Furthermore, in a recent study, we could demonstrate that ranolazine inhibits peak and late sodium current in isolated human atrial myocytes [5].…”

Section: Discussionmentioning

confidence: 95%

“…Ranolazine has been proposed to exert inhibitory effects on atrial sodium channel parameters as well as on the delayed rectifier potassium current (I Kr ) slightly prolonging the atrial action potential [3]. This probably explains an increased effective refractory period (to a greater extent than in the ventricle) and prolonged atrial conduction time in a frequency-dependent manner in the porcine heart [4].…”

Section: Discussionmentioning

confidence: 99%

Ranolazine Maintained Sinus Rhythm in a Patient with Refractory Symptomatic Atrial Fibrillation

Sossalla

Sohns

Seegers

et al. 2013

Cardiovascular Therapeutics

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SUMMARYWe report on a patient who was treated with several antiarrhythmic drugs as well as different ablation strategies. Nevertheless, symptomatic atrial fibrillation always recurred until an off-label use with ranolazine was started. We could demonstrate potent effects of ranolazine on atrial fibrillation in a "wash-in wash-out" situation. Although promising controlled studies are needed to investigate a potential role of ranolazine for the treatment of atrial fibrillation.

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“…Atrial-selective inhibition of sodium channels has previously been demonstrated for several antiarrhythmic agents (Burashnikov et al 2007;Sicouri et al 2010) and represents a property likely contributing to dronedarone's antiarrhythmic effect. Atrial sodium channel blockade leads to alterations of various biophysical parameters of sodium current (I Na ) that produce post-repolarization refractoriness without a major effect on action potential duration (APD).…”

mentioning

confidence: 93%

Atrial-selective sodium channel block by dronedarone: sufficient to terminate atrial fibrillation?

Ehrlich

Dobrev

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Presently available drugs used for atrial fibrillation (AF) therapy have major limitations (moderate efficacy and increased risk of potentially life-threatening proarrhythmia), making new drug developments crucial. Novel drugs like the multichannel blocker dronedarone have the potential to convert AF to prevent AF-related stroke and to reduce cardiovascular morbidity and mortality, opening new directions for innovative antiarrhythmic options. Here we summarize mechanistic evidence for atrial-selective sodium channel block as anti-AF principle putting it into perspective to the work by Bogdan et al. 2011, which demonstrated stronger sodium current inhibition by dronedarone at depolarized potentials resulting in atrial selectivity. We also discuss pertinent facts about remodeling processes induced by and leading to AF which likely explain why pharmacological cardioversion is effective in very early stages of AF only.Atrial selectivity of sodium channel block is a novel anti-AF approach that exploits atrial-ventricular differences in sodium current properties (more negative half-inactivation in atria) and in resting membrane potential (more positive in atria leaving a greater proportion of sodium channels in the inactivated state), leading to reduced atrial current availability at any given membrane potential. Therefore inactivated-state sodium channel blockers like dronedarone preferentially suppress atrial sodium currents, especially during rapid atrial rhythms like in AF. However, dronedarone less effectively terminates AF compared to amiodarone having only a moderate overall efficacy. Much more work is needed to precisely define the contribution of atrial-selective sodium current inhibition for dronedarone's overall anti-AF efficacy.AF is an increasing health problem and is associated with substantial cardiovascular morbidity and mortality, with stroke representing the most critical complication. Presently available drugs used for therapy of AF (antiarrhythmic drugs and anticoagulants) have major limitations because of moderate efficacy and inherent risk of potentially life-threatening proarrhythmia or bleeding complications, making new drug developments crucial (Dobrev and Nattel 2010). Novel drugs like dronedarone have the potential to prevent AF-related stroke and to reduce cardiovascular morbidity and mortality ), opening a new avenue for innovative antiarrhythmic options.In January 2010 dronedarone has been approved for the treatment of nonpersistent AF in Europe. It is an antiarrhythmic compound with rate-and rhythm-controlling properties, which has been developed as a structurally related, multichannelblocking congener of amiodarone with a similarly broad spectrum of inhibitory actions on ion channels (Ehrlich and Nattel 2009). In the April issue of Naunyn-Schmiedeberg's Archive of Pharmacology, Bogdan and colleagues (2011) illustrate the mode of dronedarone action on sodium channels and identify a peculiar behavior of the substance to inhibit inactivated channels at more depolarized potentials more effe...

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Atrium-Selective Sodium Channel Block as a Strategy for Suppression of Atrial Fibrillation

Cited by 361 publications

References 30 publications

Impact of ranolazine on ventricular arrhythmias – A systematic review

Impact of ranolazine on ventricular arrhythmias – A systematic review

Ranolazine Maintained Sinus Rhythm in a Patient with Refractory Symptomatic Atrial Fibrillation

Atrial-selective sodium channel block by dronedarone: sufficient to terminate atrial fibrillation?

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