What is the clinical evidence from this study?

Study design: Other. Population: Long QT-3 Syndrome (in vitro model). Intervention: Amiodarone and N-desethylamiodarone vs. Control (0 µM drug solution). Primary outcome: Persistent INa (%) in 1KPQ mutant with 2.5 µM DES (p=<0.01).

What does this research mean for the field?

Amiodarone and its metabolite N-desethylamiodarone exert pro-arrhythmic effects by significantly increasing late sodium currents and window currents in cardiac NaV1.5 channels, with N-desethylamiodarone demonstrating a greater pro-arrhythmic effect, particularly in the Long QT-3-causing ΔKPQ mutant. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

March 1, 2016Open Access

Effects of Amiodarone and N-desethylamiodarone on Cardiac Voltage-Gated Sodium Channels

Q: What are the key findings of this study?

Amiodarone and its metabolite N-desethylamiodarone significantly increased late sodium currents and window currents in NaV1.5 channels, particularly in the 1KPQ mutant, suggesting pro-arrhythmic effects.

Q: What does this research mean for the field?

Amiodarone and its metabolite N-desethylamiodarone exert pro-arrhythmic effects by significantly increasing late sodium currents and window currents in cardiac NaV1.5 channels, with N-desethylamiodarone demonstrating a greater pro-arrhythmic effect, particularly in the Long QT-3-causing ΔKPQ mutant. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

Amiodarone and its metabolite N-desethylamiodarone significantly increased late sodium currents and window currents in NaV1.5 channels, particularly in the 1KPQ mutant, suggesting pro-arrhythmic effects.

Structured PICO

Population

Chinese hamster ovary (CHO) cells transiently transfected with cDNA encoding either wild-type or the ΔKPQ mutant form of NaV1.5.

Intervention

Amiodarone (AMD) and N-desethylamiodarone (DES) at 0.5 µM and 2.5 µM concentrations.

Comparator

Control solutions (no drug perfusion).

Outcome

Effects on peak and late sodium currents (INa,P and INa,L), steady-state activation, and steady-state fast-inactivation.surrogate

Amiodarone and its metabolite N-desethylamiodarone increase late sodium currents and window currents in NaV1.5 channels, particularly in the ΔKPQ mutant, suggesting a mechanism for their pro-arrhythmic potential in Long QT-3 syndrome.

Main Result

Absolute Event Rate: 12.6% vs 2.79%

p-value: p=<0.01

Limitations

Study performed in CHO cells rather than human cardiomyocytes to reduce confounding effects of complex genetic backgrounds.

Abstract

Amiodarone (AMD) is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (INa,P and INa,L) and determine whether these effects change as AMD is metabolized into N-desethylamiodarone (DES). We hypothesized that AMD and DES block both INa,P and INa,L with similar profiles due to structural similarities. Given the inherent small amounts of INa,L in NaV1.5, we screened AMD and DES against the Long QT-3-causing mutation, ΔKPQ, to better detect any drug-mediated effect on INa,L. Our results show that AMD and DES do not affect WT or ΔKPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block ΔKPQ peak conductance compared to WT. Both compounds significantly increase INa,L and window currents. We conclude that both compounds have pro-arrhythmic effects on NaV1.5, especially ΔKPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD.

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