Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone

• Published in: Cardiovascular research 2008-02, Vol.77 (3), p.481-488
• Main Authors: Wu, Lin, Rajamani, Sridharan, Shryock, John C., Li, Hong, Ruskin, Jeremy, Antzelevitch, Charles, Belardinelli, Luiz
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Amiodarone - pharmacology; Animals; Antiarrhythmic agents; Antiarythmic agents; Arrhythmia (mechanism); Arrhythmias, Cardiac - chemically induced; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiovascular system; Cnidarian Venoms - pharmacology; Dose-Response Relationship, Drug; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - physiology; Female; Heart; Humans; In Vitro Techniques; Ion channels; Long QT syndrome; Long QT Syndrome - etiology; Medical sciences; Membrane potentials; Muscle Proteins - physiology; NAV1.5 Voltage-Gated Sodium Channel; Pharmacology. Drug treatments; Rabbits; Sodium Channels - physiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvm069

Aim Clinical use of amiodarone is associated with occasional development of torsade de pointes (TdP). However, preclinical models have failed to demonstrate the proarrhythmic potential of amiodarone. The objective of this study was to reveal and explain the pro- and anti-arrhythmic effects of acute exposure to amiodarone in an animal model. Methods and results Endo- and epicardial monophasic action potentials (MAPs) and 12-lead electrocardiogram were recorded in female rabbit isolated hearts. Ion channel currents were measured in human embryonic kidney cells expressing SCN5A Na+ and HERG K+ channels. Acute amiodarone alone caused an insignificant increase in duration of MAP (MAPD90) without causing TdP. In the presence of 3 nM sea anemone toxin (ATX-II), amiodarone (1–30 nM) prolonged MAPD90 from 217 ± 5 to 250 ± 8 ms (n = 16, P < 0.01), increased transmural dispersion of repolarization (TDR) from 59 ± 9 to 70 ± 10 ms and beat-to-beat variability (BVR) of MAPD90 from 0.75 ± 0.03 to 1.06 ± 0.13 ms (P < 0.05). At 30–300 nM, amiodarone induced TdP in 16 out of 17 hearts. A further increase of amiodarone concentration to 1–10 µM abbreviated MAPD90 to 211 ± 9 ms, decreased BVR to 0.5 ± 0.01 ms, decreased TDR (n = 7, P < 0.05), and suppressed TdP. Amiodarone inhibited HERG K+ and late Na+ currents with IC50s of 0.8 ± 0.1 and 3.0 ± 0.9 µM, respectively. Conclusion In hearts in which late INa is augmented to mimic congenital or acquired pathological conditions, amiodarone has a concentration-dependent biphasic effect to induce and then suppress arrhythmic activity, secondary to inhibition of HERG K+ and late Na+ currents. This is the first preclinical model demonstrating the potential for amiodarone to induce TdP.